Breast pain is one of the most common breast-related patient complaints and is found to affect at least 50% of the female population.¹ Most cases are self-limiting and are related to hormonal and normal fibrocystic changes. The median age of onset of symptoms is 36 years, with most women experiencing pain for 5 to 12 years.² Because the cause of breast pain is not always clear, its presence can produce anxiety in patients and physicians over the possibility of underlying malignancy. Although breast cancer is not associated with breast pain, many patients presenting with pain are referred for diagnostic imaging (usually with negative results). The majority of women with mastalgia and normal clinical examination findings can be reassured with education about the many benign causes of breast pain.

What are causes of breast pain without an imaging abnormality?

Hormones. Mastalgia can be focal or generalized and is mostly due to hormonal changes. Elevated estrogen can stimulate the growth of breast tissue, which is known as epithelial hyperplasia.³ Fluctuations in hormone levels can occur in perimenopausal women in their forties and can result in new symptoms of breast pain.⁴ Sometimes starting a new contraceptive medication or hormone replacement therapy can exacerbate the pain. Switching brands or medications may help. Another cause of mastalgia may be elevated prolactin levels, with hypothalamic-pituitary dysfunction.^5,6

Diet. There is evidence to link a high-fat diet with breast pain. The pain has been shown to improve when lipid intake is reduced and high- and low-density lipoprotein cholesterol levels are normalized. As estrogen is a steroid hormone that can be synthesized from lipids and fatty acids, elevated lipid metabolism can increase estrogen levels and exacerbate breast pain symptoms.^7,8 Essential fatty acids, such as evening primrose oil and vitamin E, have been used to treat mastalgia because they reduce inflammation in fatty breast tissue through the prostaglandin pathway.^9,10

Caffeine. Methylxanthines can be found in coffee, tea, and chocolate and can aggravate mastalgia by enhancing the cyclin adenosine monophosphate (cAMP) pathway. This pathway stimulates cellular proliferation and fibrocystic changes which in turn can exacerbate breast pain.¹¹

Smoking. In my clinical practice I have clearly noted a higher incidence of breast pain in patients who smoke. The pain tends to improve significantly when the patient quits or even cuts back on smoking. The exact reasons for smoking’s effects on breast pain are not well known; however, they are thought to be related to acceleration of the cAMP pathway.

Large breast size. Very large breasts will strain and weaken the suspensory ligaments, leading to pain and discomfort. It has been shown that wearing a supportive sports bra during episodes of breast pain is effective.

Types of breast pain

Cyclical

Women with fibrocystic breasts tend to experience more breast pain. Breast sensitivity can be localized to the upper outer quadrants or to the nipple and sub-areolar area. It also can be generalized. The pain tends to peak with ovulation, improve with menses, and to recur every few weeks. Patients who have had partial hysterectomy (with ovaries in situ) or endometrial ablation will be unable to correlate their symptoms to menstruation. Therefore, women are encouraged to keep a diary or calendar of their symptoms to detect any correlation with their ovarian cycle. Such correlation is reassuring.

Continue to: Noncyclical...

Noncyclical

Noncyclical breast pain is not associated with the menstrual cycle and can be unilateral or bilateral. Providers should perform a good history of patients presenting with noncyclicalbreast pain, to include character, onset, duration, location, radiation, alleviating, and aggravating factors. A physical examination may elicit point tenderness at the chest by pushing the breast tissue off of the chest wall while the patient is in supine position and pressing directly over the ribs. Lack of tenderness on palpation of the breast parenchyma, but pain on the chest wall, points to a musculoskeletal etiology. Chest wall pain may be related to muscle spasm or muscle strain, trauma, rib fracture, or costochondritis (Tietze syndrome). Finally, based on history of review of systems and physical examination, referred pain from biliary or cardiac etiology should be considered.

When breast pain occurs with skin changes

Skin changes usually have an underlying pathology. Infectious processes, such as infected epidermal inclusion cyst, hidradenitis of the cleavage and inframammary crease, or breast abscess will present with pain and induration with an acute onset of 5 to 10 days. Large pendulous breasts may develop yeast infection at the inframammary crease. Chronic infectious irritation can lead to hyperpigmentation of that area. Eczema or contact dermatitis frequently can affect the areola and become confused with Paget disease (ductal carcinoma in situ of the nipple). With Paget, the excoriation always starts at the nipple and can then spread to the areola. However, with dermatitis, the rash begins on the peri-areolar skin, without affecting the nipple itself.

When breast pain occurs with nipple discharge

Breast pain with nipple discharge usually is bilateral and more common in patients with significant fibrocystic changes who smoke. If the nipple discharge is bilateral, serous and non-bloody, and multiduct, it is considered benign and physiologic. Physiologic nipple discharge can be multifactorial and hormonal. It may be related to thyroid disorders or medications such as antidepressants, selective serotonin reuptake inhibitors (SSRIs), mood stabilizers, or antipsychotics. The only nipple discharge that is considered pathologic is unilateral spontaneous bloody discharge for which diagnostic imaging and breast surgeon referral is indicated. Women should be discouraged from self-expressing their nipples, as 80% will experience serous nipple discharge upon manual self-expression.

Management of mastalgia

Appropriate breast pain management begins with a good history and physical examination. The decision to perform imaging should depend on clinical exam findings and not on symptoms of breast pain. If there is a palpable mass, then breast imaging and possible biopsy is appropriate. However, if clinical exam is normal, there is no indication for breast imaging in low-risk women under the age of 40 whose only symptom is breast pain. Women older than age 40 can undergo diagnostic imaging, if they have not had a negative screening mammogram in the past year.

Breast pain with abnormal clinical exam

In the patient who is younger than age 30 with a palpable mass. For this patient order targeted breast ultrasound (US) (FIGURE 1). If results are negative, repeat the clinical examination 1 week after menses. If the mass is persistent, refer the patient to a breast surgeon. If diagnostic imaging results are negative, consider breast MRI, especially if there is a strong family history of breast cancer.

In the patient who is aged 30 and older with a palpable mass. For this patient, bilateral diagnostic mammogram and US are in order. The testing is best performed 1 week after menses to reduce false-positive findings. If imaging is negative and the patient still has a clinically suspicious finding or mass, refer her to a breast surgeon and consider breast MRI. At this point if there is a persistent firm dominant mass, a biopsy is indicated as part of the triple test. If the mass resolves with menses, the patient can be reassured that the cause is most likely benign, with clinical examination repeated in 3 months.

Continue to: Breast pain and normal clinical exam...

Breast pain and normal clinical exam

When women who report breast pain have normal clinical examination findings (and have a negative screening mammogram in the past 12 months if older than age 40), there are several management strategies you can offer (FIGURE 2).

Reassurance and education. The majority of women with breast pain can be managed with reassurance and education, which are often sufficient to reduce their anxieties.

Supportive bra. The most effective intervention is to wear and sleep in a well-fitted supportive sports bra for 4 to 12 weeks. In a nonrandomized single-center trial of danazol versus sports bra, 85% of women reported relief of their breast pain with bra alone (vs 58% with danazol).¹² A supportive bra is the first-line management of mastalgia (Level II evidence).

Symptom diary/calendar. Many women do not know whether or not their symptoms correspond to their ovarian cycle or are related to hormonal fluctuations. Therefore, it is reassuring and informative for them to keep a calendar or a diary of their symptoms to determine whether their symptoms occur or are exacerbated in a cyclical pattern.

Diet and lifestyle modification. Women should avoid caffeine (especially when having pain). Studies on methylxanthines have demonstrated some symptom relief with reducing caffeine intake.^11,13 One cup of coffee or tea per day most likely will not make a difference. However, if a woman is drinking large quantities of caffeinated beverages throughout the day, it will very likely improve her breast pain if she cuts back. This is especially true during the times of exacerbated pain prior to her menses.

In addition, recommend reduced dietary fat (overall good health). This is good advice for any patient. There were 2 small studies that showed improvement in breast pain with a 15% reduction in dietary fat.^7,8

Finally, advise that patients stop smoking. Smoking aggravates and exacerbates fibrocystic changes, and these will lead to more breast pain.

Medical management. Over-the-counter medications that are found in the vitamin section of a local drug store are vitamin E and evening primrose oil. There are no significant adverse effects with these treatments. Their efficacy is theoretical, however; 3 randomized controlled trials demonstrated no significant clinical benefit with evening primrose oil versus placebo for treatment of mastalgia.¹⁴

Topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs; Voltaren gel, topical compound pain creams) are useful as second-line management after using a supportive bra. Three randomized controlled trials have demonstrated up to 90% improvement of mastalgia with topical NSAIDs.^15-17

Tamoxifen is a selective estrogen-receptor modulator (SERM), which is an antagonist to the estrogen receptor (ER) in the breast and an agonist to the ER in the endometrium. Tamoxifen has been found to reduce symptoms of mastalgia by 70% even at a lower dosage of 10-mg per day (for 6 months), or as a topical gel (afimoxifene). The oral form can have some adverse effects, including hot flashes, and has a low risk for thromboembolic events and endometrial neoplasia.^18-20

Danazol is very effective in reducing breast pain symptoms (by 80%), with a higher relapse after stopping the medication. Danazol is less tolerated due to its androgenic effects, such as hirsutism, acne, menorrhagia, and voice changes. Both danazol and tamoxifen can be teratogenic and should be used with caution in women of child-bearing age.²¹

Finally, bromocriptine inhibits serum prolactin and has been reported to provide 65% improvement in breast pain. Its use for breast pain is not US Food and Drug Administration–approved and adverse effects include nausea, dizziness, and hypotension.²²

Tamoxifen, danazol, and bromocriptine can be considered as third-line management options for severe treatment-resistant mastalgia.

Continue to: FIGURE 2 Treatment algorithm for breast pain...

In summary

Evaluation and counseling for breast pain should be managed by women’s health care providers in a primary care setting. Most patients need reassurance and medical explanation of their symptoms. They should be educated that more than 95% of the time breast pain is not caused by an underlying malignancy but rather due to hormonal and fibrocystic changes, which can be managed conservatively. If the clinical breast examination and recent screening mammogram (in women over age 40) results are negative, patients should be educated that their pain is benign and undergo a trial of conservative measures: wear and sleep in a supporting bra; keep a calendar of symptoms to determine any relation to cyclical changes; and avoid nicotine, caffeine, and fatty food. Topical pain creams with diclofenac and evening primrose oil also can be effective in ameliorating the symptoms. Breast pain is not a surgical disease; referral to a surgical specialist and diagnostic imaging can be unnecessary and expensive.

Breast pain is one of the most common breast-related patient complaints and is found to affect at least 50% of the female population.¹ Most cases are self-limiting and are related to hormonal and normal fibrocystic changes. The median age of onset of symptoms is 36 years, with most women experiencing pain for 5 to 12 years.² Because the cause of breast pain is not always clear, its presence can produce anxiety in patients and physicians over the possibility of underlying malignancy. Although breast cancer is not associated with breast pain, many patients presenting with pain are referred for diagnostic imaging (usually with negative results). The majority of women with mastalgia and normal clinical examination findings can be reassured with education about the many benign causes of breast pain.

What are causes of breast pain without an imaging abnormality?

Hormones. Mastalgia can be focal or generalized and is mostly due to hormonal changes. Elevated estrogen can stimulate the growth of breast tissue, which is known as epithelial hyperplasia.³ Fluctuations in hormone levels can occur in perimenopausal women in their forties and can result in new symptoms of breast pain.⁴ Sometimes starting a new contraceptive medication or hormone replacement therapy can exacerbate the pain. Switching brands or medications may help. Another cause of mastalgia may be elevated prolactin levels, with hypothalamic-pituitary dysfunction.^5,6

Diet. There is evidence to link a high-fat diet with breast pain. The pain has been shown to improve when lipid intake is reduced and high- and low-density lipoprotein cholesterol levels are normalized. As estrogen is a steroid hormone that can be synthesized from lipids and fatty acids, elevated lipid metabolism can increase estrogen levels and exacerbate breast pain symptoms.^7,8 Essential fatty acids, such as evening primrose oil and vitamin E, have been used to treat mastalgia because they reduce inflammation in fatty breast tissue through the prostaglandin pathway.^9,10

Caffeine. Methylxanthines can be found in coffee, tea, and chocolate and can aggravate mastalgia by enhancing the cyclin adenosine monophosphate (cAMP) pathway. This pathway stimulates cellular proliferation and fibrocystic changes which in turn can exacerbate breast pain.¹¹

Smoking. In my clinical practice I have clearly noted a higher incidence of breast pain in patients who smoke. The pain tends to improve significantly when the patient quits or even cuts back on smoking. The exact reasons for smoking’s effects on breast pain are not well known; however, they are thought to be related to acceleration of the cAMP pathway.

Large breast size. Very large breasts will strain and weaken the suspensory ligaments, leading to pain and discomfort. It has been shown that wearing a supportive sports bra during episodes of breast pain is effective.

Types of breast pain

Cyclical

Women with fibrocystic breasts tend to experience more breast pain. Breast sensitivity can be localized to the upper outer quadrants or to the nipple and sub-areolar area. It also can be generalized. The pain tends to peak with ovulation, improve with menses, and to recur every few weeks. Patients who have had partial hysterectomy (with ovaries in situ) or endometrial ablation will be unable to correlate their symptoms to menstruation. Therefore, women are encouraged to keep a diary or calendar of their symptoms to detect any correlation with their ovarian cycle. Such correlation is reassuring.

Continue to: Noncyclical...

Noncyclical

Noncyclical breast pain is not associated with the menstrual cycle and can be unilateral or bilateral. Providers should perform a good history of patients presenting with noncyclicalbreast pain, to include character, onset, duration, location, radiation, alleviating, and aggravating factors. A physical examination may elicit point tenderness at the chest by pushing the breast tissue off of the chest wall while the patient is in supine position and pressing directly over the ribs. Lack of tenderness on palpation of the breast parenchyma, but pain on the chest wall, points to a musculoskeletal etiology. Chest wall pain may be related to muscle spasm or muscle strain, trauma, rib fracture, or costochondritis (Tietze syndrome). Finally, based on history of review of systems and physical examination, referred pain from biliary or cardiac etiology should be considered.

When breast pain occurs with skin changes

Skin changes usually have an underlying pathology. Infectious processes, such as infected epidermal inclusion cyst, hidradenitis of the cleavage and inframammary crease, or breast abscess will present with pain and induration with an acute onset of 5 to 10 days. Large pendulous breasts may develop yeast infection at the inframammary crease. Chronic infectious irritation can lead to hyperpigmentation of that area. Eczema or contact dermatitis frequently can affect the areola and become confused with Paget disease (ductal carcinoma in situ of the nipple). With Paget, the excoriation always starts at the nipple and can then spread to the areola. However, with dermatitis, the rash begins on the peri-areolar skin, without affecting the nipple itself.

When breast pain occurs with nipple discharge

Breast pain with nipple discharge usually is bilateral and more common in patients with significant fibrocystic changes who smoke. If the nipple discharge is bilateral, serous and non-bloody, and multiduct, it is considered benign and physiologic. Physiologic nipple discharge can be multifactorial and hormonal. It may be related to thyroid disorders or medications such as antidepressants, selective serotonin reuptake inhibitors (SSRIs), mood stabilizers, or antipsychotics. The only nipple discharge that is considered pathologic is unilateral spontaneous bloody discharge for which diagnostic imaging and breast surgeon referral is indicated. Women should be discouraged from self-expressing their nipples, as 80% will experience serous nipple discharge upon manual self-expression.

Management of mastalgia

Appropriate breast pain management begins with a good history and physical examination. The decision to perform imaging should depend on clinical exam findings and not on symptoms of breast pain. If there is a palpable mass, then breast imaging and possible biopsy is appropriate. However, if clinical exam is normal, there is no indication for breast imaging in low-risk women under the age of 40 whose only symptom is breast pain. Women older than age 40 can undergo diagnostic imaging, if they have not had a negative screening mammogram in the past year.

Breast pain with abnormal clinical exam

In the patient who is younger than age 30 with a palpable mass. For this patient order targeted breast ultrasound (US) (FIGURE 1). If results are negative, repeat the clinical examination 1 week after menses. If the mass is persistent, refer the patient to a breast surgeon. If diagnostic imaging results are negative, consider breast MRI, especially if there is a strong family history of breast cancer.

In the patient who is aged 30 and older with a palpable mass. For this patient, bilateral diagnostic mammogram and US are in order. The testing is best performed 1 week after menses to reduce false-positive findings. If imaging is negative and the patient still has a clinically suspicious finding or mass, refer her to a breast surgeon and consider breast MRI. At this point if there is a persistent firm dominant mass, a biopsy is indicated as part of the triple test. If the mass resolves with menses, the patient can be reassured that the cause is most likely benign, with clinical examination repeated in 3 months.

Continue to: Breast pain and normal clinical exam...

Breast pain and normal clinical exam

When women who report breast pain have normal clinical examination findings (and have a negative screening mammogram in the past 12 months if older than age 40), there are several management strategies you can offer (FIGURE 2).

Reassurance and education. The majority of women with breast pain can be managed with reassurance and education, which are often sufficient to reduce their anxieties.

Supportive bra. The most effective intervention is to wear and sleep in a well-fitted supportive sports bra for 4 to 12 weeks. In a nonrandomized single-center trial of danazol versus sports bra, 85% of women reported relief of their breast pain with bra alone (vs 58% with danazol).¹² A supportive bra is the first-line management of mastalgia (Level II evidence).

Symptom diary/calendar. Many women do not know whether or not their symptoms correspond to their ovarian cycle or are related to hormonal fluctuations. Therefore, it is reassuring and informative for them to keep a calendar or a diary of their symptoms to determine whether their symptoms occur or are exacerbated in a cyclical pattern.

Diet and lifestyle modification. Women should avoid caffeine (especially when having pain). Studies on methylxanthines have demonstrated some symptom relief with reducing caffeine intake.^11,13 One cup of coffee or tea per day most likely will not make a difference. However, if a woman is drinking large quantities of caffeinated beverages throughout the day, it will very likely improve her breast pain if she cuts back. This is especially true during the times of exacerbated pain prior to her menses.

In addition, recommend reduced dietary fat (overall good health). This is good advice for any patient. There were 2 small studies that showed improvement in breast pain with a 15% reduction in dietary fat.^7,8

Finally, advise that patients stop smoking. Smoking aggravates and exacerbates fibrocystic changes, and these will lead to more breast pain.

Medical management. Over-the-counter medications that are found in the vitamin section of a local drug store are vitamin E and evening primrose oil. There are no significant adverse effects with these treatments. Their efficacy is theoretical, however; 3 randomized controlled trials demonstrated no significant clinical benefit with evening primrose oil versus placebo for treatment of mastalgia.¹⁴

Topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs; Voltaren gel, topical compound pain creams) are useful as second-line management after using a supportive bra. Three randomized controlled trials have demonstrated up to 90% improvement of mastalgia with topical NSAIDs.^15-17

Tamoxifen is a selective estrogen-receptor modulator (SERM), which is an antagonist to the estrogen receptor (ER) in the breast and an agonist to the ER in the endometrium. Tamoxifen has been found to reduce symptoms of mastalgia by 70% even at a lower dosage of 10-mg per day (for 6 months), or as a topical gel (afimoxifene). The oral form can have some adverse effects, including hot flashes, and has a low risk for thromboembolic events and endometrial neoplasia.^18-20

Danazol is very effective in reducing breast pain symptoms (by 80%), with a higher relapse after stopping the medication. Danazol is less tolerated due to its androgenic effects, such as hirsutism, acne, menorrhagia, and voice changes. Both danazol and tamoxifen can be teratogenic and should be used with caution in women of child-bearing age.²¹

Finally, bromocriptine inhibits serum prolactin and has been reported to provide 65% improvement in breast pain. Its use for breast pain is not US Food and Drug Administration–approved and adverse effects include nausea, dizziness, and hypotension.²²

Tamoxifen, danazol, and bromocriptine can be considered as third-line management options for severe treatment-resistant mastalgia.

Continue to: FIGURE 2 Treatment algorithm for breast pain...

In summary

Evaluation and counseling for breast pain should be managed by women’s health care providers in a primary care setting. Most patients need reassurance and medical explanation of their symptoms. They should be educated that more than 95% of the time breast pain is not caused by an underlying malignancy but rather due to hormonal and fibrocystic changes, which can be managed conservatively. If the clinical breast examination and recent screening mammogram (in women over age 40) results are negative, patients should be educated that their pain is benign and undergo a trial of conservative measures: wear and sleep in a supporting bra; keep a calendar of symptoms to determine any relation to cyclical changes; and avoid nicotine, caffeine, and fatty food. Topical pain creams with diclofenac and evening primrose oil also can be effective in ameliorating the symptoms. Breast pain is not a surgical disease; referral to a surgical specialist and diagnostic imaging can be unnecessary and expensive.

Breast pain is one of the most common breast-related patient complaints and is found to affect at least 50% of the female population.¹ Most cases are self-limiting and are related to hormonal and normal fibrocystic changes. The median age of onset of symptoms is 36 years, with most women experiencing pain for 5 to 12 years.² Because the cause of breast pain is not always clear, its presence can produce anxiety in patients and physicians over the possibility of underlying malignancy. Although breast cancer is not associated with breast pain, many patients presenting with pain are referred for diagnostic imaging (usually with negative results). The majority of women with mastalgia and normal clinical examination findings can be reassured with education about the many benign causes of breast pain.

What are causes of breast pain without an imaging abnormality?

Hormones. Mastalgia can be focal or generalized and is mostly due to hormonal changes. Elevated estrogen can stimulate the growth of breast tissue, which is known as epithelial hyperplasia.³ Fluctuations in hormone levels can occur in perimenopausal women in their forties and can result in new symptoms of breast pain.⁴ Sometimes starting a new contraceptive medication or hormone replacement therapy can exacerbate the pain. Switching brands or medications may help. Another cause of mastalgia may be elevated prolactin levels, with hypothalamic-pituitary dysfunction.^5,6

Diet. There is evidence to link a high-fat diet with breast pain. The pain has been shown to improve when lipid intake is reduced and high- and low-density lipoprotein cholesterol levels are normalized. As estrogen is a steroid hormone that can be synthesized from lipids and fatty acids, elevated lipid metabolism can increase estrogen levels and exacerbate breast pain symptoms.^7,8 Essential fatty acids, such as evening primrose oil and vitamin E, have been used to treat mastalgia because they reduce inflammation in fatty breast tissue through the prostaglandin pathway.^9,10

Caffeine. Methylxanthines can be found in coffee, tea, and chocolate and can aggravate mastalgia by enhancing the cyclin adenosine monophosphate (cAMP) pathway. This pathway stimulates cellular proliferation and fibrocystic changes which in turn can exacerbate breast pain.¹¹

Smoking. In my clinical practice I have clearly noted a higher incidence of breast pain in patients who smoke. The pain tends to improve significantly when the patient quits or even cuts back on smoking. The exact reasons for smoking’s effects on breast pain are not well known; however, they are thought to be related to acceleration of the cAMP pathway.

Large breast size. Very large breasts will strain and weaken the suspensory ligaments, leading to pain and discomfort. It has been shown that wearing a supportive sports bra during episodes of breast pain is effective.

Types of breast pain

Cyclical

Women with fibrocystic breasts tend to experience more breast pain. Breast sensitivity can be localized to the upper outer quadrants or to the nipple and sub-areolar area. It also can be generalized. The pain tends to peak with ovulation, improve with menses, and to recur every few weeks. Patients who have had partial hysterectomy (with ovaries in situ) or endometrial ablation will be unable to correlate their symptoms to menstruation. Therefore, women are encouraged to keep a diary or calendar of their symptoms to detect any correlation with their ovarian cycle. Such correlation is reassuring.

Continue to: Noncyclical...

Noncyclical

Noncyclical breast pain is not associated with the menstrual cycle and can be unilateral or bilateral. Providers should perform a good history of patients presenting with noncyclicalbreast pain, to include character, onset, duration, location, radiation, alleviating, and aggravating factors. A physical examination may elicit point tenderness at the chest by pushing the breast tissue off of the chest wall while the patient is in supine position and pressing directly over the ribs. Lack of tenderness on palpation of the breast parenchyma, but pain on the chest wall, points to a musculoskeletal etiology. Chest wall pain may be related to muscle spasm or muscle strain, trauma, rib fracture, or costochondritis (Tietze syndrome). Finally, based on history of review of systems and physical examination, referred pain from biliary or cardiac etiology should be considered.

When breast pain occurs with skin changes

Skin changes usually have an underlying pathology. Infectious processes, such as infected epidermal inclusion cyst, hidradenitis of the cleavage and inframammary crease, or breast abscess will present with pain and induration with an acute onset of 5 to 10 days. Large pendulous breasts may develop yeast infection at the inframammary crease. Chronic infectious irritation can lead to hyperpigmentation of that area. Eczema or contact dermatitis frequently can affect the areola and become confused with Paget disease (ductal carcinoma in situ of the nipple). With Paget, the excoriation always starts at the nipple and can then spread to the areola. However, with dermatitis, the rash begins on the peri-areolar skin, without affecting the nipple itself.

When breast pain occurs with nipple discharge

Breast pain with nipple discharge usually is bilateral and more common in patients with significant fibrocystic changes who smoke. If the nipple discharge is bilateral, serous and non-bloody, and multiduct, it is considered benign and physiologic. Physiologic nipple discharge can be multifactorial and hormonal. It may be related to thyroid disorders or medications such as antidepressants, selective serotonin reuptake inhibitors (SSRIs), mood stabilizers, or antipsychotics. The only nipple discharge that is considered pathologic is unilateral spontaneous bloody discharge for which diagnostic imaging and breast surgeon referral is indicated. Women should be discouraged from self-expressing their nipples, as 80% will experience serous nipple discharge upon manual self-expression.

Management of mastalgia

Appropriate breast pain management begins with a good history and physical examination. The decision to perform imaging should depend on clinical exam findings and not on symptoms of breast pain. If there is a palpable mass, then breast imaging and possible biopsy is appropriate. However, if clinical exam is normal, there is no indication for breast imaging in low-risk women under the age of 40 whose only symptom is breast pain. Women older than age 40 can undergo diagnostic imaging, if they have not had a negative screening mammogram in the past year.

Breast pain with abnormal clinical exam

In the patient who is younger than age 30 with a palpable mass. For this patient order targeted breast ultrasound (US) (FIGURE 1). If results are negative, repeat the clinical examination 1 week after menses. If the mass is persistent, refer the patient to a breast surgeon. If diagnostic imaging results are negative, consider breast MRI, especially if there is a strong family history of breast cancer.

In the patient who is aged 30 and older with a palpable mass. For this patient, bilateral diagnostic mammogram and US are in order. The testing is best performed 1 week after menses to reduce false-positive findings. If imaging is negative and the patient still has a clinically suspicious finding or mass, refer her to a breast surgeon and consider breast MRI. At this point if there is a persistent firm dominant mass, a biopsy is indicated as part of the triple test. If the mass resolves with menses, the patient can be reassured that the cause is most likely benign, with clinical examination repeated in 3 months.

Continue to: Breast pain and normal clinical exam...

Breast pain and normal clinical exam

When women who report breast pain have normal clinical examination findings (and have a negative screening mammogram in the past 12 months if older than age 40), there are several management strategies you can offer (FIGURE 2).

Reassurance and education. The majority of women with breast pain can be managed with reassurance and education, which are often sufficient to reduce their anxieties.

Supportive bra. The most effective intervention is to wear and sleep in a well-fitted supportive sports bra for 4 to 12 weeks. In a nonrandomized single-center trial of danazol versus sports bra, 85% of women reported relief of their breast pain with bra alone (vs 58% with danazol).¹² A supportive bra is the first-line management of mastalgia (Level II evidence).

Symptom diary/calendar. Many women do not know whether or not their symptoms correspond to their ovarian cycle or are related to hormonal fluctuations. Therefore, it is reassuring and informative for them to keep a calendar or a diary of their symptoms to determine whether their symptoms occur or are exacerbated in a cyclical pattern.

Diet and lifestyle modification. Women should avoid caffeine (especially when having pain). Studies on methylxanthines have demonstrated some symptom relief with reducing caffeine intake.^11,13 One cup of coffee or tea per day most likely will not make a difference. However, if a woman is drinking large quantities of caffeinated beverages throughout the day, it will very likely improve her breast pain if she cuts back. This is especially true during the times of exacerbated pain prior to her menses.

In addition, recommend reduced dietary fat (overall good health). This is good advice for any patient. There were 2 small studies that showed improvement in breast pain with a 15% reduction in dietary fat.^7,8

Finally, advise that patients stop smoking. Smoking aggravates and exacerbates fibrocystic changes, and these will lead to more breast pain.

Medical management. Over-the-counter medications that are found in the vitamin section of a local drug store are vitamin E and evening primrose oil. There are no significant adverse effects with these treatments. Their efficacy is theoretical, however; 3 randomized controlled trials demonstrated no significant clinical benefit with evening primrose oil versus placebo for treatment of mastalgia.¹⁴

Topical or oral nonsteroidal anti-inflammatory drugs (NSAIDs; Voltaren gel, topical compound pain creams) are useful as second-line management after using a supportive bra. Three randomized controlled trials have demonstrated up to 90% improvement of mastalgia with topical NSAIDs.^15-17

Tamoxifen is a selective estrogen-receptor modulator (SERM), which is an antagonist to the estrogen receptor (ER) in the breast and an agonist to the ER in the endometrium. Tamoxifen has been found to reduce symptoms of mastalgia by 70% even at a lower dosage of 10-mg per day (for 6 months), or as a topical gel (afimoxifene). The oral form can have some adverse effects, including hot flashes, and has a low risk for thromboembolic events and endometrial neoplasia.^18-20

Danazol is very effective in reducing breast pain symptoms (by 80%), with a higher relapse after stopping the medication. Danazol is less tolerated due to its androgenic effects, such as hirsutism, acne, menorrhagia, and voice changes. Both danazol and tamoxifen can be teratogenic and should be used with caution in women of child-bearing age.²¹

Finally, bromocriptine inhibits serum prolactin and has been reported to provide 65% improvement in breast pain. Its use for breast pain is not US Food and Drug Administration–approved and adverse effects include nausea, dizziness, and hypotension.²²

Tamoxifen, danazol, and bromocriptine can be considered as third-line management options for severe treatment-resistant mastalgia.

Continue to: FIGURE 2 Treatment algorithm for breast pain...

In summary

Evaluation and counseling for breast pain should be managed by women’s health care providers in a primary care setting. Most patients need reassurance and medical explanation of their symptoms. They should be educated that more than 95% of the time breast pain is not caused by an underlying malignancy but rather due to hormonal and fibrocystic changes, which can be managed conservatively. If the clinical breast examination and recent screening mammogram (in women over age 40) results are negative, patients should be educated that their pain is benign and undergo a trial of conservative measures: wear and sleep in a supporting bra; keep a calendar of symptoms to determine any relation to cyclical changes; and avoid nicotine, caffeine, and fatty food. Topical pain creams with diclofenac and evening primrose oil also can be effective in ameliorating the symptoms. Breast pain is not a surgical disease; referral to a surgical specialist and diagnostic imaging can be unnecessary and expensive.

This article is part of a series that illustrates strategies intended to redesign primary care education at the Veterans Health Administration (VHA), using interprofessional workplace learning. All have been implemented in the VA Centers of Excellence in Primary Care Education (CoEPCE). These models embody visionary transformation of clinical and educational environments that have potential for replication and dissemination throughout VA and other primary care clinical educational environments. For an introduction to the series see Klink K. Transforming primary care clinical learning environments to optimize education, outcomes, and satisfaction. Fed Pract. 2018;35(9):8-10.

Background

In 2011, 5 US Department of Veterans Affairs (VA) medical centers were selected by the VA Office of Academic Affiliations (OAA) to establish Centers of Excellence in Primary Care Education (CoEPCE). Part of the New Models of Care initiative, the 5 CoEPCEs use VA primary care settings to develop and test innovative approaches to prepare physician residents, medical students, advanced practice registered nurses, undergraduate nursing students, and other health professions’ trainees, such as social workers, pharmacists, psychologists, and physician assistants, for improved primary care practice. The CoEPCEs are interprofessional Academic PACTs (iAPACTs) with ≥ 2 professions of trainees engaged in learning on the PACT team.

The VA Puget Sound Seattle CoEPCE curriculum is embedded in a well-established academic VA primary care training site.¹ Trainees include doctor of nursing practice (DNP) students in adult, family, and psychiatric mental health nurse practitioner (NP) programs; NP residents; internal medicine physician residents; postgraduate pharmacy residents; and other health professions’ trainees. A Seattle CoEPCE priority is to provide DNP students, DNP residents, and physician residents with a longitudinal experience in team-based care as well as interprofessional education and collaborative practice (IPECP). Learners spend the majority of CoEPCE time in supervised, direct patient care, including primary care, women’s health, deployment health, homeless care, and home care. Formal IPECP activities comprise about 20% of time, supported by 3 educational strategies: (1) Panel management (PM)/quality improvement (QI); (2) Team building/ communications; and (3) Clinical content seminars to expand trainee clinical knowledge and skills and curriculum developed with the CoEPCE enterprise core domains in mind (Table).

Panel Management

Clinicians are increasingly being required to proactively optimize the health of an assigned population of patients in addition to assessing and managing the health of individual patients presenting for care. To address the objectives of increased accountability for population health outcomes and improved face-to-face care, Seattle CoEPCE developed curriculum for trainees to learn PM, a set of tools and processes that can be applied in the primary care setting.

PM clinical providers use data to proactively provide care to their patients between traditional clinic visits. The process is proactive in that gaps are identified whether or not an in-person visit occurs and involves an outreach mechanism to increase continuity of care, such as follow-up communications with the patients.² PM also has been associated with improvements in chronic disease care.^3-5

The Seattle CoEPCE developed an interprofessional team approach to PM that teaches trainees about the tools and resources used to close the gaps in care, including the use of clinical team members as health care systems subject matter experts. CoEPCE trainees are taught to analyze the care they provide to their panel of veterans (eg, identifying patients who have not refilled chronic medications or those who use the emergency department [ED] for nonacute conditions) and take action to improve care. PM yields rich discussions on systems resources and processes and is easily applied to a range of health conditions as well as delivery system issues. PM gives learners the tools they can use to close these gaps, such as the expertise of their peers, clinical team, and specialists.⁶

Planning and Implementation

In addition to completing a literature review to determine the state of PM practice and models, CoEPCE faculty polled recent graduates inquiring about strategies they did not learn prior to graduation. Based on their responses, CoEPCE faculty identified 2 skill deficits: management of chronic diseases and proficiency with data and statistics about performance improvement in panel patient care over time. Addressing these unmet needs became the impetus for developing curriculum for conducting PM. Planning and launching the CoEPCE approach to PM took about 3 months and involved CoEPCE faculty, a data manager, and administrative support. The learning objectives of Seattle’s PM initiative are to:

• Promote preventive health and chronic disease care by use performance data;
• Develop individual- and populationfocused action plans;
• Work collaboratively, strategically, and effectively with an interprofessional care team; and
• Learn how to effectively use system resources.

Curriculum

The PM curriculum is a longitudinal, experiential approach to learning how to manage chronic diseases between visits by using patient data. It is designed for trainees in a continuity clinic to review the care of their patients on a regular basis. Seattle CoEPCE medicine residents are assigned patient panels, which increase from 70 patients in the first year to about 140 patients by the end of the third year. DNP postgraduate trainees are assigned an initial panel of 50 patients that increases incrementally over the year-long residency.

CoEPCE faculty determined the focus of PM sessions to be diabetes mellitus (DM), hypertension, obesity, chronic opioid therapy, and low-acuity ED use. Because PM sessions are designed to allow participants to identify systems issues that may affect multiple patients, some of these topics have expanded into QI projects. PM sessions run 2 to 3 hours per session and are held 4 to 6 times a year. Each session is repeated twice to accommodate diverse trainee schedules. PM participants must have their patient visit time blocked for each session (Appendix).

Faculty Roles and Development

PM faculty involved in any individual session may include a combination of a CoEPCE clinical pharmacy specialist, a registered nurse (RN) care manager, a social worker, a NP, a physician, a clinical psychologist, and a medicine outpatient chief resident (PGY4, termed clinician-teacher fellow at Seattle VA medical center). The chief resident is a medicine residency graduate and takes on teaching responsibilities depending on the topic of the session. The CoEPCE clinical pharmacist role varies depending on the session topic: They may facilitate the session or provide recommendations for medication management for individual cases. The RN care manager often knows the patients and brings a unique perspective that complements that of the primary care providers and ideally participates in every session. The patients of multiple RN care managers may be presented at each session, and it was not feasible to include all RN care managers in every session. After case discussions, trainees often communicated with the RN care managers about the case, using instant messaging, and CoEPCE provides other avenues for patient care discussion through huddles involving the provider, RN care manager, clinical pharmacist, and other clinical professions.

Resources

The primary resource required to support PM is an information technology (IT) system that provides relevant health outcome and health care utilization data on patients assigned to trainees. PM sessions include teaching trainees how to access patient data. Since discussion about the care of panel patients during the learning sessions often results in real-time adjustments in the care plan, modest administrative support required post-PM sessions, such as clerical scheduling of the requested clinic or telephone follow-up with the physician, nurse, or pharmacist.

Monitoring and Assessment

Panel performance is evaluated at each educational session. To assess the CoEPCE PM curriculum, participants provide feedback in 8 questions over 3 domains: trainee perception of curriculum content, confidence in performing PM involving completion of a PM workshop, and likelihood of using PM techniques in the future. CoEPCE faculty use the feedback to improve their instruction of panel management skill and develop new sessions that target additional population groups. Evaluation of the curriculum also includes monitoring of panel patients’ chronic disease measures.

Several partnerships have contributed to the success and integrations of PM into facility activities. First, having the primary care clinic director as a member of the Co- EPCE faculty has encouraged faculty and staff to operationalize and implement PM broadly by distributing data monthly to all clinic staff. Second, high facility staff interest outside the CoEPCE and primary care clinic has facilitated establishing communications outside the CoEPCE regarding clinic data.

Challenges and Solutions

Trainees at earlier academic levels often desire more instruction in clinical knowledge, such as treatment options for DM or goals of therapy in hypertension. In contrast, advanced trainees are able to review patient data, brainstorm, and optimize solutions. Seattle CoEPCE balances these different learning needs via a flexible approach to the 3-hour sessions. For example, advanced trainees progress from structured short lectures to informal sessions, which train them to perform PM on their own. In addition, the flexible design integrates trainees with diverse schedules, particularly among DNP students and residents, pharmacy residents, and physician residents. Some of this work falls on the RN care management team and administrative support staff.

Competing Priorities

The demand for direct patient care points to the importance of indirect patient care activities like PM to demonstrate improved results. Managing chronic conditions and matching appropriate services and resources should improve clinical outcomes and efficiency longterm. In the interim, it is important to note that PM demonstrates the continuous aspect of clinical care, particularly for trainees who have strict guidelines defining clinical care for the experiences to count toward eligibility for licensure. Additionally, PM results in trainees who are making decisions with VA patients and are more efficiently providing and supporting patient care. Therefore, it is critical to secure important resources, such as provider time for conducting PM.

Data Access

No single data system in VA covers the broad range of topics covered in the PM sessions, and not all trainees have their own assigned panels. For example, health professions students are not assigned a panel of patients. While they do not have access to panel data such as those generated by Primary Care Almanac in VSSC (a data source in the VA Support Service Center database),the Seattle CoEPCE data manager pulls a set of patient data from the students’ paired faculty preceptors’ panels for review. Thus they learn PM principles and strategies for improving patient care via PM as part of the unique VA longitudinal clinic experience and the opportunity to learn from a multidisciplinary team that is not available at other clinical sites. Postgraduate NP residents in CoEPCE training have their own panels of patients and thus the ability to directly access their panel performance data.

Success Factors

A key success factor includes CoEPCE faculty’s ability to develop and operationalize a panel management model that simultaneously aligns with the educational goals of an interprofessional education training program and supports VA adoption of the medical home or patient aligned care teams (PACT). The CoEPCE contributes staff expertise in accessing and reporting patient data, accessing appropriate teaching space, managing panels of patients with chronic diseases, and facilitating a team-based approach to care. Additionally, the CoEPCE brand is helpful for getting buy-in from the clinical and academic stakeholders necessary for moving PM forward.

Colocating CoEPCE trainees and faculty in the primary care clinic promotes team identity around the RN care managers and facilitated communications with non-CoEPCE clinical teams that have trainees from other professions. RN care managers serve as the locus of highquality PM since they share patient panels with the trainees and already track admissions, ED visits, and numerous chronic health care metrics. RN care managers offer a level of insight into chronic disease that other providers may not possess, such as the specific details on medication adherence and the impact of adverse effects (AEs) for that particular patient. RN care managers are able to teach about their team role and responsibilities, strengthening the model.

PM is an opportunity to expand CoEPCE interprofessional education capacity by creating colocation of different trainee and faculty professions during the PM sessions; the sharing of data with trainees; and sharing and reflecting on data, strengthening communications between professions and within the PACT. The Seattle CoEPCE now has systems in place that allow the RN care manager to send notes to a physician and DNP resident, and the resident is expected to respond. In addition, the PM approach provides experience with analyzing data to improve care in an interprofessional team setting, which is a requirement of the Accreditation Council for Graduate Medical Education.

Interprofessional Collaboration

PM sessions are intentionally designed to improve communication among team members and foster a team approach to care. PM sessions provide an opportunity for trainees and clinician faculty to be together and learn about each profession’s perspectives. For example, early in the process physician and DNP trainees learn about the importance of clinical pharmacists to the team who prescribe and make medication adjustments within their scope of practice as well as the importance of making appropriate pharmacy referrals. Additionally, the RN care manager and clinical pharmacy specialists who serve as faculty in the CoEPCE provide pertinent information on individual patients, increasing integration with the PACT. Finally, there is anecdotal evidence that faculty also are learning more about interprofessional education and expanding their own skills.

Clinical Performance

CoEPCE trainees, non-CoEPCE physician residents, and CoEPCE faculty participants regularly receive patient data with which they can proactively develop or amend a treatment plan between visits. PM has resulted in improved data sharing with providers. Instead of once a year, providers and clinic staff now receive patient data monthly on chronic conditions from the clinic director. Trainees on ambulatory rotations are expected to review their panel data at least a half day per week. CoEPCE staff evaluate trainee likelihood to use PM and ability to identify patients who benefit from team-based care.

At the population level of chronic disease management, preliminary evidence demonstrates that primary care clinic patient panels are increasingly within target for DM and blood pressure measures, as assessed by periodic clinical reports to providers. Some of the PM topics have resulted in systems-level improvements, such as reducing unnecessary ED use for nonacute conditions and better opioid prescription monitoring. Moreover, PM supports everyone working at the top of his/her professional capability. For example, the RN care manager has the impetus to initiate DM education with a particular patient.

Since CoEPCE began teaching PM, the Seattle primary care clinic has committed to the regular access and review of data. This has encouraged the alignment of standards of care for chronic disease management so that all care providers are working toward the same benchmark goals.

Patient Outcomes

At the individual level, PM provide a mechanism to systemically review trainee panel patients with out-of-target clinical measures, and develop new care approaches involving interprofessional strategies and problem solving. PM also helps identify patients who have missed follow-up, reducing the risk that patients with chronic care needs will be lost to clinical engagement if they are not reminded or do not pursue appointments. The PM-trained PACT reaches out to patients who might not otherwise get care before the next clinic visit and provides new care plans. Second, patients have the benefit of a team that manages their health needs. For example, including the clinical pharmacists in the PM sessions ensures timely identification of medication interactions and the potential AEs. Additionally, PM contributes to the care coordination model by involving individuals on the primary care team who know the patient. These members review the patient’s data between visits and initiate team-based changes to the care plan to improve care. More team members connect with a patient, resulting in more intense care and quicker follow-up to determine the effectiveness of a treatment plan.

PM topics have spun off QI projects resulting in new clinic processes and programs, including processes for managing wounds in primary care and to assure timely post-ED visit follow-ups. Areas for expansion include a follow-up QI project to reduce nonacute ED visits by patients on the homeless PACT panel and interventions for better management of care for women veterans with mental health needs. PM also has extended to non-Co- EPCE teams and to other clinic activities, such as strengthening huddles of team members specifically related to panel data and addressing selected patient cases between visits. Pharmacy residents and faculty are more involved in reviewing the panel before patients are seen to review medication lists and identify duplications.

The Future

Under stage 2 of the program, the Seattle CoEPCE intends to lead in the creation of a PM toolkit as well as a data access guide that will allow VA facilities with limited data management expertise to access chronic disease metrics. Second, the CoEPCE will continue its dissemination efforts locally to other residents in the internal medicine residency program in all of its continuity clinics. Additionally, there is high interest by DNP training programs to expand and export longitudinal training experience PM curriculum to non-VA based students.

This article is part of a series that illustrates strategies intended to redesign primary care education at the Veterans Health Administration (VHA), using interprofessional workplace learning. All have been implemented in the VA Centers of Excellence in Primary Care Education (CoEPCE). These models embody visionary transformation of clinical and educational environments that have potential for replication and dissemination throughout VA and other primary care clinical educational environments. For an introduction to the series see Klink K. Transforming primary care clinical learning environments to optimize education, outcomes, and satisfaction. Fed Pract. 2018;35(9):8-10.

Background

In 2011, 5 US Department of Veterans Affairs (VA) medical centers were selected by the VA Office of Academic Affiliations (OAA) to establish Centers of Excellence in Primary Care Education (CoEPCE). Part of the New Models of Care initiative, the 5 CoEPCEs use VA primary care settings to develop and test innovative approaches to prepare physician residents, medical students, advanced practice registered nurses, undergraduate nursing students, and other health professions’ trainees, such as social workers, pharmacists, psychologists, and physician assistants, for improved primary care practice. The CoEPCEs are interprofessional Academic PACTs (iAPACTs) with ≥ 2 professions of trainees engaged in learning on the PACT team.

The VA Puget Sound Seattle CoEPCE curriculum is embedded in a well-established academic VA primary care training site.¹ Trainees include doctor of nursing practice (DNP) students in adult, family, and psychiatric mental health nurse practitioner (NP) programs; NP residents; internal medicine physician residents; postgraduate pharmacy residents; and other health professions’ trainees. A Seattle CoEPCE priority is to provide DNP students, DNP residents, and physician residents with a longitudinal experience in team-based care as well as interprofessional education and collaborative practice (IPECP). Learners spend the majority of CoEPCE time in supervised, direct patient care, including primary care, women’s health, deployment health, homeless care, and home care. Formal IPECP activities comprise about 20% of time, supported by 3 educational strategies: (1) Panel management (PM)/quality improvement (QI); (2) Team building/ communications; and (3) Clinical content seminars to expand trainee clinical knowledge and skills and curriculum developed with the CoEPCE enterprise core domains in mind (Table).

Panel Management

Clinicians are increasingly being required to proactively optimize the health of an assigned population of patients in addition to assessing and managing the health of individual patients presenting for care. To address the objectives of increased accountability for population health outcomes and improved face-to-face care, Seattle CoEPCE developed curriculum for trainees to learn PM, a set of tools and processes that can be applied in the primary care setting.

PM clinical providers use data to proactively provide care to their patients between traditional clinic visits. The process is proactive in that gaps are identified whether or not an in-person visit occurs and involves an outreach mechanism to increase continuity of care, such as follow-up communications with the patients.² PM also has been associated with improvements in chronic disease care.^3-5

The Seattle CoEPCE developed an interprofessional team approach to PM that teaches trainees about the tools and resources used to close the gaps in care, including the use of clinical team members as health care systems subject matter experts. CoEPCE trainees are taught to analyze the care they provide to their panel of veterans (eg, identifying patients who have not refilled chronic medications or those who use the emergency department [ED] for nonacute conditions) and take action to improve care. PM yields rich discussions on systems resources and processes and is easily applied to a range of health conditions as well as delivery system issues. PM gives learners the tools they can use to close these gaps, such as the expertise of their peers, clinical team, and specialists.⁶

Planning and Implementation

In addition to completing a literature review to determine the state of PM practice and models, CoEPCE faculty polled recent graduates inquiring about strategies they did not learn prior to graduation. Based on their responses, CoEPCE faculty identified 2 skill deficits: management of chronic diseases and proficiency with data and statistics about performance improvement in panel patient care over time. Addressing these unmet needs became the impetus for developing curriculum for conducting PM. Planning and launching the CoEPCE approach to PM took about 3 months and involved CoEPCE faculty, a data manager, and administrative support. The learning objectives of Seattle’s PM initiative are to:

• Promote preventive health and chronic disease care by use performance data;
• Develop individual- and populationfocused action plans;
• Work collaboratively, strategically, and effectively with an interprofessional care team; and
• Learn how to effectively use system resources.

Curriculum

The PM curriculum is a longitudinal, experiential approach to learning how to manage chronic diseases between visits by using patient data. It is designed for trainees in a continuity clinic to review the care of their patients on a regular basis. Seattle CoEPCE medicine residents are assigned patient panels, which increase from 70 patients in the first year to about 140 patients by the end of the third year. DNP postgraduate trainees are assigned an initial panel of 50 patients that increases incrementally over the year-long residency.

CoEPCE faculty determined the focus of PM sessions to be diabetes mellitus (DM), hypertension, obesity, chronic opioid therapy, and low-acuity ED use. Because PM sessions are designed to allow participants to identify systems issues that may affect multiple patients, some of these topics have expanded into QI projects. PM sessions run 2 to 3 hours per session and are held 4 to 6 times a year. Each session is repeated twice to accommodate diverse trainee schedules. PM participants must have their patient visit time blocked for each session (Appendix).

Faculty Roles and Development

PM faculty involved in any individual session may include a combination of a CoEPCE clinical pharmacy specialist, a registered nurse (RN) care manager, a social worker, a NP, a physician, a clinical psychologist, and a medicine outpatient chief resident (PGY4, termed clinician-teacher fellow at Seattle VA medical center). The chief resident is a medicine residency graduate and takes on teaching responsibilities depending on the topic of the session. The CoEPCE clinical pharmacist role varies depending on the session topic: They may facilitate the session or provide recommendations for medication management for individual cases. The RN care manager often knows the patients and brings a unique perspective that complements that of the primary care providers and ideally participates in every session. The patients of multiple RN care managers may be presented at each session, and it was not feasible to include all RN care managers in every session. After case discussions, trainees often communicated with the RN care managers about the case, using instant messaging, and CoEPCE provides other avenues for patient care discussion through huddles involving the provider, RN care manager, clinical pharmacist, and other clinical professions.

Resources

The primary resource required to support PM is an information technology (IT) system that provides relevant health outcome and health care utilization data on patients assigned to trainees. PM sessions include teaching trainees how to access patient data. Since discussion about the care of panel patients during the learning sessions often results in real-time adjustments in the care plan, modest administrative support required post-PM sessions, such as clerical scheduling of the requested clinic or telephone follow-up with the physician, nurse, or pharmacist.

Monitoring and Assessment

Panel performance is evaluated at each educational session. To assess the CoEPCE PM curriculum, participants provide feedback in 8 questions over 3 domains: trainee perception of curriculum content, confidence in performing PM involving completion of a PM workshop, and likelihood of using PM techniques in the future. CoEPCE faculty use the feedback to improve their instruction of panel management skill and develop new sessions that target additional population groups. Evaluation of the curriculum also includes monitoring of panel patients’ chronic disease measures.

Several partnerships have contributed to the success and integrations of PM into facility activities. First, having the primary care clinic director as a member of the Co- EPCE faculty has encouraged faculty and staff to operationalize and implement PM broadly by distributing data monthly to all clinic staff. Second, high facility staff interest outside the CoEPCE and primary care clinic has facilitated establishing communications outside the CoEPCE regarding clinic data.

Challenges and Solutions

Trainees at earlier academic levels often desire more instruction in clinical knowledge, such as treatment options for DM or goals of therapy in hypertension. In contrast, advanced trainees are able to review patient data, brainstorm, and optimize solutions. Seattle CoEPCE balances these different learning needs via a flexible approach to the 3-hour sessions. For example, advanced trainees progress from structured short lectures to informal sessions, which train them to perform PM on their own. In addition, the flexible design integrates trainees with diverse schedules, particularly among DNP students and residents, pharmacy residents, and physician residents. Some of this work falls on the RN care management team and administrative support staff.

Competing Priorities

The demand for direct patient care points to the importance of indirect patient care activities like PM to demonstrate improved results. Managing chronic conditions and matching appropriate services and resources should improve clinical outcomes and efficiency longterm. In the interim, it is important to note that PM demonstrates the continuous aspect of clinical care, particularly for trainees who have strict guidelines defining clinical care for the experiences to count toward eligibility for licensure. Additionally, PM results in trainees who are making decisions with VA patients and are more efficiently providing and supporting patient care. Therefore, it is critical to secure important resources, such as provider time for conducting PM.

Data Access

No single data system in VA covers the broad range of topics covered in the PM sessions, and not all trainees have their own assigned panels. For example, health professions students are not assigned a panel of patients. While they do not have access to panel data such as those generated by Primary Care Almanac in VSSC (a data source in the VA Support Service Center database),the Seattle CoEPCE data manager pulls a set of patient data from the students’ paired faculty preceptors’ panels for review. Thus they learn PM principles and strategies for improving patient care via PM as part of the unique VA longitudinal clinic experience and the opportunity to learn from a multidisciplinary team that is not available at other clinical sites. Postgraduate NP residents in CoEPCE training have their own panels of patients and thus the ability to directly access their panel performance data.

Success Factors

A key success factor includes CoEPCE faculty’s ability to develop and operationalize a panel management model that simultaneously aligns with the educational goals of an interprofessional education training program and supports VA adoption of the medical home or patient aligned care teams (PACT). The CoEPCE contributes staff expertise in accessing and reporting patient data, accessing appropriate teaching space, managing panels of patients with chronic diseases, and facilitating a team-based approach to care. Additionally, the CoEPCE brand is helpful for getting buy-in from the clinical and academic stakeholders necessary for moving PM forward.

Colocating CoEPCE trainees and faculty in the primary care clinic promotes team identity around the RN care managers and facilitated communications with non-CoEPCE clinical teams that have trainees from other professions. RN care managers serve as the locus of highquality PM since they share patient panels with the trainees and already track admissions, ED visits, and numerous chronic health care metrics. RN care managers offer a level of insight into chronic disease that other providers may not possess, such as the specific details on medication adherence and the impact of adverse effects (AEs) for that particular patient. RN care managers are able to teach about their team role and responsibilities, strengthening the model.

PM is an opportunity to expand CoEPCE interprofessional education capacity by creating colocation of different trainee and faculty professions during the PM sessions; the sharing of data with trainees; and sharing and reflecting on data, strengthening communications between professions and within the PACT. The Seattle CoEPCE now has systems in place that allow the RN care manager to send notes to a physician and DNP resident, and the resident is expected to respond. In addition, the PM approach provides experience with analyzing data to improve care in an interprofessional team setting, which is a requirement of the Accreditation Council for Graduate Medical Education.

Interprofessional Collaboration

PM sessions are intentionally designed to improve communication among team members and foster a team approach to care. PM sessions provide an opportunity for trainees and clinician faculty to be together and learn about each profession’s perspectives. For example, early in the process physician and DNP trainees learn about the importance of clinical pharmacists to the team who prescribe and make medication adjustments within their scope of practice as well as the importance of making appropriate pharmacy referrals. Additionally, the RN care manager and clinical pharmacy specialists who serve as faculty in the CoEPCE provide pertinent information on individual patients, increasing integration with the PACT. Finally, there is anecdotal evidence that faculty also are learning more about interprofessional education and expanding their own skills.

Clinical Performance

CoEPCE trainees, non-CoEPCE physician residents, and CoEPCE faculty participants regularly receive patient data with which they can proactively develop or amend a treatment plan between visits. PM has resulted in improved data sharing with providers. Instead of once a year, providers and clinic staff now receive patient data monthly on chronic conditions from the clinic director. Trainees on ambulatory rotations are expected to review their panel data at least a half day per week. CoEPCE staff evaluate trainee likelihood to use PM and ability to identify patients who benefit from team-based care.

At the population level of chronic disease management, preliminary evidence demonstrates that primary care clinic patient panels are increasingly within target for DM and blood pressure measures, as assessed by periodic clinical reports to providers. Some of the PM topics have resulted in systems-level improvements, such as reducing unnecessary ED use for nonacute conditions and better opioid prescription monitoring. Moreover, PM supports everyone working at the top of his/her professional capability. For example, the RN care manager has the impetus to initiate DM education with a particular patient.

Since CoEPCE began teaching PM, the Seattle primary care clinic has committed to the regular access and review of data. This has encouraged the alignment of standards of care for chronic disease management so that all care providers are working toward the same benchmark goals.

Patient Outcomes

At the individual level, PM provide a mechanism to systemically review trainee panel patients with out-of-target clinical measures, and develop new care approaches involving interprofessional strategies and problem solving. PM also helps identify patients who have missed follow-up, reducing the risk that patients with chronic care needs will be lost to clinical engagement if they are not reminded or do not pursue appointments. The PM-trained PACT reaches out to patients who might not otherwise get care before the next clinic visit and provides new care plans. Second, patients have the benefit of a team that manages their health needs. For example, including the clinical pharmacists in the PM sessions ensures timely identification of medication interactions and the potential AEs. Additionally, PM contributes to the care coordination model by involving individuals on the primary care team who know the patient. These members review the patient’s data between visits and initiate team-based changes to the care plan to improve care. More team members connect with a patient, resulting in more intense care and quicker follow-up to determine the effectiveness of a treatment plan.

PM topics have spun off QI projects resulting in new clinic processes and programs, including processes for managing wounds in primary care and to assure timely post-ED visit follow-ups. Areas for expansion include a follow-up QI project to reduce nonacute ED visits by patients on the homeless PACT panel and interventions for better management of care for women veterans with mental health needs. PM also has extended to non-Co- EPCE teams and to other clinic activities, such as strengthening huddles of team members specifically related to panel data and addressing selected patient cases between visits. Pharmacy residents and faculty are more involved in reviewing the panel before patients are seen to review medication lists and identify duplications.

The Future

Under stage 2 of the program, the Seattle CoEPCE intends to lead in the creation of a PM toolkit as well as a data access guide that will allow VA facilities with limited data management expertise to access chronic disease metrics. Second, the CoEPCE will continue its dissemination efforts locally to other residents in the internal medicine residency program in all of its continuity clinics. Additionally, there is high interest by DNP training programs to expand and export longitudinal training experience PM curriculum to non-VA based students.

This article is part of a series that illustrates strategies intended to redesign primary care education at the Veterans Health Administration (VHA), using interprofessional workplace learning. All have been implemented in the VA Centers of Excellence in Primary Care Education (CoEPCE). These models embody visionary transformation of clinical and educational environments that have potential for replication and dissemination throughout VA and other primary care clinical educational environments. For an introduction to the series see Klink K. Transforming primary care clinical learning environments to optimize education, outcomes, and satisfaction. Fed Pract. 2018;35(9):8-10.

Background

In 2011, 5 US Department of Veterans Affairs (VA) medical centers were selected by the VA Office of Academic Affiliations (OAA) to establish Centers of Excellence in Primary Care Education (CoEPCE). Part of the New Models of Care initiative, the 5 CoEPCEs use VA primary care settings to develop and test innovative approaches to prepare physician residents, medical students, advanced practice registered nurses, undergraduate nursing students, and other health professions’ trainees, such as social workers, pharmacists, psychologists, and physician assistants, for improved primary care practice. The CoEPCEs are interprofessional Academic PACTs (iAPACTs) with ≥ 2 professions of trainees engaged in learning on the PACT team.

The VA Puget Sound Seattle CoEPCE curriculum is embedded in a well-established academic VA primary care training site.¹ Trainees include doctor of nursing practice (DNP) students in adult, family, and psychiatric mental health nurse practitioner (NP) programs; NP residents; internal medicine physician residents; postgraduate pharmacy residents; and other health professions’ trainees. A Seattle CoEPCE priority is to provide DNP students, DNP residents, and physician residents with a longitudinal experience in team-based care as well as interprofessional education and collaborative practice (IPECP). Learners spend the majority of CoEPCE time in supervised, direct patient care, including primary care, women’s health, deployment health, homeless care, and home care. Formal IPECP activities comprise about 20% of time, supported by 3 educational strategies: (1) Panel management (PM)/quality improvement (QI); (2) Team building/ communications; and (3) Clinical content seminars to expand trainee clinical knowledge and skills and curriculum developed with the CoEPCE enterprise core domains in mind (Table).

Panel Management

Clinicians are increasingly being required to proactively optimize the health of an assigned population of patients in addition to assessing and managing the health of individual patients presenting for care. To address the objectives of increased accountability for population health outcomes and improved face-to-face care, Seattle CoEPCE developed curriculum for trainees to learn PM, a set of tools and processes that can be applied in the primary care setting.

PM clinical providers use data to proactively provide care to their patients between traditional clinic visits. The process is proactive in that gaps are identified whether or not an in-person visit occurs and involves an outreach mechanism to increase continuity of care, such as follow-up communications with the patients.² PM also has been associated with improvements in chronic disease care.^3-5

The Seattle CoEPCE developed an interprofessional team approach to PM that teaches trainees about the tools and resources used to close the gaps in care, including the use of clinical team members as health care systems subject matter experts. CoEPCE trainees are taught to analyze the care they provide to their panel of veterans (eg, identifying patients who have not refilled chronic medications or those who use the emergency department [ED] for nonacute conditions) and take action to improve care. PM yields rich discussions on systems resources and processes and is easily applied to a range of health conditions as well as delivery system issues. PM gives learners the tools they can use to close these gaps, such as the expertise of their peers, clinical team, and specialists.⁶

Planning and Implementation

In addition to completing a literature review to determine the state of PM practice and models, CoEPCE faculty polled recent graduates inquiring about strategies they did not learn prior to graduation. Based on their responses, CoEPCE faculty identified 2 skill deficits: management of chronic diseases and proficiency with data and statistics about performance improvement in panel patient care over time. Addressing these unmet needs became the impetus for developing curriculum for conducting PM. Planning and launching the CoEPCE approach to PM took about 3 months and involved CoEPCE faculty, a data manager, and administrative support. The learning objectives of Seattle’s PM initiative are to:

• Promote preventive health and chronic disease care by use performance data;
• Develop individual- and populationfocused action plans;
• Work collaboratively, strategically, and effectively with an interprofessional care team; and
• Learn how to effectively use system resources.

Curriculum

The PM curriculum is a longitudinal, experiential approach to learning how to manage chronic diseases between visits by using patient data. It is designed for trainees in a continuity clinic to review the care of their patients on a regular basis. Seattle CoEPCE medicine residents are assigned patient panels, which increase from 70 patients in the first year to about 140 patients by the end of the third year. DNP postgraduate trainees are assigned an initial panel of 50 patients that increases incrementally over the year-long residency.

CoEPCE faculty determined the focus of PM sessions to be diabetes mellitus (DM), hypertension, obesity, chronic opioid therapy, and low-acuity ED use. Because PM sessions are designed to allow participants to identify systems issues that may affect multiple patients, some of these topics have expanded into QI projects. PM sessions run 2 to 3 hours per session and are held 4 to 6 times a year. Each session is repeated twice to accommodate diverse trainee schedules. PM participants must have their patient visit time blocked for each session (Appendix).

Faculty Roles and Development

PM faculty involved in any individual session may include a combination of a CoEPCE clinical pharmacy specialist, a registered nurse (RN) care manager, a social worker, a NP, a physician, a clinical psychologist, and a medicine outpatient chief resident (PGY4, termed clinician-teacher fellow at Seattle VA medical center). The chief resident is a medicine residency graduate and takes on teaching responsibilities depending on the topic of the session. The CoEPCE clinical pharmacist role varies depending on the session topic: They may facilitate the session or provide recommendations for medication management for individual cases. The RN care manager often knows the patients and brings a unique perspective that complements that of the primary care providers and ideally participates in every session. The patients of multiple RN care managers may be presented at each session, and it was not feasible to include all RN care managers in every session. After case discussions, trainees often communicated with the RN care managers about the case, using instant messaging, and CoEPCE provides other avenues for patient care discussion through huddles involving the provider, RN care manager, clinical pharmacist, and other clinical professions.

Resources

The primary resource required to support PM is an information technology (IT) system that provides relevant health outcome and health care utilization data on patients assigned to trainees. PM sessions include teaching trainees how to access patient data. Since discussion about the care of panel patients during the learning sessions often results in real-time adjustments in the care plan, modest administrative support required post-PM sessions, such as clerical scheduling of the requested clinic or telephone follow-up with the physician, nurse, or pharmacist.

Monitoring and Assessment

Panel performance is evaluated at each educational session. To assess the CoEPCE PM curriculum, participants provide feedback in 8 questions over 3 domains: trainee perception of curriculum content, confidence in performing PM involving completion of a PM workshop, and likelihood of using PM techniques in the future. CoEPCE faculty use the feedback to improve their instruction of panel management skill and develop new sessions that target additional population groups. Evaluation of the curriculum also includes monitoring of panel patients’ chronic disease measures.

Several partnerships have contributed to the success and integrations of PM into facility activities. First, having the primary care clinic director as a member of the Co- EPCE faculty has encouraged faculty and staff to operationalize and implement PM broadly by distributing data monthly to all clinic staff. Second, high facility staff interest outside the CoEPCE and primary care clinic has facilitated establishing communications outside the CoEPCE regarding clinic data.

Challenges and Solutions

Trainees at earlier academic levels often desire more instruction in clinical knowledge, such as treatment options for DM or goals of therapy in hypertension. In contrast, advanced trainees are able to review patient data, brainstorm, and optimize solutions. Seattle CoEPCE balances these different learning needs via a flexible approach to the 3-hour sessions. For example, advanced trainees progress from structured short lectures to informal sessions, which train them to perform PM on their own. In addition, the flexible design integrates trainees with diverse schedules, particularly among DNP students and residents, pharmacy residents, and physician residents. Some of this work falls on the RN care management team and administrative support staff.

Competing Priorities

The demand for direct patient care points to the importance of indirect patient care activities like PM to demonstrate improved results. Managing chronic conditions and matching appropriate services and resources should improve clinical outcomes and efficiency longterm. In the interim, it is important to note that PM demonstrates the continuous aspect of clinical care, particularly for trainees who have strict guidelines defining clinical care for the experiences to count toward eligibility for licensure. Additionally, PM results in trainees who are making decisions with VA patients and are more efficiently providing and supporting patient care. Therefore, it is critical to secure important resources, such as provider time for conducting PM.

Data Access

No single data system in VA covers the broad range of topics covered in the PM sessions, and not all trainees have their own assigned panels. For example, health professions students are not assigned a panel of patients. While they do not have access to panel data such as those generated by Primary Care Almanac in VSSC (a data source in the VA Support Service Center database),the Seattle CoEPCE data manager pulls a set of patient data from the students’ paired faculty preceptors’ panels for review. Thus they learn PM principles and strategies for improving patient care via PM as part of the unique VA longitudinal clinic experience and the opportunity to learn from a multidisciplinary team that is not available at other clinical sites. Postgraduate NP residents in CoEPCE training have their own panels of patients and thus the ability to directly access their panel performance data.

Success Factors

A key success factor includes CoEPCE faculty’s ability to develop and operationalize a panel management model that simultaneously aligns with the educational goals of an interprofessional education training program and supports VA adoption of the medical home or patient aligned care teams (PACT). The CoEPCE contributes staff expertise in accessing and reporting patient data, accessing appropriate teaching space, managing panels of patients with chronic diseases, and facilitating a team-based approach to care. Additionally, the CoEPCE brand is helpful for getting buy-in from the clinical and academic stakeholders necessary for moving PM forward.

Colocating CoEPCE trainees and faculty in the primary care clinic promotes team identity around the RN care managers and facilitated communications with non-CoEPCE clinical teams that have trainees from other professions. RN care managers serve as the locus of highquality PM since they share patient panels with the trainees and already track admissions, ED visits, and numerous chronic health care metrics. RN care managers offer a level of insight into chronic disease that other providers may not possess, such as the specific details on medication adherence and the impact of adverse effects (AEs) for that particular patient. RN care managers are able to teach about their team role and responsibilities, strengthening the model.

PM is an opportunity to expand CoEPCE interprofessional education capacity by creating colocation of different trainee and faculty professions during the PM sessions; the sharing of data with trainees; and sharing and reflecting on data, strengthening communications between professions and within the PACT. The Seattle CoEPCE now has systems in place that allow the RN care manager to send notes to a physician and DNP resident, and the resident is expected to respond. In addition, the PM approach provides experience with analyzing data to improve care in an interprofessional team setting, which is a requirement of the Accreditation Council for Graduate Medical Education.

Interprofessional Collaboration

PM sessions are intentionally designed to improve communication among team members and foster a team approach to care. PM sessions provide an opportunity for trainees and clinician faculty to be together and learn about each profession’s perspectives. For example, early in the process physician and DNP trainees learn about the importance of clinical pharmacists to the team who prescribe and make medication adjustments within their scope of practice as well as the importance of making appropriate pharmacy referrals. Additionally, the RN care manager and clinical pharmacy specialists who serve as faculty in the CoEPCE provide pertinent information on individual patients, increasing integration with the PACT. Finally, there is anecdotal evidence that faculty also are learning more about interprofessional education and expanding their own skills.

Clinical Performance

CoEPCE trainees, non-CoEPCE physician residents, and CoEPCE faculty participants regularly receive patient data with which they can proactively develop or amend a treatment plan between visits. PM has resulted in improved data sharing with providers. Instead of once a year, providers and clinic staff now receive patient data monthly on chronic conditions from the clinic director. Trainees on ambulatory rotations are expected to review their panel data at least a half day per week. CoEPCE staff evaluate trainee likelihood to use PM and ability to identify patients who benefit from team-based care.

At the population level of chronic disease management, preliminary evidence demonstrates that primary care clinic patient panels are increasingly within target for DM and blood pressure measures, as assessed by periodic clinical reports to providers. Some of the PM topics have resulted in systems-level improvements, such as reducing unnecessary ED use for nonacute conditions and better opioid prescription monitoring. Moreover, PM supports everyone working at the top of his/her professional capability. For example, the RN care manager has the impetus to initiate DM education with a particular patient.

Since CoEPCE began teaching PM, the Seattle primary care clinic has committed to the regular access and review of data. This has encouraged the alignment of standards of care for chronic disease management so that all care providers are working toward the same benchmark goals.

Patient Outcomes

At the individual level, PM provide a mechanism to systemically review trainee panel patients with out-of-target clinical measures, and develop new care approaches involving interprofessional strategies and problem solving. PM also helps identify patients who have missed follow-up, reducing the risk that patients with chronic care needs will be lost to clinical engagement if they are not reminded or do not pursue appointments. The PM-trained PACT reaches out to patients who might not otherwise get care before the next clinic visit and provides new care plans. Second, patients have the benefit of a team that manages their health needs. For example, including the clinical pharmacists in the PM sessions ensures timely identification of medication interactions and the potential AEs. Additionally, PM contributes to the care coordination model by involving individuals on the primary care team who know the patient. These members review the patient’s data between visits and initiate team-based changes to the care plan to improve care. More team members connect with a patient, resulting in more intense care and quicker follow-up to determine the effectiveness of a treatment plan.

PM topics have spun off QI projects resulting in new clinic processes and programs, including processes for managing wounds in primary care and to assure timely post-ED visit follow-ups. Areas for expansion include a follow-up QI project to reduce nonacute ED visits by patients on the homeless PACT panel and interventions for better management of care for women veterans with mental health needs. PM also has extended to non-Co- EPCE teams and to other clinic activities, such as strengthening huddles of team members specifically related to panel data and addressing selected patient cases between visits. Pharmacy residents and faculty are more involved in reviewing the panel before patients are seen to review medication lists and identify duplications.

The Future

Under stage 2 of the program, the Seattle CoEPCE intends to lead in the creation of a PM toolkit as well as a data access guide that will allow VA facilities with limited data management expertise to access chronic disease metrics. Second, the CoEPCE will continue its dissemination efforts locally to other residents in the internal medicine residency program in all of its continuity clinics. Additionally, there is high interest by DNP training programs to expand and export longitudinal training experience PM curriculum to non-VA based students.

The viscous homemade children’s plaything known as “slime” has been associated with allergic, as well as irritant, contact dermatitis of the hands thanks to an array of possible compounds with which it can be made, according to a case report in Pediatric Dermatology. The report details many possible compounds causing the dermatitis reactions seen by health care professionals.

In the case, which was reported by L. Elizabeth Anderson, MD, of the Children’s Hospital of Philadelphia and colleagues, an 11-year-old girl with a history of atopic dermatitis presented with hand dermatitis that was suspected to be related to playing with slime. After her dermatitis failed to respond to strong topical steroids, she was referred for patch testing, with positivity for methylchloroisothiazolinone/methylisothiazolinone (MCI/MI). After all contact with any products containing MCI/MI was eliminated, her hand dermatitis cleared, and bodywide atopic dermatitis improved some as well.

MCI/MI and MI are among the most commonly suspected culprits in cases of slime-related contact dermatitis. Although most cases are irritant contact dermatitis, some are allergic and can be detected using patch tests. MCI/MI is included in the T.R.U.E. Test, but according to the case report, 37% of patients with allergy to MI alone will not have positive response with the T.R.U.E. Test because of the low concentrations of MI in that test. The authors of this case report also listed many other the potential allergens in popular slime recipes; however, many are not included in the T.R.U.E. Test.

“While the T.R.U.E. Test does not capture most of the potential allergens in popular slime recipes, the recently published Pediatric Baseline Patch Test Series by Yu et al. [Dermatitis. 2018;29:206-12] does and is recommended for use in patients suspected of having dermatitis secondary to slime,” Dr. Anderson and associates wrote.

cpalmer@mdedge.com

SOURCE: Anderson LE et al. Pediatr Dermatol. 2019 Mar 13. doi: 10.1111/pde.13792.

The viscous homemade children’s plaything known as “slime” has been associated with allergic, as well as irritant, contact dermatitis of the hands thanks to an array of possible compounds with which it can be made, according to a case report in Pediatric Dermatology. The report details many possible compounds causing the dermatitis reactions seen by health care professionals.

In the case, which was reported by L. Elizabeth Anderson, MD, of the Children’s Hospital of Philadelphia and colleagues, an 11-year-old girl with a history of atopic dermatitis presented with hand dermatitis that was suspected to be related to playing with slime. After her dermatitis failed to respond to strong topical steroids, she was referred for patch testing, with positivity for methylchloroisothiazolinone/methylisothiazolinone (MCI/MI). After all contact with any products containing MCI/MI was eliminated, her hand dermatitis cleared, and bodywide atopic dermatitis improved some as well.

MCI/MI and MI are among the most commonly suspected culprits in cases of slime-related contact dermatitis. Although most cases are irritant contact dermatitis, some are allergic and can be detected using patch tests. MCI/MI is included in the T.R.U.E. Test, but according to the case report, 37% of patients with allergy to MI alone will not have positive response with the T.R.U.E. Test because of the low concentrations of MI in that test. The authors of this case report also listed many other the potential allergens in popular slime recipes; however, many are not included in the T.R.U.E. Test.

“While the T.R.U.E. Test does not capture most of the potential allergens in popular slime recipes, the recently published Pediatric Baseline Patch Test Series by Yu et al. [Dermatitis. 2018;29:206-12] does and is recommended for use in patients suspected of having dermatitis secondary to slime,” Dr. Anderson and associates wrote.

cpalmer@mdedge.com

SOURCE: Anderson LE et al. Pediatr Dermatol. 2019 Mar 13. doi: 10.1111/pde.13792.

The viscous homemade children’s plaything known as “slime” has been associated with allergic, as well as irritant, contact dermatitis of the hands thanks to an array of possible compounds with which it can be made, according to a case report in Pediatric Dermatology. The report details many possible compounds causing the dermatitis reactions seen by health care professionals.

In the case, which was reported by L. Elizabeth Anderson, MD, of the Children’s Hospital of Philadelphia and colleagues, an 11-year-old girl with a history of atopic dermatitis presented with hand dermatitis that was suspected to be related to playing with slime. After her dermatitis failed to respond to strong topical steroids, she was referred for patch testing, with positivity for methylchloroisothiazolinone/methylisothiazolinone (MCI/MI). After all contact with any products containing MCI/MI was eliminated, her hand dermatitis cleared, and bodywide atopic dermatitis improved some as well.

MCI/MI and MI are among the most commonly suspected culprits in cases of slime-related contact dermatitis. Although most cases are irritant contact dermatitis, some are allergic and can be detected using patch tests. MCI/MI is included in the T.R.U.E. Test, but according to the case report, 37% of patients with allergy to MI alone will not have positive response with the T.R.U.E. Test because of the low concentrations of MI in that test. The authors of this case report also listed many other the potential allergens in popular slime recipes; however, many are not included in the T.R.U.E. Test.

“While the T.R.U.E. Test does not capture most of the potential allergens in popular slime recipes, the recently published Pediatric Baseline Patch Test Series by Yu et al. [Dermatitis. 2018;29:206-12] does and is recommended for use in patients suspected of having dermatitis secondary to slime,” Dr. Anderson and associates wrote.

cpalmer@mdedge.com

SOURCE: Anderson LE et al. Pediatr Dermatol. 2019 Mar 13. doi: 10.1111/pde.13792.

A potent oral inhibitor of acetyl-coenzyme-A carboxylase approximately halved the production of facial sebum, most of which arises from de novo lipogenesis, researchers reported.

The production of sebum triglycerides, wax esters, and free fatty acids all depend on local flux through this de novo lipogenesis (DNL) pathway in sebocytes, explained William P. Esler, PhD, and associates. Oral treatment with the investigational agent PF-05175157, a potent inhibitor of acetyl-coenzyme-A carboxylase (ACC) 1 and 2, reduced levels of these sebum components by about 66%, but did not affect levels of compounds that do not depend on the DNL pathway. The results of their mechanistic studies “identify sebocyte DNL as a pathway of importance in the biology of human skin and in the pathogenesis of acne vulgaris,” the researchers wrote in Science Translational Medicine. “Moreover, the observed dependence of human sebum production on local DNL flux and the effectiveness of DNL inhibition by an ACC inhibitor to suppress sebum production in humans indicate that clinical evaluation of this pathway for the treatment of acne may be warranted.”

Sebum helps moisturize and protect human skin, but increased production is linked to acne vulgaris severity. While sebaceous glands contain ACC and undergo DNL, the role of this pathway in sebum production relative to the recycling of circulating lipids was unknown. For the study, Dr. Esler of Pfizer Global Research and Development in Cambridge, Mass., and associates administered heavy water to 22 healthy volunteers to measure how much stable isotope was incorporated into newly synthesized fatty acids in sebocytes. They found that most skin sebum originated from local flux through the DNL pathway, including 80% of sebum palmitate and more than 80% of sebum sapienate. Furthermore, compared with 10 individuals with acne-free skin, 9 patients with acne vulgaris had about 20% greater sebum production and DNL pathway flux.


Oral therapy for 2 weeks with the ACC inhibitor (200 mg twice daily) was well tolerated and reduced baseline sebum production by 49% when administered to 10 healthy volunteers, the investigators wrote. This effect was not observed in a small placebo comparator group. Importantly, studies of hamsters and guinea pigs failed to implicate the DNL pathway in sebum production, even though these animals have been widely used to model sebum production in humans.

The researchers recommended studying the effects of ACC inhibition in patients with acne vulgaris, the effects of topical ACC inhibition on sebum production, and whether DNL pathway inhibition reduces the number and severity of acne lesions.

Pfizer provided funding; Dr. Esler and 12 coinvestigators are Pfizer employees and stockholders. Two additional coinvestigators are former Pfizer employees while three are current or prior scientific consultants for Pfizer.

SOURCE: Esler WP et al. Sci Transl Med. 2019 May 15. doi: 10.1126/scitranslmed.aau8465.
 

A potent oral inhibitor of acetyl-coenzyme-A carboxylase approximately halved the production of facial sebum, most of which arises from de novo lipogenesis, researchers reported.

The production of sebum triglycerides, wax esters, and free fatty acids all depend on local flux through this de novo lipogenesis (DNL) pathway in sebocytes, explained William P. Esler, PhD, and associates. Oral treatment with the investigational agent PF-05175157, a potent inhibitor of acetyl-coenzyme-A carboxylase (ACC) 1 and 2, reduced levels of these sebum components by about 66%, but did not affect levels of compounds that do not depend on the DNL pathway. The results of their mechanistic studies “identify sebocyte DNL as a pathway of importance in the biology of human skin and in the pathogenesis of acne vulgaris,” the researchers wrote in Science Translational Medicine. “Moreover, the observed dependence of human sebum production on local DNL flux and the effectiveness of DNL inhibition by an ACC inhibitor to suppress sebum production in humans indicate that clinical evaluation of this pathway for the treatment of acne may be warranted.”

Sebum helps moisturize and protect human skin, but increased production is linked to acne vulgaris severity. While sebaceous glands contain ACC and undergo DNL, the role of this pathway in sebum production relative to the recycling of circulating lipids was unknown. For the study, Dr. Esler of Pfizer Global Research and Development in Cambridge, Mass., and associates administered heavy water to 22 healthy volunteers to measure how much stable isotope was incorporated into newly synthesized fatty acids in sebocytes. They found that most skin sebum originated from local flux through the DNL pathway, including 80% of sebum palmitate and more than 80% of sebum sapienate. Furthermore, compared with 10 individuals with acne-free skin, 9 patients with acne vulgaris had about 20% greater sebum production and DNL pathway flux.


Oral therapy for 2 weeks with the ACC inhibitor (200 mg twice daily) was well tolerated and reduced baseline sebum production by 49% when administered to 10 healthy volunteers, the investigators wrote. This effect was not observed in a small placebo comparator group. Importantly, studies of hamsters and guinea pigs failed to implicate the DNL pathway in sebum production, even though these animals have been widely used to model sebum production in humans.

The researchers recommended studying the effects of ACC inhibition in patients with acne vulgaris, the effects of topical ACC inhibition on sebum production, and whether DNL pathway inhibition reduces the number and severity of acne lesions.

Pfizer provided funding; Dr. Esler and 12 coinvestigators are Pfizer employees and stockholders. Two additional coinvestigators are former Pfizer employees while three are current or prior scientific consultants for Pfizer.

SOURCE: Esler WP et al. Sci Transl Med. 2019 May 15. doi: 10.1126/scitranslmed.aau8465.
 

A potent oral inhibitor of acetyl-coenzyme-A carboxylase approximately halved the production of facial sebum, most of which arises from de novo lipogenesis, researchers reported.

The production of sebum triglycerides, wax esters, and free fatty acids all depend on local flux through this de novo lipogenesis (DNL) pathway in sebocytes, explained William P. Esler, PhD, and associates. Oral treatment with the investigational agent PF-05175157, a potent inhibitor of acetyl-coenzyme-A carboxylase (ACC) 1 and 2, reduced levels of these sebum components by about 66%, but did not affect levels of compounds that do not depend on the DNL pathway. The results of their mechanistic studies “identify sebocyte DNL as a pathway of importance in the biology of human skin and in the pathogenesis of acne vulgaris,” the researchers wrote in Science Translational Medicine. “Moreover, the observed dependence of human sebum production on local DNL flux and the effectiveness of DNL inhibition by an ACC inhibitor to suppress sebum production in humans indicate that clinical evaluation of this pathway for the treatment of acne may be warranted.”

Sebum helps moisturize and protect human skin, but increased production is linked to acne vulgaris severity. While sebaceous glands contain ACC and undergo DNL, the role of this pathway in sebum production relative to the recycling of circulating lipids was unknown. For the study, Dr. Esler of Pfizer Global Research and Development in Cambridge, Mass., and associates administered heavy water to 22 healthy volunteers to measure how much stable isotope was incorporated into newly synthesized fatty acids in sebocytes. They found that most skin sebum originated from local flux through the DNL pathway, including 80% of sebum palmitate and more than 80% of sebum sapienate. Furthermore, compared with 10 individuals with acne-free skin, 9 patients with acne vulgaris had about 20% greater sebum production and DNL pathway flux.


Oral therapy for 2 weeks with the ACC inhibitor (200 mg twice daily) was well tolerated and reduced baseline sebum production by 49% when administered to 10 healthy volunteers, the investigators wrote. This effect was not observed in a small placebo comparator group. Importantly, studies of hamsters and guinea pigs failed to implicate the DNL pathway in sebum production, even though these animals have been widely used to model sebum production in humans.

The researchers recommended studying the effects of ACC inhibition in patients with acne vulgaris, the effects of topical ACC inhibition on sebum production, and whether DNL pathway inhibition reduces the number and severity of acne lesions.

Pfizer provided funding; Dr. Esler and 12 coinvestigators are Pfizer employees and stockholders. Two additional coinvestigators are former Pfizer employees while three are current or prior scientific consultants for Pfizer.

SOURCE: Esler WP et al. Sci Transl Med. 2019 May 15. doi: 10.1126/scitranslmed.aau8465.
 

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – A “surprisingly low” prevalence of protective antibodies against measles is present in adolescents and adults living with HIV infection despite their prior vaccination against the resurgent disease, Raquel M. Simakawa, MD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Bruce Jancin/MDedge News

“With the present concern about the global reemergence of measles, we should consider measuring measles antibodies in people living with HIV, especially those who acquired the infection vertically, and then revaccinating those with low titers,” said Dr. Simakawa of the Federal University of São Paolo.

She presented interim findings of an ongoing study of the measles immunologic status of persons living with HIV, which for this analysis included 57 patients who acquired HIV from their mother via vertical transmission and 24 with horizontally acquired HIV. The vertical-transmission group was significantly younger, with a median age of 20 years, compared with 31 years in the horizontal group, who were diagnosed with HIV infection at an average age of 24 years. The vast majority of subjects were on combination antiretroviral therapy. No detectable HIV viral load had been present for a median of 70 months in the vertical group and 25 months in the horizontal group.

Only a mere 7% of the vertical transmission group had protective levels of measles IgG antibodies as measured by enzyme-linked immunosorbent assay, as did 29% of the horizontal group. The likely explanation for the higher rate of protection in the horizontal group, she said, is that they received their routine measles vaccination before they acquired HIV infection, and some of them didn’t lose their protective antibodies during their immune system’s fight against HIV infection.

Session chair Nico G. Hartwig, MD, of Franciscus Hospital in Rotterdam, the Netherlands, posed a question: Given the sky-high rate of measles seronegativity status among the vertically transmitted HIV-positive group – the patient population pediatricians focus on – why bother to measure their measles antibody level? Why not just give them all a measles booster?

Dr. Simakawa replied that that’s worth considering in routine clinical practice now that her study has shown that this group is more vulnerable to measles because of their poor response to immunization. But the study is ongoing, with larger numbers of patients to be enrolled. Also, in the second phase of the study, which will include a control group, measles IgG antibodies will be remeasured 1 month after administration of a new dose of measles vaccine.

She reported having no financial conflicts regarding this study, conducted free of commercial support.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – The first dose of rotavirus vaccine emerged as the strongest independent risk factor for intussusception in infancy, but breastfeeding had a protective effect in a German case-control study.

©Maxim Tupikov/iStockphoto.com

Two other potent risk factors for intussusception in children less than 1 year old were identified: a family history of intussusception, and an episode of gastroenteritis, Doris F. Oberle, MD, PhD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Dr. Oberle, of the Paul Ehrlich Institute in Langen, Germany, presented a retrospective study of 116 meticulously validated cases of intussusception in infancy treated at 19 German pediatric centers during 2010-2014 and 272 controls matched by birth month, sex, and location. A standardized interview was conducted with the parents of all study participants.

Rotavirus vaccine was added to the German national vaccination schedule in 2013. In a multivariate logistic regression analysis, the risk of intussusception was increased by 5.4-fold following the first dose of the vaccine, compared with nonrecipients. However, subsequent doses of rotavirus vaccine were not associated with any excess risk.

In addition, a family history of intussusception was linked to a 4.2-fold increased risk, while an episode of gastroenteritis during the first year of life was associated with a 4.7-fold elevated risk.

In a novel finding, breastfeeding was independently associated with a 44% reduction in the risk of intussusception, compared with that of bottle-fed babies.

The most common presenting signs and symptoms of intussusception were vomiting, abdominal pain, hematochezia, pallor, and reduced appetite, each present in at least half of affected infants.

Dr. Oberle reported having no financial conflicts regarding her study, supported by the Paul Ehrlich Institute.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – The first dose of rotavirus vaccine emerged as the strongest independent risk factor for intussusception in infancy, but breastfeeding had a protective effect in a German case-control study.

©Maxim Tupikov/iStockphoto.com

Two other potent risk factors for intussusception in children less than 1 year old were identified: a family history of intussusception, and an episode of gastroenteritis, Doris F. Oberle, MD, PhD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Dr. Oberle, of the Paul Ehrlich Institute in Langen, Germany, presented a retrospective study of 116 meticulously validated cases of intussusception in infancy treated at 19 German pediatric centers during 2010-2014 and 272 controls matched by birth month, sex, and location. A standardized interview was conducted with the parents of all study participants.

Rotavirus vaccine was added to the German national vaccination schedule in 2013. In a multivariate logistic regression analysis, the risk of intussusception was increased by 5.4-fold following the first dose of the vaccine, compared with nonrecipients. However, subsequent doses of rotavirus vaccine were not associated with any excess risk.

In addition, a family history of intussusception was linked to a 4.2-fold increased risk, while an episode of gastroenteritis during the first year of life was associated with a 4.7-fold elevated risk.

In a novel finding, breastfeeding was independently associated with a 44% reduction in the risk of intussusception, compared with that of bottle-fed babies.

The most common presenting signs and symptoms of intussusception were vomiting, abdominal pain, hematochezia, pallor, and reduced appetite, each present in at least half of affected infants.

Dr. Oberle reported having no financial conflicts regarding her study, supported by the Paul Ehrlich Institute.

bjancin@mdedge.com

LJUBLJANA, SLOVENIA – The first dose of rotavirus vaccine emerged as the strongest independent risk factor for intussusception in infancy, but breastfeeding had a protective effect in a German case-control study.

©Maxim Tupikov/iStockphoto.com

Two other potent risk factors for intussusception in children less than 1 year old were identified: a family history of intussusception, and an episode of gastroenteritis, Doris F. Oberle, MD, PhD, reported at the annual meeting of the European Society for Paediatric Infectious Diseases.

Dr. Oberle, of the Paul Ehrlich Institute in Langen, Germany, presented a retrospective study of 116 meticulously validated cases of intussusception in infancy treated at 19 German pediatric centers during 2010-2014 and 272 controls matched by birth month, sex, and location. A standardized interview was conducted with the parents of all study participants.

Rotavirus vaccine was added to the German national vaccination schedule in 2013. In a multivariate logistic regression analysis, the risk of intussusception was increased by 5.4-fold following the first dose of the vaccine, compared with nonrecipients. However, subsequent doses of rotavirus vaccine were not associated with any excess risk.

In addition, a family history of intussusception was linked to a 4.2-fold increased risk, while an episode of gastroenteritis during the first year of life was associated with a 4.7-fold elevated risk.

In a novel finding, breastfeeding was independently associated with a 44% reduction in the risk of intussusception, compared with that of bottle-fed babies.

The most common presenting signs and symptoms of intussusception were vomiting, abdominal pain, hematochezia, pallor, and reduced appetite, each present in at least half of affected infants.

Dr. Oberle reported having no financial conflicts regarding her study, supported by the Paul Ehrlich Institute.

bjancin@mdedge.com

From the Moffitt Cancer Center, Tampa, FL.

Abstract

• Objective: To outline the approach to selecting a tyrosine kinase inhibitor (TKI) for initial treatment of chronic myeloid leukemia (CML) and monitoring patients following initiation of therapy.
• Methods: Review of the literature and evidence-based guidelines.
• Results: The development and availability of TKIs has improved survival for patients diagnosed with CML. The life expectancy of patients diagnosed with chronic-phase CML (CP-CML) is similar to that of the general population, provided they receive appropriate TKI therapy and adhere to treatment. Selection of the most appropriate first-line TKI for newly diagnosed CP-CML requires incorporation of the patient’s baseline karyotype and Sokal or EURO risk score, and a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy. After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, close monitoring and follow-up are necessary to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses.
• Conclusion: Given the successful treatments available for patients with CML, it is crucial to identify patients with this diagnosis; ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing; and select the best therapy for each individual patient.

Keywords: chronic myeloid leukemia; CML; tyrosine kinase inhibitor; TKI; cancer; BCR-ABL protein.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2)), resulting in the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase.¹ BCR-ABL has constitutive tyrosine kinase activity that promotes growth, replication, and survival of hematopoietic cells through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

Typical treatment for CML involves lifelong use of oral BCR-ABL tyrosine kinase inhibitors (TKIs). Currently, 5 TKIs have regulatory approval for treatment of this disease. The advent of TKIs, a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with chronic-phase CML (CP-CML) now have a life expectancy that is similar to that of the general population, as long as they receive appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML; ensure they receive a complete, appropriate diagnostic workup; and select the best therapy for each patient.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed CP-CML has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

 

 

Diagnosis

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the white blood cell differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

Testing

Bone marrow biopsy. There are 3 distinct phases of CML: CP, accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

Diagnostic criteria. The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of 1 of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100,000/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosome abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

PCR assay. The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate or high risk scores compared to those with a low risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Monitoring Response to Therapy

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of CML patients relies on close monitoring and follow-up to ensure they are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²⁰

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a complete cytogenetic response (CCyR) implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²¹

 

 

Molecular Response

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,22 As noted, the IS has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,23 Molecular responses are based on a log reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that, if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁴ A value of 1% IS is approximately equivalent to a CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival (PFS), and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁴ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,22 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,25

Selecting First-line TKI Therapy

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues in order to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy.

 

 

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein’s tyrosine kinase activity.²⁶

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon alfa (IFNa) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNa plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to AP or BP, and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.²¹ The long-term follow-up of the IRIS trial reported an 83% estimated 10-year OS and 79% estimated event-free survival for patients on the imatinib arm of this study.¹⁵ The cumulative rate of CCyR was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a MMR and 63.2% had a MR4.5, suggesting durable, deep molecular responses for many patients. The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.²⁷

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib, followed by a switch to nilotinib in those failing to achieve desired milestones, could be an effective strategy for managing newly diagnosed CP-CML.²⁸

Toxicity. The standard starting dose of imatinib in CP-CML patients is 400 mg. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.²⁹ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.¹⁹

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^15,29 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.¹⁹

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib’s ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial, which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year PFS was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.³⁰

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) trial. More patients on the dasatinib arm achieved an EMR of BCR-ABL1 transcripts ≤ 10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33% with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).¹⁶ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity. Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.¹⁶ Depending on the severity, pleural effusion may be treated with diuretics, dose interruption, and, in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.¹⁹ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^16,19 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).¹⁶ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.³¹

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a MCyR and 45% achieving a CCyR. With a median follow-up time of 4 years, the OS was 78%.³² 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.³³ Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹⁷ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹⁷

Toxicity. Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.³³ Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily, as compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.³³

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.¹⁹

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.¹⁹

Bosutinib

Bosutinib is a second-generation BCR-ABL TKI with activity against the Src family of kinases; it was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CCyR, and the OS was 87%.³⁴

Five-year follow-up from the phase 1/2 clinical trial that studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.³⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response, compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).³⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁸

Toxicity. On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁸

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁸

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤ 2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal are consistent with Hy’s law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade 3 or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.¹⁹

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.¹⁹

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs, including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.³⁷ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.³⁷ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity. In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events, including fatal myocardial infarctions and cerebrovascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥ 90% of responders maintained their response for up to 40 months.³⁸ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.³⁸

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. If an occlusive event occurs, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, or smoking history, is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option, resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.¹⁹

If ponatinib-induced transaminitis greater than 3 times the upper limit of normal occurs, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.¹⁹

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.¹⁹

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life expectancy that is similar to that of the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Corresponding author: Kendra Sweet, MD, MS, Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Financial disclosures: Dr. Sweet has served on the Advisory Board and Speakers Bureau of Novartis, Bristol-Meyers Squibb, Ariad Pharmaceuticals, and Pfizer, and has served as a consultant to Pfizer.

From the Moffitt Cancer Center, Tampa, FL.

Abstract

• Objective: To outline the approach to selecting a tyrosine kinase inhibitor (TKI) for initial treatment of chronic myeloid leukemia (CML) and monitoring patients following initiation of therapy.
• Methods: Review of the literature and evidence-based guidelines.
• Results: The development and availability of TKIs has improved survival for patients diagnosed with CML. The life expectancy of patients diagnosed with chronic-phase CML (CP-CML) is similar to that of the general population, provided they receive appropriate TKI therapy and adhere to treatment. Selection of the most appropriate first-line TKI for newly diagnosed CP-CML requires incorporation of the patient’s baseline karyotype and Sokal or EURO risk score, and a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy. After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, close monitoring and follow-up are necessary to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses.
• Conclusion: Given the successful treatments available for patients with CML, it is crucial to identify patients with this diagnosis; ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing; and select the best therapy for each individual patient.

Keywords: chronic myeloid leukemia; CML; tyrosine kinase inhibitor; TKI; cancer; BCR-ABL protein.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2)), resulting in the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase.¹ BCR-ABL has constitutive tyrosine kinase activity that promotes growth, replication, and survival of hematopoietic cells through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

Typical treatment for CML involves lifelong use of oral BCR-ABL tyrosine kinase inhibitors (TKIs). Currently, 5 TKIs have regulatory approval for treatment of this disease. The advent of TKIs, a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with chronic-phase CML (CP-CML) now have a life expectancy that is similar to that of the general population, as long as they receive appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML; ensure they receive a complete, appropriate diagnostic workup; and select the best therapy for each patient.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed CP-CML has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

 

 

Diagnosis

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the white blood cell differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

Testing

Bone marrow biopsy. There are 3 distinct phases of CML: CP, accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

Diagnostic criteria. The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of 1 of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100,000/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosome abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

PCR assay. The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate or high risk scores compared to those with a low risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Monitoring Response to Therapy

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of CML patients relies on close monitoring and follow-up to ensure they are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²⁰

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a complete cytogenetic response (CCyR) implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²¹

 

 

Molecular Response

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,22 As noted, the IS has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,23 Molecular responses are based on a log reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that, if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁴ A value of 1% IS is approximately equivalent to a CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival (PFS), and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁴ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,22 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,25

Selecting First-line TKI Therapy

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues in order to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy.

 

 

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein’s tyrosine kinase activity.²⁶

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon alfa (IFNa) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNa plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to AP or BP, and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.²¹ The long-term follow-up of the IRIS trial reported an 83% estimated 10-year OS and 79% estimated event-free survival for patients on the imatinib arm of this study.¹⁵ The cumulative rate of CCyR was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a MMR and 63.2% had a MR4.5, suggesting durable, deep molecular responses for many patients. The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.²⁷

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib, followed by a switch to nilotinib in those failing to achieve desired milestones, could be an effective strategy for managing newly diagnosed CP-CML.²⁸

Toxicity. The standard starting dose of imatinib in CP-CML patients is 400 mg. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.²⁹ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.¹⁹

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^15,29 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.¹⁹

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib’s ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial, which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year PFS was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.³⁰

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) trial. More patients on the dasatinib arm achieved an EMR of BCR-ABL1 transcripts ≤ 10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33% with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).¹⁶ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity. Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.¹⁶ Depending on the severity, pleural effusion may be treated with diuretics, dose interruption, and, in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.¹⁹ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^16,19 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).¹⁶ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.³¹

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a MCyR and 45% achieving a CCyR. With a median follow-up time of 4 years, the OS was 78%.³² 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.³³ Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹⁷ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹⁷

Toxicity. Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.³³ Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily, as compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.³³

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.¹⁹

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.¹⁹

Bosutinib

Bosutinib is a second-generation BCR-ABL TKI with activity against the Src family of kinases; it was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CCyR, and the OS was 87%.³⁴

Five-year follow-up from the phase 1/2 clinical trial that studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.³⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response, compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).³⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁸

Toxicity. On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁸

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁸

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤ 2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal are consistent with Hy’s law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade 3 or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.¹⁹

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.¹⁹

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs, including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.³⁷ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.³⁷ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity. In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events, including fatal myocardial infarctions and cerebrovascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥ 90% of responders maintained their response for up to 40 months.³⁸ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.³⁸

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. If an occlusive event occurs, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, or smoking history, is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option, resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.¹⁹

If ponatinib-induced transaminitis greater than 3 times the upper limit of normal occurs, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.¹⁹

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.¹⁹

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life expectancy that is similar to that of the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Corresponding author: Kendra Sweet, MD, MS, Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Financial disclosures: Dr. Sweet has served on the Advisory Board and Speakers Bureau of Novartis, Bristol-Meyers Squibb, Ariad Pharmaceuticals, and Pfizer, and has served as a consultant to Pfizer.

From the Moffitt Cancer Center, Tampa, FL.

Abstract

• Objective: To outline the approach to selecting a tyrosine kinase inhibitor (TKI) for initial treatment of chronic myeloid leukemia (CML) and monitoring patients following initiation of therapy.
• Methods: Review of the literature and evidence-based guidelines.
• Results: The development and availability of TKIs has improved survival for patients diagnosed with CML. The life expectancy of patients diagnosed with chronic-phase CML (CP-CML) is similar to that of the general population, provided they receive appropriate TKI therapy and adhere to treatment. Selection of the most appropriate first-line TKI for newly diagnosed CP-CML requires incorporation of the patient’s baseline karyotype and Sokal or EURO risk score, and a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy. After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, close monitoring and follow-up are necessary to ensure patients are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses.
• Conclusion: Given the successful treatments available for patients with CML, it is crucial to identify patients with this diagnosis; ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing; and select the best therapy for each individual patient.

Keywords: chronic myeloid leukemia; CML; tyrosine kinase inhibitor; TKI; cancer; BCR-ABL protein.

Chronic myeloid leukemia (CML) is a rare myeloproliferative neoplasm that is characterized by the presence of the Philadelphia (Ph) chromosome and uninhibited expansion of bone marrow stem cells. The Ph chromosome arises from a reciprocal translocation between the Abelson (ABL) region on chromosome 9 and the breakpoint cluster region (BCR) of chromosome 22 (t(9;22)(q34;q11.2)), resulting in the BCR-ABL1 fusion gene and its protein product, BCR-ABL tyrosine kinase.¹ BCR-ABL has constitutive tyrosine kinase activity that promotes growth, replication, and survival of hematopoietic cells through downstream pathways, which is the driving factor in the pathogenesis of CML.¹

CML is divided into 3 phases based on the number of myeloblasts observed in the blood or bone marrow: chronic, accelerated, and blast. Most cases of CML are diagnosed in the chronic phase (CP), which is marked by proliferation of primarily the myeloid element.

Typical treatment for CML involves lifelong use of oral BCR-ABL tyrosine kinase inhibitors (TKIs). Currently, 5 TKIs have regulatory approval for treatment of this disease. The advent of TKIs, a class of small molecules targeting the tyrosine kinases, particularly the BCR-ABL tyrosine kinase, led to rapid changes in the management of CML and improved survival for patients. Patients diagnosed with chronic-phase CML (CP-CML) now have a life expectancy that is similar to that of the general population, as long as they receive appropriate TKI therapy and adhere to treatment. As such, it is crucial to identify patients with CML; ensure they receive a complete, appropriate diagnostic workup; and select the best therapy for each patient.

Epidemiology

According to SEER data estimates, 8430 new cases of CML were diagnosed in the United States in 2018. CML is a disease of older adults, with a median age of 65 years at diagnosis, and there is a slight male predominance. Between 2011 and 2015, the number of new CML cases was 1.8 per 100,000 persons. The median overall survival (OS) in patients with newly diagnosed CP-CML has not been reached.² Given the effective treatments available for managing CML, it is estimated that the prevalence of CML in the United States will plateau at 180,000 patients by 2050.³

 

 

Diagnosis

Clinical Features

The diagnosis of CML is often suspected based on an incidental finding of leukocytosis and, in some cases, thrombocytosis. In many cases, this is an incidental finding on routine blood work, but approximately 50% of patients will present with constitutional symptoms associated with the disease. Characteristic features of the white blood cell differential include left-shifted maturation with neutrophilia and immature circulating myeloid cells. Basophilia and eosinophilia are often present as well. Splenomegaly is a common sign, present in 50% to 90% of patients at diagnosis. In those patients with symptoms related to CML at diagnosis, the most common presentation includes increasing fatigue, fevers, night sweats, early satiety, and weight loss. The diagnosis is confirmed by cytogenetic studies showing the Ph chromosome abnormality, t(9; 22)(q3.4;q1.1), and/or reverse transcriptase polymerase chain reaction (PCR) showing BCR-ABL1 transcripts.

Testing

Bone marrow biopsy. There are 3 distinct phases of CML: CP, accelerated phase (AP), and blast phase (BP). Bone marrow biopsy and aspiration at diagnosis are mandatory in order to determine the phase of the disease at diagnosis. This distinction is based on the percentage of blasts, promyelocytes, and basophils present as well as the platelet count and presence or absence of extramedullary disease.⁴ The vast majority of patients at diagnosis have CML that is in the chronic phase. The typical appearance in CP-CML is a hypercellular marrow with granulocytic and occasionally megakaryocytic hyperplasia. In many cases, basophilia and/or eosinophilia are noted as well. Dysplasia is not a typical finding in CML.⁵ Bone marrow fibrosis can be seen in up to one-third of patients at diagnosis, and may indicate a slightly worse prognosis.⁶ Although a diagnosis of CML can be made without a bone marrow biopsy, complete staging and prognostication are only possible with information gained from this test, including baseline karyotype and confirmation of CP versus a more advanced phase of CML.

Diagnostic criteria. The criteria for diagnosing AP-CML has not been agreed upon by various groups, but the modified MD Anderson Cancer Center (MDACC) criteria are used in the majority of clinical trials evaluating the efficacy of TKIs in preventing progression to advanced phases of CML. MDACC criteria define AP-CML as the presence of 1 of the following: 15% to 29% blasts in the peripheral blood or bone marrow, ≥ 30% peripheral blasts plus promyelocytes, ≥ 20% basophils in the blood or bone marrow, platelet count ≤ 100,000/μL unrelated to therapy, and clonal cytogenetic evolution in Ph-positive metaphases (Table).⁷

The defining feature of CML is the presence of the Ph chromosome abnormality. In a small subset of patients, additional chromosome abnormalities (ACA) in the Ph-positive cells may be identified at diagnosis. Some reports indicate that the presence of “major route” ACA (trisomy 8, isochromosome 17q, a second Ph chromosome, or trisomy 19) at diagnosis may negatively impact prognosis, but other reports contradict these findings.^10,11

PCR assay. The typical BCR breakpoint in CML is the major breakpoint cluster region (M-BCR), which results in a 210-kDa protein (p210). Alternate breakpoints that are less frequently identified are the minor BCR (mBCR or p190), which is more commonly found in Ph-positive acute lymphoblastic leukemia (ALL), and the micro BCR (µBCR or p230), which is much less common and is often characterized by chronic neutrophilia.¹² Identifying which BCR-ABL1 transcript is present in each patient using qualitative PCR is crucial in order to ensure proper monitoring during treatment.

The most sensitive method for detecting BCR-ABL1 mRNA transcripts is the quantitative real-time PCR (RQ-PCR) assay, which is typically done on peripheral blood. RQ-PCR is capable of detecting a single CML cell in the presence of ≥ 100,000 normal cells. This test should be done during the initial diagnostic workup in order to confirm the presence of BCR-ABL1 transcripts, and it is used as a standard method for monitoring response to TKI therapy.¹³ The International Scale (IS) is a standardized approach to reporting RQ-PCR results that was developed to allow comparison of results across various laboratories and has become the gold standard for reporting BCR-ABL1 transcript values.¹⁴

Determining Risk Scores

Calculating a patient’s Sokal score or EURO risk score at diagnosis remains an important component of the diagnostic workup in CP-CML, as this information has prognostic and therapeutic implications (an online calculator is available through European LeukemiaNet [ELN]). The risk for disease progression to the accelerated or blast phases is higher in patients with intermediate or high risk scores compared to those with a low risk score at diagnosis. The risk of progression in intermediate- or high-risk patients is lower when a second-generation TKI (dasatinib, nilotinib, or bosutinib) is used as frontline therapy compared to imatinib, and therefore, the National Comprehensive Cancer Network (NCCN) CML Panel recommends starting with a second-generation TKI in these patients.^15-19

Monitoring Response to Therapy

After confirming a diagnosis of CML and selecting the most appropriate TKI for first-line therapy, the successful management of CML patients relies on close monitoring and follow-up to ensure they are meeting the desired treatment milestones. Responses in CML can be assessed based on hematologic parameters, cytogenetic results, and molecular responses. A complete hematologic response (CHR) implies complete normalization of peripheral blood counts (with the exception of TKI-induced cytopenias) and resolution of any palpable splenomegaly. The majority of patients will achieve a CHR within 4 to 6 weeks after initiating CML-directed therapy.²⁰

Cytogenetic Response

Cytogenetic responses are defined by the decrease in the number of Ph chromosome–positive metaphases when assessed on bone marrow cytogenetics. A partial cytogenetic response (PCyR) is defined as having 1% to 35% Ph-positive metaphases, a major cytogenetic response (MCyR) as having 0% to 35% Ph-positive metaphases, and a complete cytogenetic response (CCyR) implies that no Ph-positive metaphases are identified on bone marrow cytogenetics. An ideal response is the achievement of PCyR after 3 months on a TKI and a CCyR after 12 months on a TKI.²¹

 

 

Molecular Response

Once a patient has achieved a CCyR, monitoring their response to therapy can only be done using RQ-PCR to measure BCR-ABL1 transcripts in the peripheral blood. The NCCN and the ELN recommend monitoring RQ-PCR from the peripheral blood every 3 months in order to assess response to TKIs.^19,22 As noted, the IS has become the gold standard reporting system for all BCR-ABL1 transcript levels in the majority of laboratories worldwide.^14,23 Molecular responses are based on a log reduction in BCR-ABL1 transcripts from a standardized baseline. Many molecular responses can be correlated with cytogenetic responses such that, if reliable RQ-PCR testing is available, monitoring can be done using only peripheral blood RQ-PCR rather than repeat bone marrow biopsies. For example, an early molecular response (EMR) is defined as a RQ-PCR value of ≤ 10% IS, which is approximately equivalent to a PCyR.²⁴ A value of 1% IS is approximately equivalent to a CCyR. A major molecular response (MMR) is a ≥ 3-log reduction in BCR-ABL1 transcripts from baseline and is a value of ≤ 0.1% IS. Deeper levels of molecular response are best described by the log reduction in BCR-ABL1 transcripts, with a 4-log reduction denoted as MR4.0, a 4.5-log reduction as MR4.5, and so forth. Complete molecular response (CMR) is defined by the level of sensitivity of the RQ-PCR assay being used.¹⁴

The definition of relapsed disease in CML is dependent on the type of response the patient had previously achieved. Relapse could be the loss of a hematologic or cytogenetic response, but fluctuations in BCR-ABL1 transcripts on routine RQ-PCR do not necessarily indicate relapsed CML. A 1-log increase in the level of BCR-ABL1 transcripts with a concurrent loss of MMR should prompt a bone marrow biopsy in order to assess for the loss of CCyR, and thus a cytogenetic relapse; however, this loss of MMR does not define relapse in and of itself. In the setting of relapsed disease, testing should be done to look for possible ABL kinase domain mutations, and alternate therapy should be selected.¹⁹

Multiple reports have identified the prognostic relevance of achieving an EMR at 3 and 6 months after starting TKI therapy. Marin and colleagues reported that in 282 imatinib-treated patients, there was a significant improvement in 8-year OS, progression-free survival (PFS), and cumulative incidence of CCyR and CMR in patients who had BCR-ABL1 transcripts < 9.84% IS after 3 months on treatment.²⁴ This data highlights the importance of early molecular monitoring in order to ensure the best outcomes for patients with CP-CML.

The NCCN CML guidelines and ELN recommendations both agree that an ideal response after 3 months on a TKI is BCR-ABL1 transcripts < 10% IS, but treatment is not considered to be failing at this point if the patient marginally misses this milestone. After 6 months on treatment, an ideal response is considered BCR-ABL1 transcripts < 1%–10% IS. Ideally, patients will have BCR-ABL1 transcripts < 0.1%–1% IS by the time they complete 12 months of TKI therapy, suggesting that these patients have at least achieved a CCyR.^19,22 Even after patients achieve these early milestones, frequent monitoring by RQ-PCR is required to ensure that they are maintaining their response to treatment. This will help to ensure patient compliance with treatment and will also help to identify a select subset of patients who could potentially be considered for an attempt at TKI cessation (not discussed in detail here) after a minimum of 3 years on therapy.^19,25

Selecting First-line TKI Therapy

Selection of the most appropriate first-line TKI for newly diagnosed CP-CML patients requires incorporation of many patient-specific factors. These factors include baseline karyotype and confirmation of CP-CML through bone marrow biopsy, Sokal or EURO risk score, and a thorough patient history, including a clear understanding of the patient’s comorbidities. The adverse effect profile of all TKIs must be considered in conjunction with the patient’s ongoing medical issues in order to decrease the likelihood of worsening their current symptoms or causing a severe complication from TKI therapy.

 

 

Imatinib

The management of CML was revolutionized by the development and ultimate regulatory approval of imatinib mesylate in 2001. Imatinib was the first small-molecule cancer therapy developed and approved. It acts by binding to the adenosine triphosphate (ATP) binding site in the catalytic domain of BCR-ABL, thus inhibiting the oncoprotein’s tyrosine kinase activity.²⁶

The International Randomized Study of Interferon versus STI571 (IRIS) trial was a randomized phase 3 study that compared imatinib 400 mg daily to interferon alfa (IFNa) plus cytarabine. More than 1000 CP-CML patients were randomly assigned 1:1 to either imatinib or IFNa plus cytarabine and were assessed for event-free survival, hematologic and cytogenetic responses, freedom from progression to AP or BP, and toxicity. Imatinib was superior to the prior standard of care for all these outcomes.²¹ The long-term follow-up of the IRIS trial reported an 83% estimated 10-year OS and 79% estimated event-free survival for patients on the imatinib arm of this study.¹⁵ The cumulative rate of CCyR was 82.8%. Of the 204 imatinib-treated patients who could undergo a molecular response evaluation at 10 years, 93.1% had a MMR and 63.2% had a MR4.5, suggesting durable, deep molecular responses for many patients. The estimated 10-year rate of freedom from progression to AP or BP was 92.1%.

Higher doses of imatinib (600-800 mg daily) have been studied in an attempt to overcome resistance and improve cytogenetic and molecular response rates. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was a randomized phase 3 study that compared imatinib 800 mg daily to imatinib 400 mg daily. Although the 6-month assessments found increased rates of CCyR and a MMR in the higher-dose imatinib arm, these differences were no longer present at the 12-month assessment. Furthermore, the higher dose of imatinib led to a significantly higher incidence of grade 3/4 hematologic adverse events, and approximately 50% of patients on imatinib 800 mg daily required a dose reduction to less than 600 mg daily because of toxicity.²⁷

The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study used plasma trough levels of imatinib on day 22 of treatment with imatinib 600 mg daily to determine if patients should escalate the imatinib dose to 800 mg daily. In patients who did not meet molecular milestones at 3, 6, or 12 months, cohort 1 was dose escalated to imatinib 800 mg daily and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later, and cohort 2 was switched to nilotinib. At 2 years, 73% of patients achieved MMR and 34% achieved MR4.5, suggesting that initial treatment with higher-dose imatinib, followed by a switch to nilotinib in those failing to achieve desired milestones, could be an effective strategy for managing newly diagnosed CP-CML.²⁸

Toxicity. The standard starting dose of imatinib in CP-CML patients is 400 mg. The safety profile of imatinib has been very well established. In the IRIS trial, the most common adverse events (all grades in decreasing order of frequency) were peripheral and periorbital edema (60%), nausea (50%), muscle cramps (49%), musculoskeletal pain (47%), diarrhea (45%), rash (40%), fatigue (39%), abdominal pain (37%), headache (37%), and joint pain (31%). Grade 3/4 liver enzyme elevation can occur in 5% of patients.²⁹ In the event of severe liver toxicity or fluid retention, imatinib should be held until the event resolves. At that time, imatinib can be restarted if deemed appropriate, but this is dependent on the severity of the inciting event. Fluid retention can be managed by the use of supportive care, diuretics, imatinib dose reduction, dose interruption, or imatinib discontinuation if the fluid retention is severe. Muscle cramps can be managed by the use of calcium supplements or tonic water. Management of rash can include topical or systemic steroids, or in some cases imatinib dose reduction, interruption, or discontinuation.¹⁹

Grade 3/4 imatinib-induced hematologic toxicity is not uncommon, with 17% of patients experiencing neutropenia, 9% thrombocytopenia, and 4% anemia. These adverse events occurred most commonly during the first year of therapy, and the frequency decreased over time.^15,29 Depending on the degree of cytopenias, imatinib dosing should be interrupted until recovery of the absolute neutrophil count or platelet count, and can often be resumed at 400 mg daily. However, if cytopenias recur, imatinib should be held and subsequently restarted at 300 mg daily.¹⁹

Dasatinib

Dasatinib is a second-generation TKI that has regulatory approval for treatment of adult patients with newly diagnosed CP-CML or CP-CML in patients with resistance or intolerance to prior TKIs. In addition to dasatinib’s ability to inhibit ABL kinases, it is also known to be a potent inhibitor of Src family kinases. Dasatinib has shown efficacy in patients who have developed imatinib-resistant ABL kinase domain mutations.

Dasatinib was initially approved as second-line therapy in patients with resistance or intolerance to imatinib. This indication was based on the results of the phase 3 CA180-034 trial, which ultimately identified dasatinib 100 mg daily as the optimal dose. In this trial, 74% of patients enrolled had resistance to imatinib and the remainder were intolerant. The 7-year follow-up of patients randomized to dasatinib 100 mg (n = 167) daily indicated that 46% achieved MMR while on study. Of the 124 imatinib-resistant patients on dasatinib 100 mg daily, the 7-year PFS was 39% and OS was 63%. In the 43 imatinib-intolerant patients, the 7-year PFS was 51% and OS was 70%.³⁰

Dasatinib 100 mg daily was compared to imatinib 400 mg daily in newly diagnosed CP-CML patients in the randomized phase 3 DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) trial. More patients on the dasatinib arm achieved an EMR of BCR-ABL1 transcripts ≤ 10% IS after 3 months on treatment compared to imatinib (84% versus 64%). Furthermore, the 5-year follow-up reports that the cumulative incidence of MMR and MR4.5 in dasatinib-treated patients was 76% and 42%, and was 64% and 33% with imatinib (P = 0.0022 and P = 0.0251, respectively). Fewer patients treated with dasatinib progressed to AP or BP (4.6%) compared to imatinib (7.3%), but the estimated 5-year OS was similar between the 2 arms (91% for dasatinib versus 90% for imatinib).¹⁶ Regulatory approval for dasatinib as first-line therapy in newly diagnosed CML patients was based on results of the DASISION trial.

Toxicity. Most dasatinib-related toxicities are reported as grade 1 or grade 2, but grade 3/4 hematologic adverse events are fairly common. In the DASISION trial, grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 29%, 13%, and 22% of dasatinib-treated patients, respectively. Cytopenias can generally be managed with temporary dose interruptions or dose reductions.

During the 5-year follow-up of the DASISION trial, pleural effusions were reported in 28% of patients, most of which were grade 1/2. This occurred at a rate of approximately ≤ 8% per year, suggesting a stable incidence over time, and the effusions appear to be dose-dependent.¹⁶ Depending on the severity, pleural effusion may be treated with diuretics, dose interruption, and, in some instances, steroids or a thoracentesis. Typically, dasatinib can be restarted at 1 dose level lower than the previous dose once the effusion has resolved.¹⁹ Other, less common side effects of dasatinib include pulmonary hypertension (5% of patients), as well as abdominal pain, fluid retention, headaches, fatigue, musculoskeletal pain, rash, nausea, and diarrhea. Pulmonary hypertension is typically reversible after cessation of dasatinib, and thus dasatinib should be permanently discontinued once the diagnosis is confirmed. Fluid retention is often treated with diuretics and supportive care. Nausea and diarrhea are generally manageable and occur less frequently when dasatinib is taken with food and a large glass of water. Antiemetics and antidiarrheals can be used as needed. Troublesome rash can be best managed with topical or systemic steroids as well as possible dose reduction or dose interruption.^16,19 In the DASISION trial, adverse events led to therapy discontinuation more often in the dasatinib group than in the imatinib group (16% versus 7%).¹⁶ Bleeding, particularly in the setting of thrombocytopenia, has been reported in patients being treated with dasatinib as a result of the drug-induced reversible inhibition of platelet aggregation.³¹

Nilotinib

The structure of nilotinib is similar to that of imatinib; however, it has a markedly increased affinity for the ATP‐binding site on the BCR-ABL1 protein. It was initially given regulatory approval in the setting of imatinib failure. Nilotinib was studied at a dose of 400 mg twice daily in 321 patients who were imatinib-resistant or -intolerant. It proved to be highly effective at inducing cytogenetic remissions in the second-line setting, with 59% of patients achieving a MCyR and 45% achieving a CCyR. With a median follow-up time of 4 years, the OS was 78%.³² 

Nilotinib gained regulatory approval for use as a first-line TKI after completion of the randomized phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) trial. ENESTnd was a 3-arm study comparing nilotinib 300 mg twice daily versus nilotinib 400 mg twice daily versus imatinib 400 mg daily in newly diagnosed, previously untreated patients diagnosed with CP-CML. The primary endpoint of this clinical trial was rate of MMR at 12 months.³³ Nilotinib surpassed imatinib in this regard, with 44% of patients on nilotinib 300 mg twice daily achieving MMR at 12 months versus 43% of nilotinib 400 mg twice daily patients versus 22% of the imatinib-treated patients (P < 0.001 for both comparisons). Furthermore, the rate of CCyR by 12 months was significantly higher for both nilotinib arms compared with imatinib (80% for nilotinib 300 mg, 78% for nilotinib 400 mg, and 65% for imatinib) (P < 0.001).¹² Based on this data, nilotinib 300 mg twice daily was chosen as the standard dose of nilotinib in the first-line setting. After 5 years of follow-up on the ENESTnd study, there were fewer progressions to AP/BP CML in nilotinib-treated patients compared with imatinib. MMR was achieved in 77% of nilotinib 300 mg patients compared with 60.4% of patients on the imatinib arm. MR4.5 was also more common in patients treated with nilotinib 300 mg twice daily, with a rate of 53.5% at 5 years versus 31.4% in the imatinib arm.¹⁷ In spite of the deeper cytogenetic and molecular responses achieved with nilotinib, this did not translate into a significant improvement in OS. The 5-year OS rate was 93.7% in nilotinib 300 mg patients versus 91.7% in imatinib-treated patients, and this difference lacked statistical significance.¹⁷

Toxicity. Although some similarities exist between the toxicity profiles of nilotinib and imatinib, each drug has some distinct adverse events. On the ENESTnd trial, the rate of any grade 3/4 non-hematologic adverse event was fairly low; however, lower-grade toxicities were not uncommon. Patients treated with nilotinib 300 mg twice daily experienced rash (31%), headache (14%), pruritis (15%), and fatigue (11%) most commonly. The most frequently reported laboratory abnormalities included increased total bilirubin (53%), hypophosphatemia (32%), hyperglycemia (36%), elevated lipase (24%), increased alanine aminotransferase (ALT; 66%), and increased aspartate aminotransferase (AST; 40%). Any grade of neutropenia, thrombocytopenia, or anemia occurred at rates of 43%, 48%, and 38%, respectively.³³ Although nilotinib has a Black Box Warning from the US Food and Drug Administration for QT interval prolongation, no patients on the ENESTnd trial experienced a QT interval corrected for heart rate greater than 500 msec.¹²

More recent concerns have emerged regarding the potential for cardiovascular toxicity after long-term use of nilotinib. The 5-year update of ENESTnd reports cardiovascular events, including ischemic heart disease, ischemic cerebrovascular events, or peripheral arterial disease occurring in 7.5% of patients treated with nilotinib 300 mg twice daily, as compared with a rate of 2.1% in imatinib-treated patients. The frequency of these cardiovascular events increased linearly over time in both arms. Elevations in total cholesterol from baseline occurred in 27.6% of nilotinib patients compared with 3.9% of imatinib patients. Furthermore, clinically meaningful increases in low-density lipoprotein cholesterol and glycated hemoglobin occurred more frequently with nilotinib therapy.³³

Nilotinib should be taken on an empty stomach; therefore, patients should be made aware of the need to fast for 2 hours prior to each dose and 1 hour after each dose. Given the potential risk of QT interval prolongation, a baseline electrocardiogram (ECG) is recommended prior to initiating treatment to ensure the QT interval is within a normal range. A repeat ECG should be done approximately 7 days after nilotinib initiation to ensure no prolongation of the QT interval after starting. Close monitoring of potassium and magnesium levels is important to decrease the risk of cardiac arrhythmias, and concomitant use of drugs considered strong CYP3A4 inhibitors should be avoided.¹⁹

If the patient experiences any grade 3 or higher laboratory abnormalities, nilotinib should be held until resolution of the toxicity, and then restarted at a lower dose. Similarly, if patients develop significant neutropenia or thrombocytopenia, nilotinib doses should be interrupted until resolution of the cytopenias. At that point, nilotinib can be reinitiated at either the same or a lower dose. Rash can be managed by the use of topical or systemic steroids as well as potential dose reduction, interruption, or discontinuation.

Given the concerns for potential cardiovascular events with long-term use of nilotinib, caution is advised when prescribing it to any patient with a history of cardiovascular disease or peripheral arterial occlusive disease. At the first sign of new occlusive disease, nilotinib should be discontinued.¹⁹

Bosutinib

Bosutinib is a second-generation BCR-ABL TKI with activity against the Src family of kinases; it was initially approved to treat patients with CP-, AP-, or BP-CML after resistance or intolerance to imatinib. Long-term data has been reported from the phase 1/2 trial of bosutinib therapy in patients with CP-CML who developed resistance or intolerance to imatinib plus dasatinib and/or nilotinib. A total of 119 patients were included in the 4-year follow-up; 38 were resistant/intolerant to imatinib and resistant to dasatinib, 50 were resistant/intolerant to imatinib and intolerant to dasatinib, 26 were resistant/intolerant to imatinib and resistant to nilotinib, and 5 were resistant/intolerant to imatinib and intolerant to nilotinib or resistant/intolerant to dasatinib and nilotinib. Bosutinib 400 mg daily was studied in this setting. Of the 38 patients with imatinib resistance/intolerance and dasatinib resistance, 39% achieved MCyR, 22% achieved CCyR, and the OS was 67%. Of the 50 patients with imatinib resistance/intolerance and dasatinib intolerance, 42% achieved MCyR, 40% achieved CCyR, and the OS was 80%. Finally, in the 26 patients with imatinib resistance/intolerance and nilotinib resistance, 38% achieved MCyR, 31% achieved CCyR, and the OS was 87%.³⁴

Five-year follow-up from the phase 1/2 clinical trial that studied bosutinib 500 mg daily in CP-CML patients after imatinib failure reported data on 284 patients. By 5 years on study, 60% of patients had achieved MCyR and 50% achieved CCyR with a 71% and 69% probability, respectively, of maintaining these responses at 5 years. The 5-year OS was 84%.³⁵ These data led to the regulatory approval of bosutinib 500 mg daily as second-line or later therapy.

Bosutinib was initially studied in the first-line setting in the randomized phase 3 BELA (Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia) trial. This trial compared bosutinib 500 mg daily to imatinib 400 mg daily in newly diagnosed, previously untreated CP-CML patients. This trial failed to meet its primary endpoint of increased rate of CCyR at 12 months, with 70% of bosutinib patients achieving this response, compared to 68% of imatinib-treated patients (P = 0.601). In spite of this, the rate of MMR at 12 months was significantly higher in the bosutinib arm (41%) compared to the imatinib arm (27%; P = 0.001).³⁶

A second phase 3 trial (BFORE) was designed to study bosutinib 400 mg daily versus imatinib in newly diagnosed, previously untreated CP-CML patients. This study enrolled 536 patients who were randomly assigned 1:1 to bosutinib versus imatinib. The primary endpoint of this trial was rate of MMR at 12 months. A significantly higher number of bosutinib-treated patients achieved this response (47.2%) compared with imatinib-treated patients (36.9%, P = 0.02). Furthermore, by 12 months 77.2% of patients on the bosutinib arm had achieved CCyR compared with 66.4% on the imatinib arm, and this difference did meet statistical significance (P = 0.0075). A lower rate of progression to AP- or BP-CML was noted in bosutinib-treated patients as well (1.6% versus 2.5%). Based on this data, bosutinib gained regulatory approval for first-line therapy in CP-CML at a dose of 400 mg daily.¹⁸

Toxicity. On the BFORE trial, the most common treatment-emergent adverse events of any grade reported in the bosutinib-treated patients were diarrhea (70.1%), nausea (35.1%), increased ALT (30.6%), and increased AST (22.8%). Musculoskeletal pain or spasms occurred in 29.5% of patients, rash in 19.8%, fatigue in 19.4%, and headache in 18.7%. Hematologic toxicity was also reported, but most was grade 1/2. Thrombocytopenia was reported in 35.1%, anemia in 18.7%, and neutropenia in 11.2%.¹⁸

Cardiovascular events occurred in 5.2% of patients on the bosutinib arm of the BFORE trial, which was similar to the rate observed in imatinib patients. The most common cardiovascular event was QT interval prolongation, which occurred in 1.5% of patients. Pleural effusions were reported in 1.9% of patients treated with bosutinib, and none were grade 3 or higher.¹⁸

If liver enzyme elevation occurs at a value greater than 5 times the institutional upper limit of normal, bosutinib should be held until the level recovers to ≤ 2.5 times the upper limit of normal, at which point bosutinib can be restarted at a lower dose. If recovery takes longer than 4 weeks, bosutinib should be permanently discontinued. Liver enzymes elevated greater than 3 times the institutional upper limit of normal and a concurrent elevation in total bilirubin to 2 times the upper limit of normal are consistent with Hy’s law, and bosutinib should be discontinued. Although diarrhea is the most common toxicity associated with bosutinib, it is commonly low grade and transient. Diarrhea occurs most frequently in the first few days after initiating bosutinib. It can often be managed with over-the-counter antidiarrheal medications, but if the diarrhea is grade 3 or higher, bosutinib should be held until recovery to grade 1 or lower. Gastrointestinal side effects may be improved by taking bosutinib with a meal and a large glass of water. Fluid retention can be managed with diuretics and supportive care. Finally, if rash occurs, this can be addressed with topical or systemic steroids as well as bosutinib dose reduction, interruption, or discontinuation.¹⁹

Similar to other TKIs, if bosutinib-induced cytopenias occur, treatment should be held and restarted at the same or a lower dose upon blood count recovery.¹⁹

Ponatinib

The most common cause of TKI resistance in CP-CML is the development of ABL kinase domain mutations. The majority of imatinib-resistant mutations can be overcome by the use of second-generation TKIs, including dasatinib, nilotinib, or bosutinib. However, ponatinib is the only BCR-ABL TKI able to overcome a T315I mutation. The phase 2 PACE (Ponatinib Ph-positive ALL and CML Evaluation) trial enrolled patients with CP-, AP-, or BP-CML as well as patients with Ph-positive acute lymphoblastic leukemia who were resistant or intolerant to nilotinib or dasatinib, or who had evidence of a T315I mutation. The starting dose of ponatinib on this trial was 45 mg daily.³⁷ The PACE trial enrolled 267 patients with CP-CML: 203 with resistance or intolerance to nilotinib or dasatinib, and 64 with a T315I mutation. The primary endpoint in the CP cohort was rate of MCyR at any time within 12 months of starting ponatinib. The overall rate of MCyR by 12 months in the CP-CML patients was 56%. In those with a T315I mutation, 70% achieved MCyR, which compared favorably with those with resistance or intolerance to nilotinib or dasatinib, 51% of whom achieved MCyR. CCyR was achieved in 46% of CP-CML patients (40% in the resistant/intolerant cohort and 66% in the T315I cohort). In general, patients with T315I mutations received fewer prior therapies than those in the resistant/intolerant cohort, which likely contributed to the higher response rates in the T315I patients. MR4.5 was achieved in 15% of CP-CML patients by 12 months on the PACE trial.³⁷ The 5-year update to this study reported that 60%, 40%, and 24% of CP-CML patients achieved MCyR, MMR, and MR4.5, respectively. In the patients who achieved MCyR, the probability of maintaining this response for 5 years was 82% and the estimated 5-year OS was 73%.¹⁹

Toxicity. In 2013, after the regulatory approval of ponatinib, reports became available that the drug can cause an increase in arterial occlusive events, including fatal myocardial infarctions and cerebrovascular accidents. For this reason, dose reductions were implemented in patients who were deriving clinical benefit from ponatinib. In spite of these dose reductions, ≥ 90% of responders maintained their response for up to 40 months.³⁸ Although the likelihood of developing an arterial occlusive event appears higher in the first year after starting ponatinib than in later years, the cumulative incidence of events continues to increase. The 5-year follow-up to the PACE trial reports 31% of patients experiencing any grade of arterial occlusive event while on ponatinib. Aside from these events, the most common treatment-emergent adverse events in ponatinib-treated patients on the PACE trial included rash (47%), abdominal pain (46%), headache (43%), dry skin (42%), constipation (41%), and hypertension (37%). Hematologic toxicity was also common, with 46% of patients experiencing any grade of thrombocytopenia, 20% experiencing neutropenia, and 20% anemia.³⁸

Patients receiving ponatinib therapy should be monitored closely for any evidence of arterial or venous thrombosis. If an occlusive event occurs, ponatinib should be discontinued. Similarly, in the setting of any new or worsening heart failure symptoms, ponatinib should be promptly discontinued. Management of any underlying cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, or smoking history, is recommended, and these patients should be referred to a cardiologist for a full evaluation. In the absence of any contraindications to aspirin, low-dose aspirin should be considered as a means of decreasing cardiovascular risks associated with ponatinib. In patients with known risk factors, a ponatinib starting dose of 30 mg daily rather than the standard 45 mg daily may be a safer option, resulting in fewer arterial occlusive events, although the efficacy of this dose is still being studied in comparison to 45 mg daily.¹⁹

If ponatinib-induced transaminitis greater than 3 times the upper limit of normal occurs, ponatinib should be held until resolution to less than 3 times the upper limit of normal, at which point it should be resumed at a lower dose. Similarly, in the setting of elevated serum lipase or symptomatic pancreatitis, ponatinib should be held and restarted at a lower dose after resolution of symptoms.¹⁹

In the event of neutropenia or thrombocytopenia, ponatinib should be held until blood count recovery and then restarted at the same dose. If cytopenias occur for a second time, the dose of ponatinib should be lowered at the time of treatment reinitiation. If rash occurs, it can be addressed with topical or systemic steroids as well as dose reduction, interruption, or discontinuation.¹⁹

Conclusion

With the development of imatinib and the subsequent TKIs, dasatinib, nilotinib, bosutinib, and ponatinib, CP-CML has become a chronic disease with a life expectancy that is similar to that of the general population. Given the successful treatments available for these patients, it is crucial to identify patients with this diagnosis, ensure they receive a complete, appropriate diagnostic workup including a bone marrow biopsy and aspiration with cytogenetic testing, and select the best therapy for each individual patient. Once on treatment, the importance of frequent monitoring cannot be overstated. This is the only way to be certain patients are achieving the desired treatment milestones that correlate with the favorable long-term outcomes that have been observed with TKI-based treatment of CP-CML. 

Corresponding author: Kendra Sweet, MD, MS, Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL.

Financial disclosures: Dr. Sweet has served on the Advisory Board and Speakers Bureau of Novartis, Bristol-Meyers Squibb, Ariad Pharmaceuticals, and Pfizer, and has served as a consultant to Pfizer.

From Saint Luke’s Mid America Heart Institute/University of Missouri–Kansas City, Kansas City, MO.

Abstract

• Objective: To outline the tools available to help understand the risk of transcatheter aortic valve replacement (TAVR) and the gaps in knowledge regarding TAVR risk estimation.
• Methods: Review of the literature.
• Results: Two models developed and validated by the American College of Cardiology can be used to estimate the risk of short-term mortality, a 6-variable in-hospital model designed for clinical use and a 41-variable 30-day model designed primarily for site comparisons and quality improvement. Importantly, neither model should be used to inform the choice of TAVR versus surgical aortic valve replacement. Regarding long-term outcomes, a risk model to estimate risk of dying or having a persistently poor quality of life at 1 year after TAVR has been developed and validated. Factors that most significantly increase a patient’s risk for poor outcomes are very poor functional status prior to TAVR, requiring home oxygen, chronic renal insufficiency, atrial fibrillation, dependencies in activities of daily living, and dementia. If a patient has ≥ 2 or 3 major risk factors for a poor outcome, this risk and the uncertainty about the degree of recovery expected after TAVR should be discussed with the patient (and family).
• Conclusion: It is important to understand the patient factors that most strongly drive risk of poor outcomes after TAVR and use this information to set appropriate expectations for recovery.

Keywords: aortic valve stenosis; risk factors; postoperative complications; TAVR.

Among patients with severe aortic stenosis, trans­catheter aortic valve replacement (TAVR) has emerged as a less invasive option for aortic valve replacement. This procedure offers substantial reductions in mortality and improvement in quality of life compared with medical therapy^1,2 and at least similar long-term outcomes compared to surgical aortic valve replacement (SAVR).^3-9

As with any emerging technology, selecting the appropriate patients for TAVR—a procedure with high initial costs¹⁰—has been an area of active investigation. As TAVR was first introduced in patients who were considered inoperable, initial efforts focused on trying to identify the patients who did not improve functionally or live longer following TAVR. Termed Cohort C patients, these patients were thought to have too many comorbidities, be too sick, and have too little reserve to recover from TAVR, and in the early trials, represented a substantial minority of the patients. For example, in pivotal clinical trials of patients at high or extreme surgical risk, approximately 1 in 4 patients who were treated with TAVR were dead at 1 year.^1,3,11 Furthermore, a number of patients who received TAVR were alive at 1 year but continued to have significant heart failure symptoms and functional limitations.^2,4 Practitioners,^12,13 regulators,¹⁴ and third-party payers¹⁵ have recommended that TAVR should not be offered to patients in whom valve replacement would not be expected to positively impact either their survival or quality of life, but how best to identify these patients has been less clear.

More recently, as the use of TAVR has moved down the risk spectrum, patient selection for TAVR has shifted to understanding which patients should be preferentially treated with TAVR versus SAVR. While patients often prefer a less invasive treatment option with faster recovery—which is what TAVR offers—there are lingering questions about valve longevity, need for a pacemaker (and the associated long-term implications), and the ability to treat other cardiovascular conditions (eg, Maze, mitral valve repair) that potentially make a patient a more appropriate candidate for valve surgery. This review outlines the tools currently available to help understand the risk of TAVR and the gaps in knowledge.

Short-Term Outcomes

When TAVR was initially introduced, the 30-day mortality rate was 5% to 8%.^1,11,16 This high mortality rate was a function of treating very ill patients and more invasive procedures with larger sheath sizes and routine use of general anesthesia, transesophageal echocardiography, pulmonary artery catheterization, and so on. Over time, however, this rate has gone down substantially, with the 30-day mortality rate in intermediate- and low-risk patients now ranging from 0.5% to 1%.^8,17-19 Although this low mortality rate indicates that the vast majority of patients will survive to discharge from the hospital, 2 models can be used to estimate the risk of short-term mortality: an in-hospital²⁰ and a 30-day model,²¹ both developed and validated by the American College of Cardiology. The in-hospital model was developed for clinical use, as it includes only 6 variables (age, renal function, severe lung disease, non-femoral access, New York Heart Association class IV, and acuity of the procedure [elective versus urgent versus shock versus emergent])²⁰ and has an online calculator (http://tools.acc.org/tavrrisk/). The 30-day model was developed for risk adjustment (primarily for site comparisons and quality improvement) and includes 41 variables (including pre-TAVR patient health status and gait speed).²¹

While 30 days is a better time frame for assessment because outcome is less impacted by differences in local post-acute care facilities, we explicitly did not create a parsimonious 30-day mortality model for clinical use due to concern that having such a model would allow for indirect comparisons with estimated risk of SAVR using the Society of Thoracic Surgeons risk model (http://riskcalc.sts.org/stswebriskcalc). It would be tempting to estimate a patient’s risk of mortality with the TAVR calculator and the SAVR calculator and use those risk estimates to inform the choice of treatment; however, these risk estimates should not be directly compared to make treatment selections, as they were built on entirely different patient populations. In real-world practice, there is minimal overlap in the characteristics of patients who are treated with TAVR and SAVR. For example, in an analysis that merged surgical and transcatheter databases, less than 25% of patients treated with TAVR could be matched to a clinically similar patient treated with SAVR.²² As such, these TAVR models should be used to estimate a patient’s risk for short-term mortality, but should not be used to contribute to the decision on TAVR versus SAVR.

The decision of selecting SAVR over TAVR is typically driven by factors other than short- or long-term mortality (eg, whether TAVR will be covered by insurance, very young age and concern about durability, need to treat concomitant mitral regurgitation or aortopathy), as clinical trials have shown that survival and quality of life outcomes are at least as good with TAVR compared with SAVR.^6,7,9,23 In fact, in an analysis that compared similar patients treated with TAVR versus SAVR and specifically looked for patient factors that might make one treatment preferable to the other, patients who had a prior cardiac operation and those on home oxygen were more likely to do better with TAVR, whereas no patient factors that favored SAVR were found.²⁴ The majority of patients, however, were expected to have similar long-term outcomes regardless of treatment choice, and as such, the benefit of TAVR appears mostly to be an earlier and easier recovery.

Long-Term Outcomes: Estimating the Risk for Failure to Recover

While many patients who undergo TAVR are quite ill prior to the procedure, with substantial limitations due to the fatigue and shortness of breath associated with severe aortic stenosis, most patients recover well after the procedure, with marked improvement in symptoms and functional capacity. Approximately 25% to 35% of patients currently treated with TAVR commercially (ie, intermediate- and high-surgical-risk patients) either die or do not recover a reasonable quality of life after the procedure. Identifying those patients prior to the procedure can be challenging. We have previously developed and externally validated a risk model to estimate risk of dying or having a persistently poor quality of life at 1 year after TAVR.^25,26 The factors that most significantly increase a patient’s risk for poor outcomes are very poor functional status prior to TAVR, requiring home oxygen, chronic renal insufficiency, atrial fibrillation, and dementia. For example, a patient who is short of breath at rest, is on home oxygen, has a serum creatinine of 2.5 mg/dL, and has atrial fibrillation has an estimated risk of poor outcome at 1 year of ~70%. However, it should be noted that ~25% of patients with no risk factors for poor outcomes (ie, those considered “low risk”) still have a poor outcome at 1 year after TAVR, as the patients who undergo TAVR are typically at an advanced age with at least some comorbidities. Therefore, a 1-year mortality rate of 10% to 15% would not be unexpected in this population independent of the TAVR, although this will likely change over time as TAVR expands to patients at low surgical risk.

Beyond clinical factors, frailty negatively impacts both survival and quality of life after TAVR. Frailty is a geriatric syndrome of impaired physiologic reserve and decreased resistance to stressors²⁷ that is characterized by weakness, slowness, exhaustion, wasting, and low activity level. Across a wide variety of clinical situations (eg, pneumonia,²⁸ myocardial infarction,²⁹ general^30,31 and cardiac surgery^32,33), frailty increases the risk of morbidity and mortality after nearly any intervention³⁴ or clinical insult, independent of traditional demographic and clinical risk factors. Frail patients often do better with less invasive interventions such as TAVR compared with traditional surgery, but nonetheless remain at increased risk for death^35-37 or failure to recover quality of life and functional status^25,37 after TAVR. However, there are unique challenges in both assessing and managing frailty in patients who are considered potential candidates for TAVR. One challenge is the lack of a laboratory or radiologic test for frailty; instead, the lack of physiologic reserve of frailty is identified through a combination of factors, such as slow gait speed, weak grip strength, and unintentional weight loss. While these factors readily identify frail patients in general elderly populations, in patients with severe symptomatic aortic stenosis, these metrics can be impacted by the disease process itself. This distinction is important as slow gait speed that is due to aortic stenosis will be “fixed” by TAVR, but slow gait speed from frailty would identify a patient who will have a difficult time recovering from the procedure. For example, in the CoreValve High Risk Pivotal Trial, 80% of patients had a slow gait speed and 67% had a weak grip strength,⁵ and yet 58% of patients in this trial were alive and with a reasonable quality of life 1 year after TAVR.⁶ A number of studies have attempted to define true frailty within the pre-TAVR population, that which represents decreased physiologic reserve and an impaired ability to recover from an insult, and the factors that appear to be most prognostically important are malnutrition³⁸ or unintentional weight loss²⁵ and the inability to be independent in activities of daily living (eg, dressing, feeding, transferring).^25,37

Even with frailty assessments, the ability to predict who is or is not going to have a poor outcome after TAVR (ie, to use pre-procedural factors to identify patients who perhaps should not be offered TAVR because he or she will not recover from the procedure) is exceedingly difficult. The Table shows how to grossly estimate risk using the major factors that impact risk based on the more precise estimates from our models.^25,26

The model shown in the Table can be used to estimate a patient’s risk for a poor outcome, but it should be noted that even at the extreme high end of risk, there will be some patients who still do well after TAVR. Furthermore, being high risk for a poor outcome after TAVR does not imply anything about how the patient would do without TAVR, as many of these patients would likely die even sooner or have worse quality of life with medical therapy only. However, if a patient has ≥ 2 or 3 major risk factors for a poor outcome, it may be worthwhile to have a serious conversation with the patient (and family) about this risk and the uncertainty about the degree of recovery expected after TAVR.

Conclusion

Calculating the risk of TAVR can be complicated. In patients who are electively treated using transfemoral access and a less invasive approach, the short-term risk of mortality is very low. Risk calculators can be used to estimate short-term risk, but the patients who are high risk for in-hospital mortality are often fairly easy to recognize, as the factors that drive that risk are not subtle (eg, the patient is in shock at the time of the procedure). The true risk of TAVR lies in the inability to recover from the procedure—being chronically ill, frail, or debilitated to a degree that the patient either dies or fails to recover a reasonable quality of life. Given the overlap of symptomatic aortic stenosis with true frailty, it is often difficult to identify these patients who will not thrive after TAVR. Understanding the patient factors that most strongly drive risk of poor outcomes after TAVR, and allowing this information to guide the conversation prior to TAVR so as to set appropriate expectations for recovery, can be a good place to start.

Corresponding author: Suzanne V. Arnold, MD, MHA, 4401 Wornall Rd., Kansas City, MO 64111.

Financial disclosures: This work was funded in part by grant K23HL116799 from the National Institutes of Health.

From Saint Luke’s Mid America Heart Institute/University of Missouri–Kansas City, Kansas City, MO.

Abstract

• Objective: To outline the tools available to help understand the risk of transcatheter aortic valve replacement (TAVR) and the gaps in knowledge regarding TAVR risk estimation.
• Methods: Review of the literature.
• Results: Two models developed and validated by the American College of Cardiology can be used to estimate the risk of short-term mortality, a 6-variable in-hospital model designed for clinical use and a 41-variable 30-day model designed primarily for site comparisons and quality improvement. Importantly, neither model should be used to inform the choice of TAVR versus surgical aortic valve replacement. Regarding long-term outcomes, a risk model to estimate risk of dying or having a persistently poor quality of life at 1 year after TAVR has been developed and validated. Factors that most significantly increase a patient’s risk for poor outcomes are very poor functional status prior to TAVR, requiring home oxygen, chronic renal insufficiency, atrial fibrillation, dependencies in activities of daily living, and dementia. If a patient has ≥ 2 or 3 major risk factors for a poor outcome, this risk and the uncertainty about the degree of recovery expected after TAVR should be discussed with the patient (and family).
• Conclusion: It is important to understand the patient factors that most strongly drive risk of poor outcomes after TAVR and use this information to set appropriate expectations for recovery.

Keywords: aortic valve stenosis; risk factors; postoperative complications; TAVR.

Among patients with severe aortic stenosis, trans­catheter aortic valve replacement (TAVR) has emerged as a less invasive option for aortic valve replacement. This procedure offers substantial reductions in mortality and improvement in quality of life compared with medical therapy^1,2 and at least similar long-term outcomes compared to surgical aortic valve replacement (SAVR).^3-9

As with any emerging technology, selecting the appropriate patients for TAVR—a procedure with high initial costs¹⁰—has been an area of active investigation. As TAVR was first introduced in patients who were considered inoperable, initial efforts focused on trying to identify the patients who did not improve functionally or live longer following TAVR. Termed Cohort C patients, these patients were thought to have too many comorbidities, be too sick, and have too little reserve to recover from TAVR, and in the early trials, represented a substantial minority of the patients. For example, in pivotal clinical trials of patients at high or extreme surgical risk, approximately 1 in 4 patients who were treated with TAVR were dead at 1 year.^1,3,11 Furthermore, a number of patients who received TAVR were alive at 1 year but continued to have significant heart failure symptoms and functional limitations.^2,4 Practitioners,^12,13 regulators,¹⁴ and third-party payers¹⁵ have recommended that TAVR should not be offered to patients in whom valve replacement would not be expected to positively impact either their survival or quality of life, but how best to identify these patients has been less clear.

More recently, as the use of TAVR has moved down the risk spectrum, patient selection for TAVR has shifted to understanding which patients should be preferentially treated with TAVR versus SAVR. While patients often prefer a less invasive treatment option with faster recovery—which is what TAVR offers—there are lingering questions about valve longevity, need for a pacemaker (and the associated long-term implications), and the ability to treat other cardiovascular conditions (eg, Maze, mitral valve repair) that potentially make a patient a more appropriate candidate for valve surgery. This review outlines the tools currently available to help understand the risk of TAVR and the gaps in knowledge.

Short-Term Outcomes

When TAVR was initially introduced, the 30-day mortality rate was 5% to 8%.^1,11,16 This high mortality rate was a function of treating very ill patients and more invasive procedures with larger sheath sizes and routine use of general anesthesia, transesophageal echocardiography, pulmonary artery catheterization, and so on. Over time, however, this rate has gone down substantially, with the 30-day mortality rate in intermediate- and low-risk patients now ranging from 0.5% to 1%.^8,17-19 Although this low mortality rate indicates that the vast majority of patients will survive to discharge from the hospital, 2 models can be used to estimate the risk of short-term mortality: an in-hospital²⁰ and a 30-day model,²¹ both developed and validated by the American College of Cardiology. The in-hospital model was developed for clinical use, as it includes only 6 variables (age, renal function, severe lung disease, non-femoral access, New York Heart Association class IV, and acuity of the procedure [elective versus urgent versus shock versus emergent])²⁰ and has an online calculator (http://tools.acc.org/tavrrisk/). The 30-day model was developed for risk adjustment (primarily for site comparisons and quality improvement) and includes 41 variables (including pre-TAVR patient health status and gait speed).²¹

While 30 days is a better time frame for assessment because outcome is less impacted by differences in local post-acute care facilities, we explicitly did not create a parsimonious 30-day mortality model for clinical use due to concern that having such a model would allow for indirect comparisons with estimated risk of SAVR using the Society of Thoracic Surgeons risk model (http://riskcalc.sts.org/stswebriskcalc). It would be tempting to estimate a patient’s risk of mortality with the TAVR calculator and the SAVR calculator and use those risk estimates to inform the choice of treatment; however, these risk estimates should not be directly compared to make treatment selections, as they were built on entirely different patient populations. In real-world practice, there is minimal overlap in the characteristics of patients who are treated with TAVR and SAVR. For example, in an analysis that merged surgical and transcatheter databases, less than 25% of patients treated with TAVR could be matched to a clinically similar patient treated with SAVR.²² As such, these TAVR models should be used to estimate a patient’s risk for short-term mortality, but should not be used to contribute to the decision on TAVR versus SAVR.

The decision of selecting SAVR over TAVR is typically driven by factors other than short- or long-term mortality (eg, whether TAVR will be covered by insurance, very young age and concern about durability, need to treat concomitant mitral regurgitation or aortopathy), as clinical trials have shown that survival and quality of life outcomes are at least as good with TAVR compared with SAVR.^6,7,9,23 In fact, in an analysis that compared similar patients treated with TAVR versus SAVR and specifically looked for patient factors that might make one treatment preferable to the other, patients who had a prior cardiac operation and those on home oxygen were more likely to do better with TAVR, whereas no patient factors that favored SAVR were found.²⁴ The majority of patients, however, were expected to have similar long-term outcomes regardless of treatment choice, and as such, the benefit of TAVR appears mostly to be an earlier and easier recovery.

Long-Term Outcomes: Estimating the Risk for Failure to Recover

While many patients who undergo TAVR are quite ill prior to the procedure, with substantial limitations due to the fatigue and shortness of breath associated with severe aortic stenosis, most patients recover well after the procedure, with marked improvement in symptoms and functional capacity. Approximately 25% to 35% of patients currently treated with TAVR commercially (ie, intermediate- and high-surgical-risk patients) either die or do not recover a reasonable quality of life after the procedure. Identifying those patients prior to the procedure can be challenging. We have previously developed and externally validated a risk model to estimate risk of dying or having a persistently poor quality of life at 1 year after TAVR.^25,26 The factors that most significantly increase a patient’s risk for poor outcomes are very poor functional status prior to TAVR, requiring home oxygen, chronic renal insufficiency, atrial fibrillation, and dementia. For example, a patient who is short of breath at rest, is on home oxygen, has a serum creatinine of 2.5 mg/dL, and has atrial fibrillation has an estimated risk of poor outcome at 1 year of ~70%. However, it should be noted that ~25% of patients with no risk factors for poor outcomes (ie, those considered “low risk”) still have a poor outcome at 1 year after TAVR, as the patients who undergo TAVR are typically at an advanced age with at least some comorbidities. Therefore, a 1-year mortality rate of 10% to 15% would not be unexpected in this population independent of the TAVR, although this will likely change over time as TAVR expands to patients at low surgical risk.

Beyond clinical factors, frailty negatively impacts both survival and quality of life after TAVR. Frailty is a geriatric syndrome of impaired physiologic reserve and decreased resistance to stressors²⁷ that is characterized by weakness, slowness, exhaustion, wasting, and low activity level. Across a wide variety of clinical situations (eg, pneumonia,²⁸ myocardial infarction,²⁹ general^30,31 and cardiac surgery^32,33), frailty increases the risk of morbidity and mortality after nearly any intervention³⁴ or clinical insult, independent of traditional demographic and clinical risk factors. Frail patients often do better with less invasive interventions such as TAVR compared with traditional surgery, but nonetheless remain at increased risk for death^35-37 or failure to recover quality of life and functional status^25,37 after TAVR. However, there are unique challenges in both assessing and managing frailty in patients who are considered potential candidates for TAVR. One challenge is the lack of a laboratory or radiologic test for frailty; instead, the lack of physiologic reserve of frailty is identified through a combination of factors, such as slow gait speed, weak grip strength, and unintentional weight loss. While these factors readily identify frail patients in general elderly populations, in patients with severe symptomatic aortic stenosis, these metrics can be impacted by the disease process itself. This distinction is important as slow gait speed that is due to aortic stenosis will be “fixed” by TAVR, but slow gait speed from frailty would identify a patient who will have a difficult time recovering from the procedure. For example, in the CoreValve High Risk Pivotal Trial, 80% of patients had a slow gait speed and 67% had a weak grip strength,⁵ and yet 58% of patients in this trial were alive and with a reasonable quality of life 1 year after TAVR.⁶ A number of studies have attempted to define true frailty within the pre-TAVR population, that which represents decreased physiologic reserve and an impaired ability to recover from an insult, and the factors that appear to be most prognostically important are malnutrition³⁸ or unintentional weight loss²⁵ and the inability to be independent in activities of daily living (eg, dressing, feeding, transferring).^25,37

Even with frailty assessments, the ability to predict who is or is not going to have a poor outcome after TAVR (ie, to use pre-procedural factors to identify patients who perhaps should not be offered TAVR because he or she will not recover from the procedure) is exceedingly difficult. The Table shows how to grossly estimate risk using the major factors that impact risk based on the more precise estimates from our models.^25,26

The model shown in the Table can be used to estimate a patient’s risk for a poor outcome, but it should be noted that even at the extreme high end of risk, there will be some patients who still do well after TAVR. Furthermore, being high risk for a poor outcome after TAVR does not imply anything about how the patient would do without TAVR, as many of these patients would likely die even sooner or have worse quality of life with medical therapy only. However, if a patient has ≥ 2 or 3 major risk factors for a poor outcome, it may be worthwhile to have a serious conversation with the patient (and family) about this risk and the uncertainty about the degree of recovery expected after TAVR.

Conclusion

Calculating the risk of TAVR can be complicated. In patients who are electively treated using transfemoral access and a less invasive approach, the short-term risk of mortality is very low. Risk calculators can be used to estimate short-term risk, but the patients who are high risk for in-hospital mortality are often fairly easy to recognize, as the factors that drive that risk are not subtle (eg, the patient is in shock at the time of the procedure). The true risk of TAVR lies in the inability to recover from the procedure—being chronically ill, frail, or debilitated to a degree that the patient either dies or fails to recover a reasonable quality of life. Given the overlap of symptomatic aortic stenosis with true frailty, it is often difficult to identify these patients who will not thrive after TAVR. Understanding the patient factors that most strongly drive risk of poor outcomes after TAVR, and allowing this information to guide the conversation prior to TAVR so as to set appropriate expectations for recovery, can be a good place to start.

Corresponding author: Suzanne V. Arnold, MD, MHA, 4401 Wornall Rd., Kansas City, MO 64111.

Financial disclosures: This work was funded in part by grant K23HL116799 from the National Institutes of Health.

From Saint Luke’s Mid America Heart Institute/University of Missouri–Kansas City, Kansas City, MO.

Abstract

• Objective: To outline the tools available to help understand the risk of transcatheter aortic valve replacement (TAVR) and the gaps in knowledge regarding TAVR risk estimation.
• Methods: Review of the literature.
• Results: Two models developed and validated by the American College of Cardiology can be used to estimate the risk of short-term mortality, a 6-variable in-hospital model designed for clinical use and a 41-variable 30-day model designed primarily for site comparisons and quality improvement. Importantly, neither model should be used to inform the choice of TAVR versus surgical aortic valve replacement. Regarding long-term outcomes, a risk model to estimate risk of dying or having a persistently poor quality of life at 1 year after TAVR has been developed and validated. Factors that most significantly increase a patient’s risk for poor outcomes are very poor functional status prior to TAVR, requiring home oxygen, chronic renal insufficiency, atrial fibrillation, dependencies in activities of daily living, and dementia. If a patient has ≥ 2 or 3 major risk factors for a poor outcome, this risk and the uncertainty about the degree of recovery expected after TAVR should be discussed with the patient (and family).
• Conclusion: It is important to understand the patient factors that most strongly drive risk of poor outcomes after TAVR and use this information to set appropriate expectations for recovery.

Keywords: aortic valve stenosis; risk factors; postoperative complications; TAVR.

Among patients with severe aortic stenosis, trans­catheter aortic valve replacement (TAVR) has emerged as a less invasive option for aortic valve replacement. This procedure offers substantial reductions in mortality and improvement in quality of life compared with medical therapy^1,2 and at least similar long-term outcomes compared to surgical aortic valve replacement (SAVR).^3-9

As with any emerging technology, selecting the appropriate patients for TAVR—a procedure with high initial costs¹⁰—has been an area of active investigation. As TAVR was first introduced in patients who were considered inoperable, initial efforts focused on trying to identify the patients who did not improve functionally or live longer following TAVR. Termed Cohort C patients, these patients were thought to have too many comorbidities, be too sick, and have too little reserve to recover from TAVR, and in the early trials, represented a substantial minority of the patients. For example, in pivotal clinical trials of patients at high or extreme surgical risk, approximately 1 in 4 patients who were treated with TAVR were dead at 1 year.^1,3,11 Furthermore, a number of patients who received TAVR were alive at 1 year but continued to have significant heart failure symptoms and functional limitations.^2,4 Practitioners,^12,13 regulators,¹⁴ and third-party payers¹⁵ have recommended that TAVR should not be offered to patients in whom valve replacement would not be expected to positively impact either their survival or quality of life, but how best to identify these patients has been less clear.

More recently, as the use of TAVR has moved down the risk spectrum, patient selection for TAVR has shifted to understanding which patients should be preferentially treated with TAVR versus SAVR. While patients often prefer a less invasive treatment option with faster recovery—which is what TAVR offers—there are lingering questions about valve longevity, need for a pacemaker (and the associated long-term implications), and the ability to treat other cardiovascular conditions (eg, Maze, mitral valve repair) that potentially make a patient a more appropriate candidate for valve surgery. This review outlines the tools currently available to help understand the risk of TAVR and the gaps in knowledge.

Short-Term Outcomes

When TAVR was initially introduced, the 30-day mortality rate was 5% to 8%.^1,11,16 This high mortality rate was a function of treating very ill patients and more invasive procedures with larger sheath sizes and routine use of general anesthesia, transesophageal echocardiography, pulmonary artery catheterization, and so on. Over time, however, this rate has gone down substantially, with the 30-day mortality rate in intermediate- and low-risk patients now ranging from 0.5% to 1%.^8,17-19 Although this low mortality rate indicates that the vast majority of patients will survive to discharge from the hospital, 2 models can be used to estimate the risk of short-term mortality: an in-hospital²⁰ and a 30-day model,²¹ both developed and validated by the American College of Cardiology. The in-hospital model was developed for clinical use, as it includes only 6 variables (age, renal function, severe lung disease, non-femoral access, New York Heart Association class IV, and acuity of the procedure [elective versus urgent versus shock versus emergent])²⁰ and has an online calculator (http://tools.acc.org/tavrrisk/). The 30-day model was developed for risk adjustment (primarily for site comparisons and quality improvement) and includes 41 variables (including pre-TAVR patient health status and gait speed).²¹

While 30 days is a better time frame for assessment because outcome is less impacted by differences in local post-acute care facilities, we explicitly did not create a parsimonious 30-day mortality model for clinical use due to concern that having such a model would allow for indirect comparisons with estimated risk of SAVR using the Society of Thoracic Surgeons risk model (http://riskcalc.sts.org/stswebriskcalc). It would be tempting to estimate a patient’s risk of mortality with the TAVR calculator and the SAVR calculator and use those risk estimates to inform the choice of treatment; however, these risk estimates should not be directly compared to make treatment selections, as they were built on entirely different patient populations. In real-world practice, there is minimal overlap in the characteristics of patients who are treated with TAVR and SAVR. For example, in an analysis that merged surgical and transcatheter databases, less than 25% of patients treated with TAVR could be matched to a clinically similar patient treated with SAVR.²² As such, these TAVR models should be used to estimate a patient’s risk for short-term mortality, but should not be used to contribute to the decision on TAVR versus SAVR.

The decision of selecting SAVR over TAVR is typically driven by factors other than short- or long-term mortality (eg, whether TAVR will be covered by insurance, very young age and concern about durability, need to treat concomitant mitral regurgitation or aortopathy), as clinical trials have shown that survival and quality of life outcomes are at least as good with TAVR compared with SAVR.^6,7,9,23 In fact, in an analysis that compared similar patients treated with TAVR versus SAVR and specifically looked for patient factors that might make one treatment preferable to the other, patients who had a prior cardiac operation and those on home oxygen were more likely to do better with TAVR, whereas no patient factors that favored SAVR were found.²⁴ The majority of patients, however, were expected to have similar long-term outcomes regardless of treatment choice, and as such, the benefit of TAVR appears mostly to be an earlier and easier recovery.

Long-Term Outcomes: Estimating the Risk for Failure to Recover

While many patients who undergo TAVR are quite ill prior to the procedure, with substantial limitations due to the fatigue and shortness of breath associated with severe aortic stenosis, most patients recover well after the procedure, with marked improvement in symptoms and functional capacity. Approximately 25% to 35% of patients currently treated with TAVR commercially (ie, intermediate- and high-surgical-risk patients) either die or do not recover a reasonable quality of life after the procedure. Identifying those patients prior to the procedure can be challenging. We have previously developed and externally validated a risk model to estimate risk of dying or having a persistently poor quality of life at 1 year after TAVR.^25,26 The factors that most significantly increase a patient’s risk for poor outcomes are very poor functional status prior to TAVR, requiring home oxygen, chronic renal insufficiency, atrial fibrillation, and dementia. For example, a patient who is short of breath at rest, is on home oxygen, has a serum creatinine of 2.5 mg/dL, and has atrial fibrillation has an estimated risk of poor outcome at 1 year of ~70%. However, it should be noted that ~25% of patients with no risk factors for poor outcomes (ie, those considered “low risk”) still have a poor outcome at 1 year after TAVR, as the patients who undergo TAVR are typically at an advanced age with at least some comorbidities. Therefore, a 1-year mortality rate of 10% to 15% would not be unexpected in this population independent of the TAVR, although this will likely change over time as TAVR expands to patients at low surgical risk.

Beyond clinical factors, frailty negatively impacts both survival and quality of life after TAVR. Frailty is a geriatric syndrome of impaired physiologic reserve and decreased resistance to stressors²⁷ that is characterized by weakness, slowness, exhaustion, wasting, and low activity level. Across a wide variety of clinical situations (eg, pneumonia,²⁸ myocardial infarction,²⁹ general^30,31 and cardiac surgery^32,33), frailty increases the risk of morbidity and mortality after nearly any intervention³⁴ or clinical insult, independent of traditional demographic and clinical risk factors. Frail patients often do better with less invasive interventions such as TAVR compared with traditional surgery, but nonetheless remain at increased risk for death^35-37 or failure to recover quality of life and functional status^25,37 after TAVR. However, there are unique challenges in both assessing and managing frailty in patients who are considered potential candidates for TAVR. One challenge is the lack of a laboratory or radiologic test for frailty; instead, the lack of physiologic reserve of frailty is identified through a combination of factors, such as slow gait speed, weak grip strength, and unintentional weight loss. While these factors readily identify frail patients in general elderly populations, in patients with severe symptomatic aortic stenosis, these metrics can be impacted by the disease process itself. This distinction is important as slow gait speed that is due to aortic stenosis will be “fixed” by TAVR, but slow gait speed from frailty would identify a patient who will have a difficult time recovering from the procedure. For example, in the CoreValve High Risk Pivotal Trial, 80% of patients had a slow gait speed and 67% had a weak grip strength,⁵ and yet 58% of patients in this trial were alive and with a reasonable quality of life 1 year after TAVR.⁶ A number of studies have attempted to define true frailty within the pre-TAVR population, that which represents decreased physiologic reserve and an impaired ability to recover from an insult, and the factors that appear to be most prognostically important are malnutrition³⁸ or unintentional weight loss²⁵ and the inability to be independent in activities of daily living (eg, dressing, feeding, transferring).^25,37

Even with frailty assessments, the ability to predict who is or is not going to have a poor outcome after TAVR (ie, to use pre-procedural factors to identify patients who perhaps should not be offered TAVR because he or she will not recover from the procedure) is exceedingly difficult. The Table shows how to grossly estimate risk using the major factors that impact risk based on the more precise estimates from our models.^25,26

The model shown in the Table can be used to estimate a patient’s risk for a poor outcome, but it should be noted that even at the extreme high end of risk, there will be some patients who still do well after TAVR. Furthermore, being high risk for a poor outcome after TAVR does not imply anything about how the patient would do without TAVR, as many of these patients would likely die even sooner or have worse quality of life with medical therapy only. However, if a patient has ≥ 2 or 3 major risk factors for a poor outcome, it may be worthwhile to have a serious conversation with the patient (and family) about this risk and the uncertainty about the degree of recovery expected after TAVR.

Conclusion

Calculating the risk of TAVR can be complicated. In patients who are electively treated using transfemoral access and a less invasive approach, the short-term risk of mortality is very low. Risk calculators can be used to estimate short-term risk, but the patients who are high risk for in-hospital mortality are often fairly easy to recognize, as the factors that drive that risk are not subtle (eg, the patient is in shock at the time of the procedure). The true risk of TAVR lies in the inability to recover from the procedure—being chronically ill, frail, or debilitated to a degree that the patient either dies or fails to recover a reasonable quality of life. Given the overlap of symptomatic aortic stenosis with true frailty, it is often difficult to identify these patients who will not thrive after TAVR. Understanding the patient factors that most strongly drive risk of poor outcomes after TAVR, and allowing this information to guide the conversation prior to TAVR so as to set appropriate expectations for recovery, can be a good place to start.

Corresponding author: Suzanne V. Arnold, MD, MHA, 4401 Wornall Rd., Kansas City, MO 64111.

Financial disclosures: This work was funded in part by grant K23HL116799 from the National Institutes of Health.

Study Overview

Objective. To investigate the 5-year clinical outcome of patients undergoing hybrid revascularization for multivessel coronary artery disease (CAD).

Design. Multicenter, open-label, prospective randomized control trial.

Setting and participants. 200 patients with multivessel CAD referred for conventional surgical revascularization were randomly assigned to undergo hybrid coronary revascularization (HCR) or coronary artery bypass grafting (CABG).

Main outcome measures. The primary endpoint was all-cause mortality at 5 years.

Main results. After excluding 9 patients who were lost to follow-up before 5 years, 191 patients (94 in HCR group and 97 in CABG group) formed the basis of the study. All-cause mortality at 5-year follow-up was similar in the 2 groups (6.4% versus 9.2%, P = 0.69). The rates of myocardial infarction (4.3% versus 7.2%, P = 0.30), repeat revascularization (37.2% versus 45.4%, P = 0.38), stroke (2.1% versus 4.1%, P = 0.35), and major adverse and cardiac and cerebrovascular events (45.2% versus 53.4%, P = 0.39) were similar in the 2 groups. These findings were consistent across all levels of risk for surgical complications (EuroScore) and for complexity of revascularization (SYNTAX score).

Conclusion. HCR has similar 5-year all-cause mortality when compared with conventional CABG.

Commentary

HCR has been proposed as a less invasive, effective alternative revascularization strategy to conventional CABG for patients with multivessel CAD. The hybrid approach typically combines the long-term durability of grafting of the left anterior descending artery (LAD) using the left internal mammary artery and the percutaneous coronary intervention (PCI) for non-LAD stenosis; this approach has been shown to have similar or perhaps even better long-term patency compared with saphenous vein grafts.^1,2 Previous studies have demonstrated the feasibility of HCR by comparing HCR to conventional CABG at 1 year.² However, the long-term outcome of HCR compared to conventional CABG has not been previously reported.

In this context, Tajstra et al reported the 5-year follow-up from their prospective randomized pilot study. They report that among the 200 patients with multivessel coronary disease randomly assigned to either HCR or CABG, all-cause mortality at 5-year follow-up was similar in the 2 groups (6.4% versus 9.2%, P = 0.69). The rates of myocardial infarction, repeat revascularization, stroke, and major adverse and cardiac and cerebrovascular event (MACCE) were also similar in the 2 groups.

This is an important study because it is the first to compare the long-term outcome of HCR with conventional CABG; previous studies have been limited due to their short- to mid-term follow-up.² However, because this study was not powered to assess the superiority of the HCR compared to conventional CABG, future randomized control trials with a larger number of patients are needed.

Future studies must address some important questions. First, the patients in the present study were younger (mean age, 62.1 ± 8.3 years) with less comorbidity and a relatively low SYNTAX score (23.6 ± 6.1 for the HCR arm). As CABG and PCI are associated with similar long- term outcomes in patients with low (< 22) to intermediate (22–32) SYNTAX score,³ comparisons between HCR and multivessel PCI using the current generation of drug-eluting stents are needed. The results from the ongoing Hybrid Coronary Revascularization Trial (NCT03089398) will shed light on this clinical question. Second, whether these findings can be extended to patients with a high baseline SYNTAX score needs further study. Nonetheless, outcomes were similar between the 2 strategies in the intermediate (n = 98) and high (n = 8) SYNTAX score groups. Interestingly, there is no clear benefit of HCR in the high surgical risk groups as measured by EuroScore. Third, in addition to the hard outcomes (death and MACCE), the quality of life of patients measured by an established metric, such as the Seattle Angina Questionnaire, need to be assessed. Last, the completeness of revascularization in each group needs to be further evaluated because incomplete revascularization is a known predictor of adverse outcomes.^4,5

Applications for Clinical Practice

In patients with multivessel coronary disease with low SYNTAX score, the 5-year outcome for HCR was similar to that of conventional CABG. Further larger studies are needed to assess the superiority of this approach.

—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO; Hiroto Kitahara, MD, University of Chicago Medical Center, Chicago, IL; and John Blair, MD, Medstar Washington Hospital Center, Washington, DC

Study Overview

Objective. To investigate the 5-year clinical outcome of patients undergoing hybrid revascularization for multivessel coronary artery disease (CAD).

Design. Multicenter, open-label, prospective randomized control trial.

Setting and participants. 200 patients with multivessel CAD referred for conventional surgical revascularization were randomly assigned to undergo hybrid coronary revascularization (HCR) or coronary artery bypass grafting (CABG).

Main outcome measures. The primary endpoint was all-cause mortality at 5 years.

Main results. After excluding 9 patients who were lost to follow-up before 5 years, 191 patients (94 in HCR group and 97 in CABG group) formed the basis of the study. All-cause mortality at 5-year follow-up was similar in the 2 groups (6.4% versus 9.2%, P = 0.69). The rates of myocardial infarction (4.3% versus 7.2%, P = 0.30), repeat revascularization (37.2% versus 45.4%, P = 0.38), stroke (2.1% versus 4.1%, P = 0.35), and major adverse and cardiac and cerebrovascular events (45.2% versus 53.4%, P = 0.39) were similar in the 2 groups. These findings were consistent across all levels of risk for surgical complications (EuroScore) and for complexity of revascularization (SYNTAX score).

Conclusion. HCR has similar 5-year all-cause mortality when compared with conventional CABG.

Commentary

HCR has been proposed as a less invasive, effective alternative revascularization strategy to conventional CABG for patients with multivessel CAD. The hybrid approach typically combines the long-term durability of grafting of the left anterior descending artery (LAD) using the left internal mammary artery and the percutaneous coronary intervention (PCI) for non-LAD stenosis; this approach has been shown to have similar or perhaps even better long-term patency compared with saphenous vein grafts.^1,2 Previous studies have demonstrated the feasibility of HCR by comparing HCR to conventional CABG at 1 year.² However, the long-term outcome of HCR compared to conventional CABG has not been previously reported.

In this context, Tajstra et al reported the 5-year follow-up from their prospective randomized pilot study. They report that among the 200 patients with multivessel coronary disease randomly assigned to either HCR or CABG, all-cause mortality at 5-year follow-up was similar in the 2 groups (6.4% versus 9.2%, P = 0.69). The rates of myocardial infarction, repeat revascularization, stroke, and major adverse and cardiac and cerebrovascular event (MACCE) were also similar in the 2 groups.

This is an important study because it is the first to compare the long-term outcome of HCR with conventional CABG; previous studies have been limited due to their short- to mid-term follow-up.² However, because this study was not powered to assess the superiority of the HCR compared to conventional CABG, future randomized control trials with a larger number of patients are needed.

Future studies must address some important questions. First, the patients in the present study were younger (mean age, 62.1 ± 8.3 years) with less comorbidity and a relatively low SYNTAX score (23.6 ± 6.1 for the HCR arm). As CABG and PCI are associated with similar long- term outcomes in patients with low (< 22) to intermediate (22–32) SYNTAX score,³ comparisons between HCR and multivessel PCI using the current generation of drug-eluting stents are needed. The results from the ongoing Hybrid Coronary Revascularization Trial (NCT03089398) will shed light on this clinical question. Second, whether these findings can be extended to patients with a high baseline SYNTAX score needs further study. Nonetheless, outcomes were similar between the 2 strategies in the intermediate (n = 98) and high (n = 8) SYNTAX score groups. Interestingly, there is no clear benefit of HCR in the high surgical risk groups as measured by EuroScore. Third, in addition to the hard outcomes (death and MACCE), the quality of life of patients measured by an established metric, such as the Seattle Angina Questionnaire, need to be assessed. Last, the completeness of revascularization in each group needs to be further evaluated because incomplete revascularization is a known predictor of adverse outcomes.^4,5

Applications for Clinical Practice

In patients with multivessel coronary disease with low SYNTAX score, the 5-year outcome for HCR was similar to that of conventional CABG. Further larger studies are needed to assess the superiority of this approach.

—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO; Hiroto Kitahara, MD, University of Chicago Medical Center, Chicago, IL; and John Blair, MD, Medstar Washington Hospital Center, Washington, DC

Study Overview

Objective. To investigate the 5-year clinical outcome of patients undergoing hybrid revascularization for multivessel coronary artery disease (CAD).

Design. Multicenter, open-label, prospective randomized control trial.

Setting and participants. 200 patients with multivessel CAD referred for conventional surgical revascularization were randomly assigned to undergo hybrid coronary revascularization (HCR) or coronary artery bypass grafting (CABG).

Main outcome measures. The primary endpoint was all-cause mortality at 5 years.

Main results. After excluding 9 patients who were lost to follow-up before 5 years, 191 patients (94 in HCR group and 97 in CABG group) formed the basis of the study. All-cause mortality at 5-year follow-up was similar in the 2 groups (6.4% versus 9.2%, P = 0.69). The rates of myocardial infarction (4.3% versus 7.2%, P = 0.30), repeat revascularization (37.2% versus 45.4%, P = 0.38), stroke (2.1% versus 4.1%, P = 0.35), and major adverse and cardiac and cerebrovascular events (45.2% versus 53.4%, P = 0.39) were similar in the 2 groups. These findings were consistent across all levels of risk for surgical complications (EuroScore) and for complexity of revascularization (SYNTAX score).

Conclusion. HCR has similar 5-year all-cause mortality when compared with conventional CABG.

Commentary

HCR has been proposed as a less invasive, effective alternative revascularization strategy to conventional CABG for patients with multivessel CAD. The hybrid approach typically combines the long-term durability of grafting of the left anterior descending artery (LAD) using the left internal mammary artery and the percutaneous coronary intervention (PCI) for non-LAD stenosis; this approach has been shown to have similar or perhaps even better long-term patency compared with saphenous vein grafts.^1,2 Previous studies have demonstrated the feasibility of HCR by comparing HCR to conventional CABG at 1 year.² However, the long-term outcome of HCR compared to conventional CABG has not been previously reported.

In this context, Tajstra et al reported the 5-year follow-up from their prospective randomized pilot study. They report that among the 200 patients with multivessel coronary disease randomly assigned to either HCR or CABG, all-cause mortality at 5-year follow-up was similar in the 2 groups (6.4% versus 9.2%, P = 0.69). The rates of myocardial infarction, repeat revascularization, stroke, and major adverse and cardiac and cerebrovascular event (MACCE) were also similar in the 2 groups.

This is an important study because it is the first to compare the long-term outcome of HCR with conventional CABG; previous studies have been limited due to their short- to mid-term follow-up.² However, because this study was not powered to assess the superiority of the HCR compared to conventional CABG, future randomized control trials with a larger number of patients are needed.

Future studies must address some important questions. First, the patients in the present study were younger (mean age, 62.1 ± 8.3 years) with less comorbidity and a relatively low SYNTAX score (23.6 ± 6.1 for the HCR arm). As CABG and PCI are associated with similar long- term outcomes in patients with low (< 22) to intermediate (22–32) SYNTAX score,³ comparisons between HCR and multivessel PCI using the current generation of drug-eluting stents are needed. The results from the ongoing Hybrid Coronary Revascularization Trial (NCT03089398) will shed light on this clinical question. Second, whether these findings can be extended to patients with a high baseline SYNTAX score needs further study. Nonetheless, outcomes were similar between the 2 strategies in the intermediate (n = 98) and high (n = 8) SYNTAX score groups. Interestingly, there is no clear benefit of HCR in the high surgical risk groups as measured by EuroScore. Third, in addition to the hard outcomes (death and MACCE), the quality of life of patients measured by an established metric, such as the Seattle Angina Questionnaire, need to be assessed. Last, the completeness of revascularization in each group needs to be further evaluated because incomplete revascularization is a known predictor of adverse outcomes.^4,5

Applications for Clinical Practice

In patients with multivessel coronary disease with low SYNTAX score, the 5-year outcome for HCR was similar to that of conventional CABG. Further larger studies are needed to assess the superiority of this approach.

—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO; Hiroto Kitahara, MD, University of Chicago Medical Center, Chicago, IL; and John Blair, MD, Medstar Washington Hospital Center, Washington, DC

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

 

 

Variables

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, Jason.DeGiovanni@tufts.edu.

Financial disclosures: None.

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

 

 

Variables

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, Jason.DeGiovanni@tufts.edu.

Financial disclosures: None.

From Tufts Medical Center, Boston, MA.

Abstract

• Objective: Audits at our academic medical center revealed near 100% compliance with protocols for perioperative venous thromboembolism (VTE) prophylaxis, but recent National Surgical Quality Improvement Program data demonstrated a higher than expected incidence of VTE (observed/expected = 1.32). The objective of this study was to identify potential causes of this discrepancy.
• Design: Retrospective case-control study.
• Setting: Urban academic medical center with high case-mix indices (Medicare approximately 2.4, non-Medicare approximately 2.0).
• Participants: 102 surgical inpatients with VTE (September 2012 to October 2015) matched with controls for age, gender, and type of procedure.
• Measurements: Prevalence of common VTE risk factors, length of stay, number of procedures, index operation times, and postoperative bed rest > 12 hours were assessed. Utilization of and compliance with our VTE risk assessment tool was also investigated.
• Results: Cases underwent more procedures and had longer lengths of stay and index procedures than controls. In addition, cases were more likely to have had > 12 hours of postoperative bed rest and central venous access than controls. Cases had more infections and were more likely to have severe lung disease, thrombophilia, and a history of prior VTE than controls. No differences in body mass index, tobacco use, current or previous malignancy, or VTE risk assessment form use were observed. Overall, care complexity and risk factors were equally important in determining VTE incidence. Our analyses also revealed lack of strict adherence to our VTE risk stratification protocol and frequent use of suboptimal prophylactic regimens.
• Conclusion: Well-accepted risk factors and overall care complexity determine VTE risk. Preventing VTE in high-risk patients requires assiduous attention to detail in VTE risk assessment and in delivery of optimal prophylaxis. Patients at especially high risk may require customized prophylactic regimens.

Keywords: hospital-acquired venous thromboembolic disease; VTE prophylaxis, surgical patients.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are well-recognized causes of morbidity and mortality in surgical patients. Between 350,000 and 600,000 cases of venous thromboembolism (VTE) occur each year in the United States, and it is responsible for approximately 10% of preventable in-hospital fatalities.^1-3 Given VTE’s impact on patients and the healthcare system and the fact that it is preventable, intense effort has been focused on developing more effective prophylactic measures to decrease its incidence.^2-4 In 2008, the surgeon general issued a “call to action” for increased efforts to prevent VTE.⁵

The American College of Chest Physicians (ACCP) guidelines subcategorize patients based on type of surgery. In addition, the ACCP guidelines support the use of a Caprini-based scoring system to aid in risk stratification and improve clinical decision-making (Table 1).^4,6-9 In general, scores ≥ 5 qualify individuals as high risk. Based on their risk category, patients receive mechanical prophylaxis, chemical prophylaxis, or a combination of the 2. Lower-risk patients who are ambulatory typically receive only mechanical prophylaxis while in bed, whereas higher-risk patients receive a combination of mechanical prophylaxis and chemoprophylaxis measures.⁷ In general, low-molecular-weight heparin (40 mg daily) and low-dose unfractionated heparin (5000 units 3 times daily) have been the standard evidence-based options for chemoprophylaxis in surgical patients. Absolute contraindications for prophylaxis include active bleeding and known increased risk of bleeding based on patient- or procedure-specific factors.

Our hospital, a 350-bed academic medical center in downtown Boston, MA, serving a diverse population with a very high case-mix index (2.4 Medicare and 2.0 non-Medicare), has strict protocols for VTE prophylaxis consistent with the ACCP guidelines and based on the Surgical Care Improvement Project (SCIP) measures published in 2006.¹⁰ The SCIP mandates allow for considerable surgeon discretion in the use of chemoprophylaxis for neurosurgical cases and general and orthopedic surgery cases deemed to be at high risk for bleeding. In addition, SCIP requires only that prophylaxis be initiated within 24 hours of surgical end time. Although recent audits revealed nearly 100% compliance with SCIP-mandated protocols, National Surgical Quality Improvement Program (NSQIP) data showed that the incidence of VTE events at our institution was higher than expected (observed/expected [O/E] = 1.32).

In order to determine the reasons for this mismatch between process and outcome performance, we investigated whether there were characteristics of our patient population that contributed to the higher than expected rates of VTE, and we scrutinized our VTE prophylaxis protocol to determine if there were aspects of our process that were also contributory.

Methods

Study Sample

This is a retrospective case-control study of surgical inpatients at our hospital during the period September 2012 to October 2015. Cases were identified as patients diagnosed with a VTE (DVT or PE). Controls were identified from a pool of surgical patients whose courses were not complicated by VTE during the same time frame as the cases and who were matched as closely as possible by procedure code, age, and gender.

 

 

Variables

Patient and hospital course variables that were analyzed included demographics, comorbidities, length of stay, number of procedures, index operation times, duration of postoperative bed rest, use of mechanical prophylaxis, and type of chemoprophylaxis and time frame within which it was initiated. Data were collected via chart review using International Classification of Diseases-9 and -10 codes to identify surgical cases within the allotted time period who were diagnosed with VTE. Demographic variables included age, sex, and ethnicity. Comorbidities included hypertension, diabetes, coronary artery disease, serious lung disease, previous or current malignancy, documented hypercoagulable state, and previous history of VTE. Body mass index (BMI) was also recorded. The aforementioned disease-specific variables were not matched between the case and control groups, as this data was obtained retrospectively during data collection.

Analysis

Associations between case and matched control were analyzed using the paired t-test for continuous variables and McNemar’s test for categorical variables. P values < 0.05 were considered statistically significant. SAS Enterprise Guide 7.15 (Cary, NC) was used for all statistical analyses.

The requirement for informed consent was waived by our Institutional Review Board, as the study was initially deemed to be a quality improvement project, and all data used for this report were de-identified.

Results

Our retrospective case-control analysis included a sample of 102 surgical patients whose courses were complicated by VTE between September 2012 and October 2015. The cases were distributed among 6 different surgical categories (Figure 1): trauma (20%), cancer (10%), cardiovascular (21%), noncancer neurosurgery (28%), elective orthopedics (11%), and miscellaneous general surgery (10%).

Comparisons between cases and controls in terms of patient demographics and risk factors are shown in Table 2. No statistically significant difference was observed in ethnicity or race between the 2 groups. Overall, cases had more hip/pelvis/leg fractures at presentation (P = 0.0008). The case group also had higher proportions of patients with postoperative bed rest greater than 12 hours (P = 0.009), central venous access (P < 0.0001), infection (P < 0.0001), and lower extremity edema documented during the hospitalization prior to development of DVT (P < 0.0001). Additionally, cases had significantly greater rates of previous VTE (P = 0.0004), inherited or acquired thrombophilia (P = 0.03), history of stroke (P = 0.0003), and severe lung disease, including pneumonia (P = 0.0008). No significant differences were noted between cases and matched controls in BMI (P = 0.43), current tobacco use (P = 0.71), current malignancy (P = 0.80), previous malignancy (P = 0.83), head trauma (P = 0.17), or acute cardiac disease (myocardial infarction or congestive heart failure; P = 0.12).

Variables felt to indicate overall complexity of hospital course for cases as compared to controls are outlined in Table 3. Cases were found to have significantly longer lengths of stay (median, 15.5 days versus 3 days, P < 0.0001). To account for the possibility that the development of VTE contributed to the increased length of stay in the cases, we also looked at the duration between admission date and the date of VTE diagnosis and determined that cases still had a longer length of stay when this was accounted for (median, 7 days versus 3 days, P < 0.0001). A much higher proportion of cases underwent more than 1 procedure compared to controls (P < 0.0001), and cases had significantly longer index operations as compared to controls (P = 0.002).

Seventeen cases received heparin on induction during their index procedure, compared to 23 controls (P = 0.24). Additionally, 63 cases began a prophylaxis regimen within 24 hours of surgery end time, compared to 68 controls (P = 0.24). The chemoprophylactic regimens utilized in cases and in controls are summarized in Figure 2. Of note, only 26 cases and 32 controls received standard prophylactic regimens with no missed doses (heparin 5000 units 3 times daily or enoxaparin 40 mg daily). Additionally, in over half of cases and a third of controls, nonstandard regimens were ordered. Examples of nonstandard regimens included nonstandard heparin or enoxaparin doses, low-dose warfarin, or aspirin alone. In most cases, nonstandard regimens were justified on the basis of high risk for bleeding.

Mechanical prophylaxis with pneumatic sequential compression devices (SCDs) was ordered in 93 (91%) cases and 87 (85%) controls; however, we were unable to accurately document uniform compliance in the use of these devices.

With regard to evaluation of our process measures, we found only 17% of cases and controls combined actually had a VTE risk assessment in their chart, and when it was present, it was often incomplete or was completed inaccurately.

Discussion

The goal of this study was to identify factors (patient characteristics and/or processes of care) that may be contributing to the higher than expected incidence of VTE events at our medical center, despite internal audits suggesting near perfect compliance with SCIP-mandated protocols. We found that in addition to usual risk factors for VTE, an overarching theme of our case cohort was their high complexity of illness. At baseline, these patients had significantly greater rates of stroke, thrombophilia, severe lung disease, infection, and history of VTE than controls. Moreover, the hospital courses of cases were significantly more complex than those of controls, as these patients had more procedures, longer lengths of stay and longer index operations, higher rates of postoperative bed rest exceeding 12 hours, and more prevalent central venous access than controls (Table 2). Several of these risk factors have been found to contribute to VTE development despite compliance with prophylaxis protocols.

Cassidy et al reviewed a cohort of nontrauma general surgery patients who developed VTE despite receiving appropriate prophylaxis and found that both multiple operations and emergency procedures contributed to the failure of VTE prophylaxis.¹¹ Similarly, Wang et al identified several independent risk factors for VTE despite thromboprophylaxis, including central venous access and infection, as well as intensive care unit admission, hospitalization for cranial surgery, and admission from a long-term care facility.¹² While our study did not capture some of these additional factors considered by Wang et al, the presence of risk factors not captured in traditional assessment tools suggests that additional consideration for complex patients is warranted.

In addition to these nonmodifiable patient characteristics, aspects of our VTE prophylaxis processes likely contributed to the higher than expected rate of VTE. While the electronic medical record at our institution does contain a VTE risk assessment tool based on the Caprini score, we found it often is not used at all or is used incorrectly/incompletely, which likely reflects the fact that physicians are neither prompted nor required to complete the assessment prior to prescribing VTE prophylaxis.

There is a significant body of evidence demonstrating that mandatory computerized VTE risk assessments can effectively reduce VTE rates and that improved outcomes occur shortly after implementation. Cassidy et al demonstrated the benefits of instituting a hospital-wide, mandatory, Caprini-based computerized VTE risk assessment that provides prophylaxis/early ambulation recommendations. Two years after implementing this system, they observed an 84% reduction in DVTs (P < 0.001) and a 55% reduction in PEs (P < 0.001).¹³ Nimeri et al had similarly impressive success, achieving a reduction in their NSQIP O/E for PE/DVT in general surgery from 6.00 in 2010 to 0.82 (for DVTs) and 0.78 (for PEs) 5 years after implementation of mandatory VTE risk assessment (though they noted that the most dramatic reduction occurred 1 year after implementation).¹⁴ Additionally, a recent systematic review and meta-analysis by Borab et al found computerized VTE risk assessments to be associated with a significant decrease in VTE events.¹⁵

The risk assessment tool used at our institution is qualitative in nature, and current literature suggests that employing a more quantitative tool may yield improved outcomes. Numerous studies have highlighted the importance of identifying patients at very high risk for VTE, as higher risk may necessitate more careful consideration of their prophylactic regimens. Obi et al found patients with Caprini scores higher than 8 to be at significantly greater risk of developing VTE compared to patients with scores of 7 or 8. Also, patients with scores of 7 or 8 were significantly more likely to have a VTE compared to those with scores of 5 or 6.¹⁶ In another study, Lobastov et al identified Caprini scores of 11 or higher as representing an extremely high-risk category for which standard prophylaxis regimens may not be effective.¹⁷ Thus, while having mandatory risk assessment has been shown to dramatically decrease VTE incidence, it is important to consider the magnitude of the numerical risk score. This is of particular importance at medical centers with high case-mix indices where patients at the highest risk might need to be managed with different prophylactic guidelines.

Another notable aspect of the process at our hospital was the great variation in the types of prophylactic regimens ordered, and the adherence to what was ordered. Only 25.5% of patients were maintained on a standard prophylactic regimen with no missed doses (heparin 5000 every 8 hours or enoxaparin 40 mg daily). Thus, the vast majority of the patients who went on to develop VTE either were prescribed a nontraditional prophylaxis regimen or missed doses of standard agents. The need for secondary surgical procedures or other invasive interventions may explain many, but not all, of the missed doses.

The timing of prophylaxis initiation for our patients was also found to deviate from accepted standards. Only 16.8% of cases received prophylaxis upon induction of anesthesia, and furthermore, 38% of cases did not receive any anticoagulation within 24 hours of their index operation. While this variability in prophylaxis implementation was acceptable within the SCIP guidelines based on “high risk for bleeding” or other considerations, it likely contributed to our suboptimal outcomes. The variations and interruptions in prophylactic regimens speak to barriers that have previously been reported as contributing factors to noncompliance with VTE prophylaxis.¹⁸

Given these known barriers and the observed underutilization and improper use of our risk assessment tool, we have recently changed our surgical admission order sets such that a mandatory quantitative risk assessment must be done for every surgical patient at the time of admission/operation before other orders can be completed. Following completion of the assessment, the physician will be presented with an appropriate standard regimen based on the individual patient’s risk assessment. Early results of our VTE quality improvement project have been satisfying: in the most recent NSQIP semi-annual report, our O/E for VTE was 0.74, placing us in the first decile. Some of these early reports may simply be the product of the Hawthorne effect; however, we are encouraged by the early improvements seen in other research. While we are hopeful that these changes will result in sustainable improvements in outcomes, patients at extremely high risk may require novel weight-based or otherwise customized aggressive prophylactic regimens. Such regimens have already been proposed for arthroplasty and other high-risk patients.

Future research may identify other risk factors not captured by traditional risk assessments. In addition, research should continue to explore the use and efficacy of standard prophylactic regimens in these populations to help determine if they are sufficient. Currently, weight-based low-molecular-weight heparin dosing and alternative regimens employing fondaparinux are under investigation for very-high-risk patients.¹⁹

There were several limitations to the present study. First, due to the retrospective design of our study, we could collect only data that had been uniformly recorded in the charts throughout the study period. Second, we were unable to accurately assess compliance with mechanical prophylaxis. While our chart review showed that the vast majority of cases and controls were ordered to have mechanical prophylaxis, it is impossible to document how often these devices were used appropriately in a retrospective analysis. Anecdotal observation suggests that once patients are out of post-anesthesia or critical care units, SCD use is not standardized. The inability to measure compliance precisely may be leading to an overestimation of our compliance with prophylaxis. Finally, because our study included only patients who underwent surgery at our hospital, our observations may not be generalizable outside our institution.

Conclusion

Our study findings reinforce the importance of attention to detail in VTE risk assessment and in ordering and administering VTE prophylactic regimens, especially in high-risk surgical patients. While we adhered to the SCIP-mandated prophylaxis requirements, the complexity of our patients and our lack of a truly standardized approach to risk assessment and prophylactic regimens resulted in suboptimal outcomes. Stricter and more quantitative mandatory VTE risk assessment, along with highly standardized VTE prophylaxis regimens, are required to achieve optimal outcomes.

Corresponding author: Jason C. DeGiovanni, MS, BA, Jason.DeGiovanni@tufts.edu.

Financial disclosures: None.