From the University of Wisconsin School of Medicine and Public Health, Madison, WI.

Abstract

• Objective: To describe the contributing etiologies, common presentations, diagnosis, evaluation, and management of abnormal uterine bleeding (AUB).
• Methods: Review of the literature in the context of 3 cases.
• Results: AUB is one of the most common reasons that reproductive-aged women seek health care. The causes are varied, depending in large part on the age and life stage of the woman. Diagnosis requires a systematic approach that is driven by a thorough health history and review of presenting symptoms.  Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation. A methodical history, physical examination, and laboratory evaluation may enable the physician to rule out causes such as pregnancy and pregnancy-related disorders, medications, iatrogenic causes, systemic conditions, and obvious genital tract pathology.
• Conclusion: Clinicians must be knowledgeable about AUB and partner with women to develop appropriate, individualized treatment plans.

Abnormal vaginal bleeding is a common complaint in primary care. The prevalence of some type of abnormal bleeding is up to 30% among women of reproductive age [1].Over 18% of all gynecology outpatient visits in the United States are for menorrhagia alone [2].A retrospective analysis of medical expenditures data compared 1.4 million women with abnormal uterine bleeding to over 50 million women without abnormal bleeding. This study found that women with abnormal bleeding were more likely to be younger, Caucasian, and obese and had poorer physical and mental health quality of life scores [3].

The estimated direct and indirect costs of abnormal bleeding are $1 billion and $12 billion annually, respectively [4]. Indirect costs of abnormal bleeding include time off from work and cost of products to protect clothing from bleeding (eg, tampons and pads). Abnormal bleeding is also a common reason for women to be referred to gynecologists and is an indication for up to 25% of all gynecologic surgeries [5].

History Taking

Taking a menstrual history is an important step in determining whether the current bleeding pattern is normal or abnormal. Regularity of menstrual bleeding is clarified by asking about the frequency of the menses and their duration. Other important questions include age at menarche, presence of premenstrual syndrome symptoms, breast tenderness, cervical mucus changes, and amount of bleeding. An ovulatory cycle will usually include premenstrual symptoms whereas an anovulatory cycle will be random in its symptomatology. Women’s estimates of the amount of menstrual bleeding are notoriously inaccurate. Traditionally, more than 80 cc of menstrual blood loss per cycle is considered menorrhagia. However, women and their health care providers do not measure menstrual blood volume outside of study settings, and one study found that only half of women who presented with menorrhagia actually had more than 80 cc of blood loss [6]. There is movement toward use of more patient-centered measures to diagnose men-orrhagia, such as bleeding interfering with a woman’s daily activities, needing to wake up at night to change tampons or pads, or inability to exercise during menses. Anemia in the setting of menorrhagia by history is a less subjective way to diagnose menorrhagia.

Nomenclature and Differential Diagnosis

Differential diagnosis will vary based on symptomatology as well as age. Pregnancy is a possible cause of any type of abnormal bleeding in any woman of reproductive age (ie, after menarche and before menopause). Many systemic illnesses and medications can affect menstrual bleeding and should be included in a broad differential diagnosis of a presenting woman.

Case 1—Heavy Menstrual Bleeding

Initial Presentation

A 42-year-old woman presents reporting increasingly heavy, somewhat painful periods over the last 6 to 8 months. She experienced menarche at age 12 and has had regular, moderately heavy periods throughout her adult life. She denies any inter-menstrual bleeding.

• What additional history should be obtained?

Heavy menstrual bleeding refers to abnormally heavy bleeding that occurs in an ovulatory, cyclical pattern. Women with anovulatory cycles can also have heavy bleeding as well, and distinguishing ovulatory vs anovulatory cycles is often the first step in the evaluation.

The initial evaluation of a woman presenting with heavy menstrual bleeding includes a detailed history and physical examination. The first goal of the history is to establish the severity of bleeding, including any symptoms of hemodynamically significant anemia such as dizziness or exertional dyspnea. Next, the clinician should determine whether the bleeding pattern is ovulatory or anovulatory. Ovulatory heavy menstrual bleeding is most often caused by structural lesions (leiomyomas, endometriosis, adenomyosis, cervical polyps, and endometrial polyps) or a coagulopathy (von Willebrand disease, anticoagulant use, etc). Less commonly, ovulatory heavy menstrual bleeding may be due to systemic illness (including thyroid disease, renal disease, and liver disease) or endometrial hyperplasia or carcinoma.

Once an ovulatory pattern is confirmed, a history of dysmenorrhea, pelvic pain, lower urinary tract symptoms, constipation, dyspareunia, or infertility should be elicited. 

Further history taking should seek to identify any symptoms suggestive of thyroid, kidney, or liver disease, 

• What are key elements of the physical examination?

The physical examination should include visual inspection and palpation of the thyroid gland as well as an abdominal exam to evaluate for hepatosplenomegaly or lower abdominal tenderness or masses. Signs of anemia such as pallor should also be noted. The gynecologic exam should include visual inspection of the external genitalia, a bimanual exam, and a speculum exam. Cervical and endometrial polyps may be visible as masses at the cervical os or extending into the vaginal canal. An enlarged mobile uterus with irregular contours is consistent with leiomyomas [8].Endometriosis may manifest as tenderness, thickening, or nodularity of the uterine corpus, the vaginal canal, the uterosacral ligaments, or the adnexa. Endometriosis may also cause an asymmetric, fixed position of the uterus, the cervix, or the adnexa [9].Adenomyosis may cause diffuse moderate uterine enlargement with or without tenderness [10].Endometrial carcinoma may also cause uterine enlargement and/or immobility.

• What laboratory testing should be performed?

• What additional testing would be useful in narrowing the differential diagnosis?

If the physical examination and initial laboratory testing is nondiagnostic, the decision to initiate a trial of symptom management or proceed with further testing (imaging and/or tissue sampling) is based on risk of endometrial cancer, severity of symptoms, and patient preference. In many women, body habitus makes a confirmatory pelvic examination difficult, which may lower the threshold for obtaining a pelvic ultrasound.

Women with risk factors for endometrial cancer should undergo office-based endometrial biopsy as the first step in evaluation of heavy menstrual bleeding [7].Risk factors include older age (45 years and older), obesity (BMI > 30), diabetes mellitus, nulliparity, and history of chronic anovulation (eg, polycystic ovary syndrome). Pelvic ultrasound is the first step in the evaluation of women with an abnormal physical exam suggesting a structural lesion [7].If the physical exam is abnormal and the pelvic ultrasound is nondiagnostic, a hysteroscopy or saline-infusion sonohysterogram should be performed, as these tests are more sensitive for the detection of intracavitary lesions and submucosal fibroids [13].Most endometrial polyps will appear as a thickened or irregular endometrium on pelvic ultrasound, but be clearly delineated on sonohysterogram. Women who have a negative initial evaluation but then go on to have persistent bleeding despite a trial of therapy also require further evaluation.

Case Continued

The patient reports that her periods are regular, with a cycle length of 30 to 31 days. She usually notes some bloating and breast tenderness in the days leading up to onset of menses. She experiences lower abdominal cramping during days 1–3 of her period. This has worsened somewhat over the last year, and sometimes radiates to her low back. Her reproductive history is significant for 3 uncomplicated vaginal deliveries and 1 first trimester spontaneous abortion. She did not experience postpartum hemorrhage, and has no history of significant oropharyngeal bleeding or unexplained bruising. Her BMI is 23.3. Her physical exam is unremarkable, including a normal thyroid, abdominal, bimanual and speculum exam. Laboratory evaluation demonstrates a low-normal hemoglobin, hematocrit, and MCV. The TSH is normal and a urine pregnancy test is negative. She had a normal pap smear and HPV assay 2 years ago.

• What is the most likely diagnosis?

• What treatment is recommended?

Oral tranexamic acid is an anti-fibrinolytic that was recently approved by the FDA for treatment of menorrhagia or heavy menstrual bleeding. It has been used for many years to prevent bleeding during surgery and to treat bleeding disorders. It has been used for over 30 years to treat menorrhagia in Europe. It has a different mechanism of action than NSAIDs and hormonal contraceptives, and is therefore an appropriate alternative for women who cannot tolerate other medication options [16,17].Tranexamic acid is contraindicated in women with an elevated risk of thromboembolic disease.

For women who have insufficient response to medical management or for women who present with more severe symptoms, anemia, or prominent bulk-related symptoms due to fibroids, gynecologic referral should be made for consideration of surgical intervention. The preferred interventional approach to the treatment of uterine fibroid tumors depends upon the type of fibroid (eg submucosal, intramural, subserosal), the number of fibroids, desire for future childbearing, risk for surgical complications, and patient preference. Effective options include myomectomy, uterine artery embolization, endometrial ablation, and hysterectomy [18].

By contrast, good evidence supports the use of medication as first-line therapy for heavy menstrual bleeding when it occurs in the setting of endometriosis. Estrogen-progestin oral contraceptive pills, oral progestins, and depot medroxyprogesterone have all been demonstrated to be effective in decreasing pain [19,20].The levonorgestrel-releasing intrauterine system is also effective in decreasing pain due to endometriosis [21].

Women who do not respond to first-line therapy should be referred to a gynecologist for consideration of other treatment options. Effective second-line treatment options include oral danazol, intramuscular GnRH agonists, and surgical approaches such as laparoscopic ablation and/or excision of endometriosis implants [22].

A similar range of treatment options appears to be effective in the management of heavy menstrual bleeding due to adenomyosis. First-line therapies include oral NSAIDs, oral tranexamic acid, estrogen-progestin oral contraceptive pills, and the levonorgestrel-releasing intrauterine system [23,24].Women with an inadequate response to first-line treatment should be referred to a gynecologist for consideration definitive treatment with hysterectomy versus uterine artery embolization or a trial of a GnRH agonist [24].

For some women with heavy menstrual bleeding, no specific underlying cause is identified. Current evidence suggests that such patients may have disorders of local endometrial hemostasis leading to increased blood loss during otherwise normal menstrual cycles [25].The levonorgestrel-releasing intrauterine system may be the most effective medical therapy for heavy menstrual bleeding in the absence of a specific target lesion [26].For women wishing to avoid hormonal treatment, scheduled oral NSAIDs or oral tranexamic acid are inexpensive and effective options for reducing blood loss [27–29].Other medical treatment options include estrogen-progestin contraceptive pills, cyclic oral progestin, and depot medroxy-progesterone.

For patients who experience treatment failure with pharmaceutical therapy or who desire definitive treatment, both endometrial ablation and hysterectomy have been shown to be effective and associated with high rates of patient satisfaction [30].

Follow-up

The patient reports that she would like to avoid invasive testing if possible. Given her relatively low risk for endometrial cancer, she elects a trial of scheduled NSAIDs. Unfortunately, after a couple of cycles she reports that her heavy bleeding has not been well-controlled. A pelvic ultrasound demonstrates an anterior submucosal fibroid measuring 2.4 cm and a posterior intramural fibroid measuring 1.5 cm. She agrees to insertion of a levonorgestrel IUD and calls 6 months later to report a significant decrease in her bleeding.

Case 2—Anovulation

Initial Presentation

A 27-year-old female presents for pregnancy testing. She is 2 weeks late for her period. She and her husband are attempting pregnancy and she seems disappointed that the pregnancy test is negative. She is having trouble tracking her periods. Her cycles range from 24 to 45 days apart and often she skips cycles altogether. Her flow is scant at times but some months are heavy with soaking tampons/pads.

• What are diagnostic considerations in evaluating this bleeding pattern?

Menstrual history can help differentiate between of ovulatory and anovulatory abnormal bleeding. Typically, anovulatory bleeding is marked by irregular or infrequent periods. Flow can be scant to excessive. Women experiencing anovulatory cycles may fail to notice common ovulation symptoms (thin watery cervical mucus) or pre-menstrual symptoms (breast tenderness) [31].

The International Federation of Gynecology and Obstetrics (FIGO) designates AUD-O as “abnormal uterine bleeding due to ovulatory dysfunction” or “anovulatory abnormal uterine bleeding” [7,31].In general, if women are having menses at regular cycles their bleeding is likely to be ovulatory.

Differential Diagnosis

Anovulatory bleeding may be physiologic. After menarche, the hypothalamic-pituitary-ovarian axis is immature. This may result in anovulatory cycles for 2 to 3 years. Women entering perimenopausal transition may also experience intermittent anovulation and subsequent abnormal uterine bleeding. Other physiologic examples include lactation and pregnancy [31].

Physical Examination

A thorough history will help to narrow the differential diagnosis. The physical exam can evaluate for other findings that indicate endocrine dysfunction such as low body weight, hirsutism, balding, acne, high blood pressure, obesity (especially centripetal fat distribution). Acanthosis nigricans is a sign of insulin resistance which is part of the pathophysiology of PCOS. The gynecologic exam is often unremarkable in AUB-O although a bimanual exam can reveal adnexal enlargement indicative of cystic ovaries. Of note, clitoromegally is not common in PCOS. This finding would increase the likelihood of other causes of hyperandrogenism [32].

• What is the pathophysiologic basis for this patient’s bleeding pattern?

Pathophysiology of Anovulatory Bleeding

Anovulatory bleeding presumes that there is a normal anatomic and genetic makeup. For example, a woman without ovaries will be, by definition, anovulatory. Using current terminology anovulatory bleeding implies a disruption in the hypothalamic-pituitary-ovarian axis and is therefore primarily an endocrine disorder [31,33].

At the level of the ovary and uterus, anovulation results in prolonged estrogen effect on the endometrium. After ovulation, the corpus luteum produces progesterone which stops endometrial thickening and stabilizes the endometrium. Without ovulation, estrogen continues endometrial stimulation and excess proliferation of endometrial lining. The endometrium becomes unstable, undifferentiated, and sheds unpredictably. The blood vessels become larger, more tortuous and have increased fragility. The result is light or heavy menstrual bleeding, decreased frequency of periods but overall unpredictable menstrual bleeding [33].

Effects of Chronic Anovulation

Irregular cycles can be more than a mere inconvenience. Women who have anovulatory cycles associated with heavy menstrual bleeding are at risk for anemia. Anovulation that is a result of hyperandrogen state or other endocrine disorder has other health ramifications. Infertility and its treatment are common sequelae. Finally, over time, unopposed estrogen in anovulation increases the risk of endometrial hyperplasia, or cancer [7,34].

Case Continued

The patient reports menarche at age 12. Her periods were irregular for the first 1–2 years but became more regular after that. She has been taking combination oral contraceptives since the age of 20 to prevent pregnancy. She stopped this 1 year ago and she and her husband began actively trying to conceive 6 months ago. Her family history is notable for diabetes and hypertension in her father. Her mother had heavy periods leading up to menopause and had a hysterectomy with no malignancy at the age of 47. She has a BMI of 33; blood pressure is mildly elevated at 134/84 mm Hg. She has oily skin and acne along her chin and neck. She has mild hirsutism of her face. Otherwise her skin is normal appearing. She has an elevated waist circumference of 35 inches. The remainder of her exam is normal.

• What is the likely diagnosis?

Women with PCOS are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease, endometrial cancer, and infertility. Women with PCOS who become pregnant have increased risk of pregnancy complications such as hypertensive disorders and gestational diabetes.

• What tests are indicated in this patient?

Appropriate laboratory testing is often determined based on findings in the history and physical as well as the patient’s age. Anovulation in the first 18 months to 3 years after menarche is common and testing for pregnancy, infection, and anemia are often sufficient. Menorrhagia in adolescents warrants testing for bleeding disorders as well [7].Within 3 years of menarche, menstrual cycles should become more regular. Persistent anovulatory cycles increase the likelihood of pathologic causes and warrant additional evaluation. Pregnancy testing, thyroid stimulation hormone and prolactin levels are recommended first line evaluation [7,32,34].If PCOS is suspected an ultrasound can be performed but as noted above, polycystic ovaries are not required to make the diagnosis after adolescence.

Additional testing includes testosterone levels to look for androgen secreting tumors. Late onset congenital adrenal hyperplasia is an uncommon cause of hyperandrogenism but is more common in women of Ashkenazi Jewish descent and those with a family history [34].Morning hydroxyprogesterone can be performed to evaluate for this. If women exhibit abrupt change in menstrual pattern and other signs of cortisol excess (hypertension, abdominal striae) 24-hour urine cortisol can detect Cushing’s syndrome [34].

In patients with PCOS, additional testing to evaluate for medical comorbidities is recommended. This includes screening for diabetes, dyslipidemia, and liver dysfunction.

Case Continued

The patient’s prolactin and TSH are normal. Tests for diabetes are normal. Her LDL is elevated to 162, triglycerides are 200, and her HDL is 38. The physician informs her that she meets criteria for PCOS and also that she has obesity and metabolic syndrome.

• What factors should be considered when making treatment recommendations for this patient?

Treatment for anovulation is guided by the goals of therapy. Since anovulation is an endocrine abnormality, medical treatment is first line [31].If secondary causes are diagnosed, these should be treated first. Other goals of treatment can include reducing amount and irregularity of menstruation, provide contraception, increasing ovulation in women with desired fertility, and reducing androgenic sequelae such as acne and hirsutism.

When treating the irregular or heavy bleeding associated with anovulation, first-line treatment is exogenous hormone. This can be in the form of combined estrogen/progesterone formulations (pill, patch, and ring). Medroxyprogesterone (medroxyprogesterone acetate 5–10 mg daily) taken 10 to 14 days per month is another option. Standard consideration for medical eligibility in prescribing these agents should be considered (see U.S. medical eligibility criteria for contraceptive use available at www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm). Combined formulations offer contraception, while cyclic progesterone does not. Both offer cyclic withdrawal bleeding. A Cochrane review did not find any RCTs comparing one to the other and therefore either are reasonable options [36].The levonorgestrel IUD is effective at treating AUB as well [31].Women may still experience intermittent vaginal bleeding or amenorrhea so it is less likely to result in cyclic withdrawal bleeding.

All of the above treatments provide the additional benefit of thinning the endometrium and preventing unopposed estrogen effect. This provides further protection the endometrial hyperplasia with chronic anovulatory cycles and unopposed estrogen [31].

In women with PCOS and associated metabolic conditions, first-line treatment is weight loss and other lifestyle interventions to improve or prevent other sequelae of the condition. Weight loss has been shown to reduce circulating androgen levels and increase ovulation. It has been shown to reduce glucose and lipid levels and hirsutism. Pregnancy rates increase as well. Weight loss achieved through medications and gastric bypass has similar effects. There is no special diet that has been shown to be more effective than another [32]. As little as a 5% weight reduction from baseline can improve PCOS symptoms [34,35].

Metformin is also commonly added to lifestyle modifications in women with PCOS to reduce risks for developing diabetes. There is little high quality evidence of added benefit above lifestyle modifications [34].Statin therapy can be considered in women with hyperlipidemia and PCOS [32].

For women with PCOS who desire to conceive, treatment should target increased ovulation. Pre-conception counseling and lifestyle modifications are again first line [32].Ovulation induction interventions carry increased risk of multiple gestation. For ovulation induction, clomiphene citrate is first line therapy. Metformin is commonly used as noted above to improve comorbidities associated with PCOS and can increase ovulation compared to placebo [37].However, RCTs do not support its use as first-line treatment of infertility treatment in PCOS. Clomiphene is 3 times more effective than metformin alone [32].

Medications can improve but often do not resolve hirsutism in women with PCOS. Combined hormonal contraceptives are commonly used off-label and no one type of pill has been shown to be superior. Anti-androgens are also off-label but empirically used. They can also improve lipid and other metabolic variables. They are all teratogenic and therefore should not be used in women who desire conception, and be used with effective contraceptives. Spironolactone is an androgen receptor antagonist. It takes months for effect. Some women will have improved menstrual frequency with this medication as well. Often adjunctive therapy such as eflornithine facial cream or laser therapy or a combination is needed to further treat hirsutism [32,35,38].

Follow-up

After discussion, the patient decides to adopt therapeutic lifestyle changes. She desires to get pregnant and does not opt for hormonal contraceptives at this time. She sees a nutritionist and begins calorie restriction and exercise. Three months later she has lost 20 pounds and feels “healthier.” Her lipid panel shows LDL of 125 and HDL of 43. Her triglycerides are now 160. Her blood pressure in the office is 118/78 mm Hg. She has lost “inches” around her middle. She has had more regular periods as well. She is still not pregnant so the physician asks her to begin tracking ovulation with cervical mucus evaluation and basal body temperature prior to considering further infertility evaluations. Three months after that she misses a period but is pleased to report a positive home pregnancy test.

Case 3—Breakthough Bleeding On Combined Hormonal Contraceptives 

A 28-year-old G0P0 in a monogamous relationship presents to her physician. She has been on oral contraceptive pills for 8 years. For the last 3 years she has been taking the pills on an extended cycle schedule. She normally takes an active pill daily for 3 cycles of pills (9 weeks), and then takes a 7-day pill-free week when she gets a menstrual period. This had been working fine until the last 6 months. She has noticed breakthrough spotting up to 2 weeks at a time during the 2nd and 3rd pack of pills.

• What is the approach to evaluation and treatment in this patient?

Bleeding in Women on Combined Hormonal Contraception

Many women are now using combined hormonal contraceptives on different schedules. Extended-cycle contraception has been shown to be as effective as the traditional 21/7 schedule of active pills/pill-free week. The FDA has approved several packaged extended-cycle contraceptives. Extended-cycle contraception decreases overall number of bleeding days and improves many menstrual-related symptoms [39].Breakthrough bleeding is the most common side effect of extended cycle contraception. It is classified as AUB-I (abnormal uterine bleeding—iatrogenic). It is most common in the first few months of use, and decreases as use continues. Up to 86% of women will have unscheduled bleeding during the first 3 months of use of extended cycle contraception, but this bleedingdecreases as use continues [40].

There is no consensus as to the underlying mechanism causing this abnormal bleeding. Most clinicians believe that it is related to the balance of estrogen/progestin in each combined hormonal contraceptive. Each woman reacts differently to this combination, making it difficult to predict who will have abnormal bleeding. In women who are beginning an extended-cycle regimen, reassurance is sufficient. Most abnormal bleeding will normalize within the first 2 to 3 months. Missed pills and smoking are consistently related to breakthrough bleeding in women who take combined oral contraceptive pills [41].In women who have previously had stable bleeding patterns and who present with new breakthrough bleeding, evaluation for secondary causes of bleeding may be considered (ie, urine hCG, TSH, STI cultures, evaluation for cervical cancer screening). A pelvic examination may help determine a possible secondary cause of bleeding, but is not necessary.

Treatment of unscheduled bleeding in women on extended-cycle contraception includes shortening the hormone-free interval and adding medications for prevention/treatment of bleeding episodes. The 7-day hormone-free interval in the context of low-dose hormonal contraception may be too long. One study demonstrated that a 7-day hormone-free interval was associated with a lack of pituitary-ovarian suppression, follicular development, and possible ovulation [42].A systematic review found that shortened hormone-free intervals decreased the amount of unscheduled bleeding [39].A small RCT (65 women) of continuous contraceptive ring users found that the group that removed the ring for 4 days during an episode of unscheduled bleeding, and then reinserted it had overall reduction in unscheduled bleeding [43].Some clinicians will also recommend trying a different pill formlation or a different schedule. There is no evidence to support this recommendation, but it can be helpful in some women.

Low-dose doxycycline (40 mg daily) for prevention of unscheduled bleeding shows promise [44].This low- dose doxycycline is also helpful to prevent more unscheduled bleeding in extended-cycle oral contraceptive users [44].However, an RCT found that traditional-dose doxycline (100 mg BID) taken for 5 days at the onset of a bleeding episode, did not decrease the amount or length of unscheduled bleeding [40].Neither estrogen dose [45]nor progestin dose [45]affected bleeding patterns. There is some suggestion based on a small study that women on pills with norethindrone may have less unscheduled bleeding than those who are on pills with levonorgestrel, but more research needs to be done before clinicians change practice [46].A Cochrane review looked at one small study that suggested third-generation progestins had more favorable bleeding profiles than second-generation progestins [47].

Follow-up

The physician investigates for secondary causes of the bleeding. The patient’s urine hCG, TSH, and prolactin levels are all normal. No fibroids or polyps are seen on ultrasound. The physician and patient discuss treatment options, including a low-dose doxycycline pill to help minimize bleeding, trying a different pill formulation, or use of naproxen during the bleeding episodes, but the patient does not want to take 2 pills every day. After further discussion, the patient decides she would like to change to the contraceptive ring with the plan of removing the ring for 4 days at the onset of any unscheduled bleeding. In a phone call 6 months later, the patient states that her unscheduled bleeding has been controlled.

Corresponding author: Sarina Schrager, MD, MS, Dept. of Family Medicine, University of Wisconsin School of Medicine and Public Health, 1100 Delaplaine Ct., Madison, WI 53715, sbschrag@wisc.edu.

From the University of Wisconsin School of Medicine and Public Health, Madison, WI.

Abstract

• Objective: To describe the contributing etiologies, common presentations, diagnosis, evaluation, and management of abnormal uterine bleeding (AUB).
• Methods: Review of the literature in the context of 3 cases.
• Results: AUB is one of the most common reasons that reproductive-aged women seek health care. The causes are varied, depending in large part on the age and life stage of the woman. Diagnosis requires a systematic approach that is driven by a thorough health history and review of presenting symptoms.  Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation. A methodical history, physical examination, and laboratory evaluation may enable the physician to rule out causes such as pregnancy and pregnancy-related disorders, medications, iatrogenic causes, systemic conditions, and obvious genital tract pathology.
• Conclusion: Clinicians must be knowledgeable about AUB and partner with women to develop appropriate, individualized treatment plans.

Abnormal vaginal bleeding is a common complaint in primary care. The prevalence of some type of abnormal bleeding is up to 30% among women of reproductive age [1].Over 18% of all gynecology outpatient visits in the United States are for menorrhagia alone [2].A retrospective analysis of medical expenditures data compared 1.4 million women with abnormal uterine bleeding to over 50 million women without abnormal bleeding. This study found that women with abnormal bleeding were more likely to be younger, Caucasian, and obese and had poorer physical and mental health quality of life scores [3].

The estimated direct and indirect costs of abnormal bleeding are $1 billion and $12 billion annually, respectively [4]. Indirect costs of abnormal bleeding include time off from work and cost of products to protect clothing from bleeding (eg, tampons and pads). Abnormal bleeding is also a common reason for women to be referred to gynecologists and is an indication for up to 25% of all gynecologic surgeries [5].

History Taking

Taking a menstrual history is an important step in determining whether the current bleeding pattern is normal or abnormal. Regularity of menstrual bleeding is clarified by asking about the frequency of the menses and their duration. Other important questions include age at menarche, presence of premenstrual syndrome symptoms, breast tenderness, cervical mucus changes, and amount of bleeding. An ovulatory cycle will usually include premenstrual symptoms whereas an anovulatory cycle will be random in its symptomatology. Women’s estimates of the amount of menstrual bleeding are notoriously inaccurate. Traditionally, more than 80 cc of menstrual blood loss per cycle is considered menorrhagia. However, women and their health care providers do not measure menstrual blood volume outside of study settings, and one study found that only half of women who presented with menorrhagia actually had more than 80 cc of blood loss [6]. There is movement toward use of more patient-centered measures to diagnose men-orrhagia, such as bleeding interfering with a woman’s daily activities, needing to wake up at night to change tampons or pads, or inability to exercise during menses. Anemia in the setting of menorrhagia by history is a less subjective way to diagnose menorrhagia.

Nomenclature and Differential Diagnosis

Differential diagnosis will vary based on symptomatology as well as age. Pregnancy is a possible cause of any type of abnormal bleeding in any woman of reproductive age (ie, after menarche and before menopause). Many systemic illnesses and medications can affect menstrual bleeding and should be included in a broad differential diagnosis of a presenting woman.

Case 1—Heavy Menstrual Bleeding

Initial Presentation

A 42-year-old woman presents reporting increasingly heavy, somewhat painful periods over the last 6 to 8 months. She experienced menarche at age 12 and has had regular, moderately heavy periods throughout her adult life. She denies any inter-menstrual bleeding.

• What additional history should be obtained?

Heavy menstrual bleeding refers to abnormally heavy bleeding that occurs in an ovulatory, cyclical pattern. Women with anovulatory cycles can also have heavy bleeding as well, and distinguishing ovulatory vs anovulatory cycles is often the first step in the evaluation.

The initial evaluation of a woman presenting with heavy menstrual bleeding includes a detailed history and physical examination. The first goal of the history is to establish the severity of bleeding, including any symptoms of hemodynamically significant anemia such as dizziness or exertional dyspnea. Next, the clinician should determine whether the bleeding pattern is ovulatory or anovulatory. Ovulatory heavy menstrual bleeding is most often caused by structural lesions (leiomyomas, endometriosis, adenomyosis, cervical polyps, and endometrial polyps) or a coagulopathy (von Willebrand disease, anticoagulant use, etc). Less commonly, ovulatory heavy menstrual bleeding may be due to systemic illness (including thyroid disease, renal disease, and liver disease) or endometrial hyperplasia or carcinoma.

Once an ovulatory pattern is confirmed, a history of dysmenorrhea, pelvic pain, lower urinary tract symptoms, constipation, dyspareunia, or infertility should be elicited. 

Further history taking should seek to identify any symptoms suggestive of thyroid, kidney, or liver disease, 

• What are key elements of the physical examination?

The physical examination should include visual inspection and palpation of the thyroid gland as well as an abdominal exam to evaluate for hepatosplenomegaly or lower abdominal tenderness or masses. Signs of anemia such as pallor should also be noted. The gynecologic exam should include visual inspection of the external genitalia, a bimanual exam, and a speculum exam. Cervical and endometrial polyps may be visible as masses at the cervical os or extending into the vaginal canal. An enlarged mobile uterus with irregular contours is consistent with leiomyomas [8].Endometriosis may manifest as tenderness, thickening, or nodularity of the uterine corpus, the vaginal canal, the uterosacral ligaments, or the adnexa. Endometriosis may also cause an asymmetric, fixed position of the uterus, the cervix, or the adnexa [9].Adenomyosis may cause diffuse moderate uterine enlargement with or without tenderness [10].Endometrial carcinoma may also cause uterine enlargement and/or immobility.

• What laboratory testing should be performed?

• What additional testing would be useful in narrowing the differential diagnosis?

If the physical examination and initial laboratory testing is nondiagnostic, the decision to initiate a trial of symptom management or proceed with further testing (imaging and/or tissue sampling) is based on risk of endometrial cancer, severity of symptoms, and patient preference. In many women, body habitus makes a confirmatory pelvic examination difficult, which may lower the threshold for obtaining a pelvic ultrasound.

Women with risk factors for endometrial cancer should undergo office-based endometrial biopsy as the first step in evaluation of heavy menstrual bleeding [7].Risk factors include older age (45 years and older), obesity (BMI > 30), diabetes mellitus, nulliparity, and history of chronic anovulation (eg, polycystic ovary syndrome). Pelvic ultrasound is the first step in the evaluation of women with an abnormal physical exam suggesting a structural lesion [7].If the physical exam is abnormal and the pelvic ultrasound is nondiagnostic, a hysteroscopy or saline-infusion sonohysterogram should be performed, as these tests are more sensitive for the detection of intracavitary lesions and submucosal fibroids [13].Most endometrial polyps will appear as a thickened or irregular endometrium on pelvic ultrasound, but be clearly delineated on sonohysterogram. Women who have a negative initial evaluation but then go on to have persistent bleeding despite a trial of therapy also require further evaluation.

Case Continued

The patient reports that her periods are regular, with a cycle length of 30 to 31 days. She usually notes some bloating and breast tenderness in the days leading up to onset of menses. She experiences lower abdominal cramping during days 1–3 of her period. This has worsened somewhat over the last year, and sometimes radiates to her low back. Her reproductive history is significant for 3 uncomplicated vaginal deliveries and 1 first trimester spontaneous abortion. She did not experience postpartum hemorrhage, and has no history of significant oropharyngeal bleeding or unexplained bruising. Her BMI is 23.3. Her physical exam is unremarkable, including a normal thyroid, abdominal, bimanual and speculum exam. Laboratory evaluation demonstrates a low-normal hemoglobin, hematocrit, and MCV. The TSH is normal and a urine pregnancy test is negative. She had a normal pap smear and HPV assay 2 years ago.

• What is the most likely diagnosis?

• What treatment is recommended?

Oral tranexamic acid is an anti-fibrinolytic that was recently approved by the FDA for treatment of menorrhagia or heavy menstrual bleeding. It has been used for many years to prevent bleeding during surgery and to treat bleeding disorders. It has been used for over 30 years to treat menorrhagia in Europe. It has a different mechanism of action than NSAIDs and hormonal contraceptives, and is therefore an appropriate alternative for women who cannot tolerate other medication options [16,17].Tranexamic acid is contraindicated in women with an elevated risk of thromboembolic disease.

For women who have insufficient response to medical management or for women who present with more severe symptoms, anemia, or prominent bulk-related symptoms due to fibroids, gynecologic referral should be made for consideration of surgical intervention. The preferred interventional approach to the treatment of uterine fibroid tumors depends upon the type of fibroid (eg submucosal, intramural, subserosal), the number of fibroids, desire for future childbearing, risk for surgical complications, and patient preference. Effective options include myomectomy, uterine artery embolization, endometrial ablation, and hysterectomy [18].

By contrast, good evidence supports the use of medication as first-line therapy for heavy menstrual bleeding when it occurs in the setting of endometriosis. Estrogen-progestin oral contraceptive pills, oral progestins, and depot medroxyprogesterone have all been demonstrated to be effective in decreasing pain [19,20].The levonorgestrel-releasing intrauterine system is also effective in decreasing pain due to endometriosis [21].

Women who do not respond to first-line therapy should be referred to a gynecologist for consideration of other treatment options. Effective second-line treatment options include oral danazol, intramuscular GnRH agonists, and surgical approaches such as laparoscopic ablation and/or excision of endometriosis implants [22].

A similar range of treatment options appears to be effective in the management of heavy menstrual bleeding due to adenomyosis. First-line therapies include oral NSAIDs, oral tranexamic acid, estrogen-progestin oral contraceptive pills, and the levonorgestrel-releasing intrauterine system [23,24].Women with an inadequate response to first-line treatment should be referred to a gynecologist for consideration definitive treatment with hysterectomy versus uterine artery embolization or a trial of a GnRH agonist [24].

For some women with heavy menstrual bleeding, no specific underlying cause is identified. Current evidence suggests that such patients may have disorders of local endometrial hemostasis leading to increased blood loss during otherwise normal menstrual cycles [25].The levonorgestrel-releasing intrauterine system may be the most effective medical therapy for heavy menstrual bleeding in the absence of a specific target lesion [26].For women wishing to avoid hormonal treatment, scheduled oral NSAIDs or oral tranexamic acid are inexpensive and effective options for reducing blood loss [27–29].Other medical treatment options include estrogen-progestin contraceptive pills, cyclic oral progestin, and depot medroxy-progesterone.

For patients who experience treatment failure with pharmaceutical therapy or who desire definitive treatment, both endometrial ablation and hysterectomy have been shown to be effective and associated with high rates of patient satisfaction [30].

Follow-up

The patient reports that she would like to avoid invasive testing if possible. Given her relatively low risk for endometrial cancer, she elects a trial of scheduled NSAIDs. Unfortunately, after a couple of cycles she reports that her heavy bleeding has not been well-controlled. A pelvic ultrasound demonstrates an anterior submucosal fibroid measuring 2.4 cm and a posterior intramural fibroid measuring 1.5 cm. She agrees to insertion of a levonorgestrel IUD and calls 6 months later to report a significant decrease in her bleeding.

Case 2—Anovulation

Initial Presentation

A 27-year-old female presents for pregnancy testing. She is 2 weeks late for her period. She and her husband are attempting pregnancy and she seems disappointed that the pregnancy test is negative. She is having trouble tracking her periods. Her cycles range from 24 to 45 days apart and often she skips cycles altogether. Her flow is scant at times but some months are heavy with soaking tampons/pads.

• What are diagnostic considerations in evaluating this bleeding pattern?

Menstrual history can help differentiate between of ovulatory and anovulatory abnormal bleeding. Typically, anovulatory bleeding is marked by irregular or infrequent periods. Flow can be scant to excessive. Women experiencing anovulatory cycles may fail to notice common ovulation symptoms (thin watery cervical mucus) or pre-menstrual symptoms (breast tenderness) [31].

The International Federation of Gynecology and Obstetrics (FIGO) designates AUD-O as “abnormal uterine bleeding due to ovulatory dysfunction” or “anovulatory abnormal uterine bleeding” [7,31].In general, if women are having menses at regular cycles their bleeding is likely to be ovulatory.

Differential Diagnosis

Anovulatory bleeding may be physiologic. After menarche, the hypothalamic-pituitary-ovarian axis is immature. This may result in anovulatory cycles for 2 to 3 years. Women entering perimenopausal transition may also experience intermittent anovulation and subsequent abnormal uterine bleeding. Other physiologic examples include lactation and pregnancy [31].

Physical Examination

A thorough history will help to narrow the differential diagnosis. The physical exam can evaluate for other findings that indicate endocrine dysfunction such as low body weight, hirsutism, balding, acne, high blood pressure, obesity (especially centripetal fat distribution). Acanthosis nigricans is a sign of insulin resistance which is part of the pathophysiology of PCOS. The gynecologic exam is often unremarkable in AUB-O although a bimanual exam can reveal adnexal enlargement indicative of cystic ovaries. Of note, clitoromegally is not common in PCOS. This finding would increase the likelihood of other causes of hyperandrogenism [32].

• What is the pathophysiologic basis for this patient’s bleeding pattern?

Pathophysiology of Anovulatory Bleeding

Anovulatory bleeding presumes that there is a normal anatomic and genetic makeup. For example, a woman without ovaries will be, by definition, anovulatory. Using current terminology anovulatory bleeding implies a disruption in the hypothalamic-pituitary-ovarian axis and is therefore primarily an endocrine disorder [31,33].

At the level of the ovary and uterus, anovulation results in prolonged estrogen effect on the endometrium. After ovulation, the corpus luteum produces progesterone which stops endometrial thickening and stabilizes the endometrium. Without ovulation, estrogen continues endometrial stimulation and excess proliferation of endometrial lining. The endometrium becomes unstable, undifferentiated, and sheds unpredictably. The blood vessels become larger, more tortuous and have increased fragility. The result is light or heavy menstrual bleeding, decreased frequency of periods but overall unpredictable menstrual bleeding [33].

Effects of Chronic Anovulation

Irregular cycles can be more than a mere inconvenience. Women who have anovulatory cycles associated with heavy menstrual bleeding are at risk for anemia. Anovulation that is a result of hyperandrogen state or other endocrine disorder has other health ramifications. Infertility and its treatment are common sequelae. Finally, over time, unopposed estrogen in anovulation increases the risk of endometrial hyperplasia, or cancer [7,34].

Case Continued

The patient reports menarche at age 12. Her periods were irregular for the first 1–2 years but became more regular after that. She has been taking combination oral contraceptives since the age of 20 to prevent pregnancy. She stopped this 1 year ago and she and her husband began actively trying to conceive 6 months ago. Her family history is notable for diabetes and hypertension in her father. Her mother had heavy periods leading up to menopause and had a hysterectomy with no malignancy at the age of 47. She has a BMI of 33; blood pressure is mildly elevated at 134/84 mm Hg. She has oily skin and acne along her chin and neck. She has mild hirsutism of her face. Otherwise her skin is normal appearing. She has an elevated waist circumference of 35 inches. The remainder of her exam is normal.

• What is the likely diagnosis?

Women with PCOS are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease, endometrial cancer, and infertility. Women with PCOS who become pregnant have increased risk of pregnancy complications such as hypertensive disorders and gestational diabetes.

• What tests are indicated in this patient?

Appropriate laboratory testing is often determined based on findings in the history and physical as well as the patient’s age. Anovulation in the first 18 months to 3 years after menarche is common and testing for pregnancy, infection, and anemia are often sufficient. Menorrhagia in adolescents warrants testing for bleeding disorders as well [7].Within 3 years of menarche, menstrual cycles should become more regular. Persistent anovulatory cycles increase the likelihood of pathologic causes and warrant additional evaluation. Pregnancy testing, thyroid stimulation hormone and prolactin levels are recommended first line evaluation [7,32,34].If PCOS is suspected an ultrasound can be performed but as noted above, polycystic ovaries are not required to make the diagnosis after adolescence.

Additional testing includes testosterone levels to look for androgen secreting tumors. Late onset congenital adrenal hyperplasia is an uncommon cause of hyperandrogenism but is more common in women of Ashkenazi Jewish descent and those with a family history [34].Morning hydroxyprogesterone can be performed to evaluate for this. If women exhibit abrupt change in menstrual pattern and other signs of cortisol excess (hypertension, abdominal striae) 24-hour urine cortisol can detect Cushing’s syndrome [34].

In patients with PCOS, additional testing to evaluate for medical comorbidities is recommended. This includes screening for diabetes, dyslipidemia, and liver dysfunction.

Case Continued

The patient’s prolactin and TSH are normal. Tests for diabetes are normal. Her LDL is elevated to 162, triglycerides are 200, and her HDL is 38. The physician informs her that she meets criteria for PCOS and also that she has obesity and metabolic syndrome.

• What factors should be considered when making treatment recommendations for this patient?

Treatment for anovulation is guided by the goals of therapy. Since anovulation is an endocrine abnormality, medical treatment is first line [31].If secondary causes are diagnosed, these should be treated first. Other goals of treatment can include reducing amount and irregularity of menstruation, provide contraception, increasing ovulation in women with desired fertility, and reducing androgenic sequelae such as acne and hirsutism.

When treating the irregular or heavy bleeding associated with anovulation, first-line treatment is exogenous hormone. This can be in the form of combined estrogen/progesterone formulations (pill, patch, and ring). Medroxyprogesterone (medroxyprogesterone acetate 5–10 mg daily) taken 10 to 14 days per month is another option. Standard consideration for medical eligibility in prescribing these agents should be considered (see U.S. medical eligibility criteria for contraceptive use available at www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm). Combined formulations offer contraception, while cyclic progesterone does not. Both offer cyclic withdrawal bleeding. A Cochrane review did not find any RCTs comparing one to the other and therefore either are reasonable options [36].The levonorgestrel IUD is effective at treating AUB as well [31].Women may still experience intermittent vaginal bleeding or amenorrhea so it is less likely to result in cyclic withdrawal bleeding.

All of the above treatments provide the additional benefit of thinning the endometrium and preventing unopposed estrogen effect. This provides further protection the endometrial hyperplasia with chronic anovulatory cycles and unopposed estrogen [31].

In women with PCOS and associated metabolic conditions, first-line treatment is weight loss and other lifestyle interventions to improve or prevent other sequelae of the condition. Weight loss has been shown to reduce circulating androgen levels and increase ovulation. It has been shown to reduce glucose and lipid levels and hirsutism. Pregnancy rates increase as well. Weight loss achieved through medications and gastric bypass has similar effects. There is no special diet that has been shown to be more effective than another [32]. As little as a 5% weight reduction from baseline can improve PCOS symptoms [34,35].

Metformin is also commonly added to lifestyle modifications in women with PCOS to reduce risks for developing diabetes. There is little high quality evidence of added benefit above lifestyle modifications [34].Statin therapy can be considered in women with hyperlipidemia and PCOS [32].

For women with PCOS who desire to conceive, treatment should target increased ovulation. Pre-conception counseling and lifestyle modifications are again first line [32].Ovulation induction interventions carry increased risk of multiple gestation. For ovulation induction, clomiphene citrate is first line therapy. Metformin is commonly used as noted above to improve comorbidities associated with PCOS and can increase ovulation compared to placebo [37].However, RCTs do not support its use as first-line treatment of infertility treatment in PCOS. Clomiphene is 3 times more effective than metformin alone [32].

Medications can improve but often do not resolve hirsutism in women with PCOS. Combined hormonal contraceptives are commonly used off-label and no one type of pill has been shown to be superior. Anti-androgens are also off-label but empirically used. They can also improve lipid and other metabolic variables. They are all teratogenic and therefore should not be used in women who desire conception, and be used with effective contraceptives. Spironolactone is an androgen receptor antagonist. It takes months for effect. Some women will have improved menstrual frequency with this medication as well. Often adjunctive therapy such as eflornithine facial cream or laser therapy or a combination is needed to further treat hirsutism [32,35,38].

Follow-up

After discussion, the patient decides to adopt therapeutic lifestyle changes. She desires to get pregnant and does not opt for hormonal contraceptives at this time. She sees a nutritionist and begins calorie restriction and exercise. Three months later she has lost 20 pounds and feels “healthier.” Her lipid panel shows LDL of 125 and HDL of 43. Her triglycerides are now 160. Her blood pressure in the office is 118/78 mm Hg. She has lost “inches” around her middle. She has had more regular periods as well. She is still not pregnant so the physician asks her to begin tracking ovulation with cervical mucus evaluation and basal body temperature prior to considering further infertility evaluations. Three months after that she misses a period but is pleased to report a positive home pregnancy test.

Case 3—Breakthough Bleeding On Combined Hormonal Contraceptives 

A 28-year-old G0P0 in a monogamous relationship presents to her physician. She has been on oral contraceptive pills for 8 years. For the last 3 years she has been taking the pills on an extended cycle schedule. She normally takes an active pill daily for 3 cycles of pills (9 weeks), and then takes a 7-day pill-free week when she gets a menstrual period. This had been working fine until the last 6 months. She has noticed breakthrough spotting up to 2 weeks at a time during the 2nd and 3rd pack of pills.

• What is the approach to evaluation and treatment in this patient?

Bleeding in Women on Combined Hormonal Contraception

Many women are now using combined hormonal contraceptives on different schedules. Extended-cycle contraception has been shown to be as effective as the traditional 21/7 schedule of active pills/pill-free week. The FDA has approved several packaged extended-cycle contraceptives. Extended-cycle contraception decreases overall number of bleeding days and improves many menstrual-related symptoms [39].Breakthrough bleeding is the most common side effect of extended cycle contraception. It is classified as AUB-I (abnormal uterine bleeding—iatrogenic). It is most common in the first few months of use, and decreases as use continues. Up to 86% of women will have unscheduled bleeding during the first 3 months of use of extended cycle contraception, but this bleedingdecreases as use continues [40].

There is no consensus as to the underlying mechanism causing this abnormal bleeding. Most clinicians believe that it is related to the balance of estrogen/progestin in each combined hormonal contraceptive. Each woman reacts differently to this combination, making it difficult to predict who will have abnormal bleeding. In women who are beginning an extended-cycle regimen, reassurance is sufficient. Most abnormal bleeding will normalize within the first 2 to 3 months. Missed pills and smoking are consistently related to breakthrough bleeding in women who take combined oral contraceptive pills [41].In women who have previously had stable bleeding patterns and who present with new breakthrough bleeding, evaluation for secondary causes of bleeding may be considered (ie, urine hCG, TSH, STI cultures, evaluation for cervical cancer screening). A pelvic examination may help determine a possible secondary cause of bleeding, but is not necessary.

Treatment of unscheduled bleeding in women on extended-cycle contraception includes shortening the hormone-free interval and adding medications for prevention/treatment of bleeding episodes. The 7-day hormone-free interval in the context of low-dose hormonal contraception may be too long. One study demonstrated that a 7-day hormone-free interval was associated with a lack of pituitary-ovarian suppression, follicular development, and possible ovulation [42].A systematic review found that shortened hormone-free intervals decreased the amount of unscheduled bleeding [39].A small RCT (65 women) of continuous contraceptive ring users found that the group that removed the ring for 4 days during an episode of unscheduled bleeding, and then reinserted it had overall reduction in unscheduled bleeding [43].Some clinicians will also recommend trying a different pill formlation or a different schedule. There is no evidence to support this recommendation, but it can be helpful in some women.

Low-dose doxycycline (40 mg daily) for prevention of unscheduled bleeding shows promise [44].This low- dose doxycycline is also helpful to prevent more unscheduled bleeding in extended-cycle oral contraceptive users [44].However, an RCT found that traditional-dose doxycline (100 mg BID) taken for 5 days at the onset of a bleeding episode, did not decrease the amount or length of unscheduled bleeding [40].Neither estrogen dose [45]nor progestin dose [45]affected bleeding patterns. There is some suggestion based on a small study that women on pills with norethindrone may have less unscheduled bleeding than those who are on pills with levonorgestrel, but more research needs to be done before clinicians change practice [46].A Cochrane review looked at one small study that suggested third-generation progestins had more favorable bleeding profiles than second-generation progestins [47].

Follow-up

The physician investigates for secondary causes of the bleeding. The patient’s urine hCG, TSH, and prolactin levels are all normal. No fibroids or polyps are seen on ultrasound. The physician and patient discuss treatment options, including a low-dose doxycycline pill to help minimize bleeding, trying a different pill formulation, or use of naproxen during the bleeding episodes, but the patient does not want to take 2 pills every day. After further discussion, the patient decides she would like to change to the contraceptive ring with the plan of removing the ring for 4 days at the onset of any unscheduled bleeding. In a phone call 6 months later, the patient states that her unscheduled bleeding has been controlled.

Corresponding author: Sarina Schrager, MD, MS, Dept. of Family Medicine, University of Wisconsin School of Medicine and Public Health, 1100 Delaplaine Ct., Madison, WI 53715, sbschrag@wisc.edu.

From the University of Wisconsin School of Medicine and Public Health, Madison, WI.

Abstract

• Objective: To describe the contributing etiologies, common presentations, diagnosis, evaluation, and management of abnormal uterine bleeding (AUB).
• Methods: Review of the literature in the context of 3 cases.
• Results: AUB is one of the most common reasons that reproductive-aged women seek health care. The causes are varied, depending in large part on the age and life stage of the woman. Diagnosis requires a systematic approach that is driven by a thorough health history and review of presenting symptoms.  Determining whether the bleeding is ovulatory or anovulatory is a central part of the evaluation. A methodical history, physical examination, and laboratory evaluation may enable the physician to rule out causes such as pregnancy and pregnancy-related disorders, medications, iatrogenic causes, systemic conditions, and obvious genital tract pathology.
• Conclusion: Clinicians must be knowledgeable about AUB and partner with women to develop appropriate, individualized treatment plans.

Abnormal vaginal bleeding is a common complaint in primary care. The prevalence of some type of abnormal bleeding is up to 30% among women of reproductive age [1].Over 18% of all gynecology outpatient visits in the United States are for menorrhagia alone [2].A retrospective analysis of medical expenditures data compared 1.4 million women with abnormal uterine bleeding to over 50 million women without abnormal bleeding. This study found that women with abnormal bleeding were more likely to be younger, Caucasian, and obese and had poorer physical and mental health quality of life scores [3].

The estimated direct and indirect costs of abnormal bleeding are $1 billion and $12 billion annually, respectively [4]. Indirect costs of abnormal bleeding include time off from work and cost of products to protect clothing from bleeding (eg, tampons and pads). Abnormal bleeding is also a common reason for women to be referred to gynecologists and is an indication for up to 25% of all gynecologic surgeries [5].

History Taking

Taking a menstrual history is an important step in determining whether the current bleeding pattern is normal or abnormal. Regularity of menstrual bleeding is clarified by asking about the frequency of the menses and their duration. Other important questions include age at menarche, presence of premenstrual syndrome symptoms, breast tenderness, cervical mucus changes, and amount of bleeding. An ovulatory cycle will usually include premenstrual symptoms whereas an anovulatory cycle will be random in its symptomatology. Women’s estimates of the amount of menstrual bleeding are notoriously inaccurate. Traditionally, more than 80 cc of menstrual blood loss per cycle is considered menorrhagia. However, women and their health care providers do not measure menstrual blood volume outside of study settings, and one study found that only half of women who presented with menorrhagia actually had more than 80 cc of blood loss [6]. There is movement toward use of more patient-centered measures to diagnose men-orrhagia, such as bleeding interfering with a woman’s daily activities, needing to wake up at night to change tampons or pads, or inability to exercise during menses. Anemia in the setting of menorrhagia by history is a less subjective way to diagnose menorrhagia.

Nomenclature and Differential Diagnosis

Differential diagnosis will vary based on symptomatology as well as age. Pregnancy is a possible cause of any type of abnormal bleeding in any woman of reproductive age (ie, after menarche and before menopause). Many systemic illnesses and medications can affect menstrual bleeding and should be included in a broad differential diagnosis of a presenting woman.

Case 1—Heavy Menstrual Bleeding

Initial Presentation

A 42-year-old woman presents reporting increasingly heavy, somewhat painful periods over the last 6 to 8 months. She experienced menarche at age 12 and has had regular, moderately heavy periods throughout her adult life. She denies any inter-menstrual bleeding.

• What additional history should be obtained?

Heavy menstrual bleeding refers to abnormally heavy bleeding that occurs in an ovulatory, cyclical pattern. Women with anovulatory cycles can also have heavy bleeding as well, and distinguishing ovulatory vs anovulatory cycles is often the first step in the evaluation.

The initial evaluation of a woman presenting with heavy menstrual bleeding includes a detailed history and physical examination. The first goal of the history is to establish the severity of bleeding, including any symptoms of hemodynamically significant anemia such as dizziness or exertional dyspnea. Next, the clinician should determine whether the bleeding pattern is ovulatory or anovulatory. Ovulatory heavy menstrual bleeding is most often caused by structural lesions (leiomyomas, endometriosis, adenomyosis, cervical polyps, and endometrial polyps) or a coagulopathy (von Willebrand disease, anticoagulant use, etc). Less commonly, ovulatory heavy menstrual bleeding may be due to systemic illness (including thyroid disease, renal disease, and liver disease) or endometrial hyperplasia or carcinoma.

Once an ovulatory pattern is confirmed, a history of dysmenorrhea, pelvic pain, lower urinary tract symptoms, constipation, dyspareunia, or infertility should be elicited. 

Further history taking should seek to identify any symptoms suggestive of thyroid, kidney, or liver disease, 

• What are key elements of the physical examination?

The physical examination should include visual inspection and palpation of the thyroid gland as well as an abdominal exam to evaluate for hepatosplenomegaly or lower abdominal tenderness or masses. Signs of anemia such as pallor should also be noted. The gynecologic exam should include visual inspection of the external genitalia, a bimanual exam, and a speculum exam. Cervical and endometrial polyps may be visible as masses at the cervical os or extending into the vaginal canal. An enlarged mobile uterus with irregular contours is consistent with leiomyomas [8].Endometriosis may manifest as tenderness, thickening, or nodularity of the uterine corpus, the vaginal canal, the uterosacral ligaments, or the adnexa. Endometriosis may also cause an asymmetric, fixed position of the uterus, the cervix, or the adnexa [9].Adenomyosis may cause diffuse moderate uterine enlargement with or without tenderness [10].Endometrial carcinoma may also cause uterine enlargement and/or immobility.

• What laboratory testing should be performed?

• What additional testing would be useful in narrowing the differential diagnosis?

If the physical examination and initial laboratory testing is nondiagnostic, the decision to initiate a trial of symptom management or proceed with further testing (imaging and/or tissue sampling) is based on risk of endometrial cancer, severity of symptoms, and patient preference. In many women, body habitus makes a confirmatory pelvic examination difficult, which may lower the threshold for obtaining a pelvic ultrasound.

Women with risk factors for endometrial cancer should undergo office-based endometrial biopsy as the first step in evaluation of heavy menstrual bleeding [7].Risk factors include older age (45 years and older), obesity (BMI > 30), diabetes mellitus, nulliparity, and history of chronic anovulation (eg, polycystic ovary syndrome). Pelvic ultrasound is the first step in the evaluation of women with an abnormal physical exam suggesting a structural lesion [7].If the physical exam is abnormal and the pelvic ultrasound is nondiagnostic, a hysteroscopy or saline-infusion sonohysterogram should be performed, as these tests are more sensitive for the detection of intracavitary lesions and submucosal fibroids [13].Most endometrial polyps will appear as a thickened or irregular endometrium on pelvic ultrasound, but be clearly delineated on sonohysterogram. Women who have a negative initial evaluation but then go on to have persistent bleeding despite a trial of therapy also require further evaluation.

Case Continued

The patient reports that her periods are regular, with a cycle length of 30 to 31 days. She usually notes some bloating and breast tenderness in the days leading up to onset of menses. She experiences lower abdominal cramping during days 1–3 of her period. This has worsened somewhat over the last year, and sometimes radiates to her low back. Her reproductive history is significant for 3 uncomplicated vaginal deliveries and 1 first trimester spontaneous abortion. She did not experience postpartum hemorrhage, and has no history of significant oropharyngeal bleeding or unexplained bruising. Her BMI is 23.3. Her physical exam is unremarkable, including a normal thyroid, abdominal, bimanual and speculum exam. Laboratory evaluation demonstrates a low-normal hemoglobin, hematocrit, and MCV. The TSH is normal and a urine pregnancy test is negative. She had a normal pap smear and HPV assay 2 years ago.

• What is the most likely diagnosis?

• What treatment is recommended?

Oral tranexamic acid is an anti-fibrinolytic that was recently approved by the FDA for treatment of menorrhagia or heavy menstrual bleeding. It has been used for many years to prevent bleeding during surgery and to treat bleeding disorders. It has been used for over 30 years to treat menorrhagia in Europe. It has a different mechanism of action than NSAIDs and hormonal contraceptives, and is therefore an appropriate alternative for women who cannot tolerate other medication options [16,17].Tranexamic acid is contraindicated in women with an elevated risk of thromboembolic disease.

For women who have insufficient response to medical management or for women who present with more severe symptoms, anemia, or prominent bulk-related symptoms due to fibroids, gynecologic referral should be made for consideration of surgical intervention. The preferred interventional approach to the treatment of uterine fibroid tumors depends upon the type of fibroid (eg submucosal, intramural, subserosal), the number of fibroids, desire for future childbearing, risk for surgical complications, and patient preference. Effective options include myomectomy, uterine artery embolization, endometrial ablation, and hysterectomy [18].

By contrast, good evidence supports the use of medication as first-line therapy for heavy menstrual bleeding when it occurs in the setting of endometriosis. Estrogen-progestin oral contraceptive pills, oral progestins, and depot medroxyprogesterone have all been demonstrated to be effective in decreasing pain [19,20].The levonorgestrel-releasing intrauterine system is also effective in decreasing pain due to endometriosis [21].

Women who do not respond to first-line therapy should be referred to a gynecologist for consideration of other treatment options. Effective second-line treatment options include oral danazol, intramuscular GnRH agonists, and surgical approaches such as laparoscopic ablation and/or excision of endometriosis implants [22].

A similar range of treatment options appears to be effective in the management of heavy menstrual bleeding due to adenomyosis. First-line therapies include oral NSAIDs, oral tranexamic acid, estrogen-progestin oral contraceptive pills, and the levonorgestrel-releasing intrauterine system [23,24].Women with an inadequate response to first-line treatment should be referred to a gynecologist for consideration definitive treatment with hysterectomy versus uterine artery embolization or a trial of a GnRH agonist [24].

For some women with heavy menstrual bleeding, no specific underlying cause is identified. Current evidence suggests that such patients may have disorders of local endometrial hemostasis leading to increased blood loss during otherwise normal menstrual cycles [25].The levonorgestrel-releasing intrauterine system may be the most effective medical therapy for heavy menstrual bleeding in the absence of a specific target lesion [26].For women wishing to avoid hormonal treatment, scheduled oral NSAIDs or oral tranexamic acid are inexpensive and effective options for reducing blood loss [27–29].Other medical treatment options include estrogen-progestin contraceptive pills, cyclic oral progestin, and depot medroxy-progesterone.

For patients who experience treatment failure with pharmaceutical therapy or who desire definitive treatment, both endometrial ablation and hysterectomy have been shown to be effective and associated with high rates of patient satisfaction [30].

Follow-up

The patient reports that she would like to avoid invasive testing if possible. Given her relatively low risk for endometrial cancer, she elects a trial of scheduled NSAIDs. Unfortunately, after a couple of cycles she reports that her heavy bleeding has not been well-controlled. A pelvic ultrasound demonstrates an anterior submucosal fibroid measuring 2.4 cm and a posterior intramural fibroid measuring 1.5 cm. She agrees to insertion of a levonorgestrel IUD and calls 6 months later to report a significant decrease in her bleeding.

Case 2—Anovulation

Initial Presentation

A 27-year-old female presents for pregnancy testing. She is 2 weeks late for her period. She and her husband are attempting pregnancy and she seems disappointed that the pregnancy test is negative. She is having trouble tracking her periods. Her cycles range from 24 to 45 days apart and often she skips cycles altogether. Her flow is scant at times but some months are heavy with soaking tampons/pads.

• What are diagnostic considerations in evaluating this bleeding pattern?

Menstrual history can help differentiate between of ovulatory and anovulatory abnormal bleeding. Typically, anovulatory bleeding is marked by irregular or infrequent periods. Flow can be scant to excessive. Women experiencing anovulatory cycles may fail to notice common ovulation symptoms (thin watery cervical mucus) or pre-menstrual symptoms (breast tenderness) [31].

The International Federation of Gynecology and Obstetrics (FIGO) designates AUD-O as “abnormal uterine bleeding due to ovulatory dysfunction” or “anovulatory abnormal uterine bleeding” [7,31].In general, if women are having menses at regular cycles their bleeding is likely to be ovulatory.

Differential Diagnosis

Anovulatory bleeding may be physiologic. After menarche, the hypothalamic-pituitary-ovarian axis is immature. This may result in anovulatory cycles for 2 to 3 years. Women entering perimenopausal transition may also experience intermittent anovulation and subsequent abnormal uterine bleeding. Other physiologic examples include lactation and pregnancy [31].

Physical Examination

A thorough history will help to narrow the differential diagnosis. The physical exam can evaluate for other findings that indicate endocrine dysfunction such as low body weight, hirsutism, balding, acne, high blood pressure, obesity (especially centripetal fat distribution). Acanthosis nigricans is a sign of insulin resistance which is part of the pathophysiology of PCOS. The gynecologic exam is often unremarkable in AUB-O although a bimanual exam can reveal adnexal enlargement indicative of cystic ovaries. Of note, clitoromegally is not common in PCOS. This finding would increase the likelihood of other causes of hyperandrogenism [32].

• What is the pathophysiologic basis for this patient’s bleeding pattern?

Pathophysiology of Anovulatory Bleeding

Anovulatory bleeding presumes that there is a normal anatomic and genetic makeup. For example, a woman without ovaries will be, by definition, anovulatory. Using current terminology anovulatory bleeding implies a disruption in the hypothalamic-pituitary-ovarian axis and is therefore primarily an endocrine disorder [31,33].

At the level of the ovary and uterus, anovulation results in prolonged estrogen effect on the endometrium. After ovulation, the corpus luteum produces progesterone which stops endometrial thickening and stabilizes the endometrium. Without ovulation, estrogen continues endometrial stimulation and excess proliferation of endometrial lining. The endometrium becomes unstable, undifferentiated, and sheds unpredictably. The blood vessels become larger, more tortuous and have increased fragility. The result is light or heavy menstrual bleeding, decreased frequency of periods but overall unpredictable menstrual bleeding [33].

Effects of Chronic Anovulation

Irregular cycles can be more than a mere inconvenience. Women who have anovulatory cycles associated with heavy menstrual bleeding are at risk for anemia. Anovulation that is a result of hyperandrogen state or other endocrine disorder has other health ramifications. Infertility and its treatment are common sequelae. Finally, over time, unopposed estrogen in anovulation increases the risk of endometrial hyperplasia, or cancer [7,34].

Case Continued

The patient reports menarche at age 12. Her periods were irregular for the first 1–2 years but became more regular after that. She has been taking combination oral contraceptives since the age of 20 to prevent pregnancy. She stopped this 1 year ago and she and her husband began actively trying to conceive 6 months ago. Her family history is notable for diabetes and hypertension in her father. Her mother had heavy periods leading up to menopause and had a hysterectomy with no malignancy at the age of 47. She has a BMI of 33; blood pressure is mildly elevated at 134/84 mm Hg. She has oily skin and acne along her chin and neck. She has mild hirsutism of her face. Otherwise her skin is normal appearing. She has an elevated waist circumference of 35 inches. The remainder of her exam is normal.

• What is the likely diagnosis?

Women with PCOS are at increased risk for metabolic syndrome, nonalcoholic fatty liver disease, type 2 diabetes and cardiovascular disease, endometrial cancer, and infertility. Women with PCOS who become pregnant have increased risk of pregnancy complications such as hypertensive disorders and gestational diabetes.

• What tests are indicated in this patient?

Appropriate laboratory testing is often determined based on findings in the history and physical as well as the patient’s age. Anovulation in the first 18 months to 3 years after menarche is common and testing for pregnancy, infection, and anemia are often sufficient. Menorrhagia in adolescents warrants testing for bleeding disorders as well [7].Within 3 years of menarche, menstrual cycles should become more regular. Persistent anovulatory cycles increase the likelihood of pathologic causes and warrant additional evaluation. Pregnancy testing, thyroid stimulation hormone and prolactin levels are recommended first line evaluation [7,32,34].If PCOS is suspected an ultrasound can be performed but as noted above, polycystic ovaries are not required to make the diagnosis after adolescence.

Additional testing includes testosterone levels to look for androgen secreting tumors. Late onset congenital adrenal hyperplasia is an uncommon cause of hyperandrogenism but is more common in women of Ashkenazi Jewish descent and those with a family history [34].Morning hydroxyprogesterone can be performed to evaluate for this. If women exhibit abrupt change in menstrual pattern and other signs of cortisol excess (hypertension, abdominal striae) 24-hour urine cortisol can detect Cushing’s syndrome [34].

In patients with PCOS, additional testing to evaluate for medical comorbidities is recommended. This includes screening for diabetes, dyslipidemia, and liver dysfunction.

Case Continued

The patient’s prolactin and TSH are normal. Tests for diabetes are normal. Her LDL is elevated to 162, triglycerides are 200, and her HDL is 38. The physician informs her that she meets criteria for PCOS and also that she has obesity and metabolic syndrome.

• What factors should be considered when making treatment recommendations for this patient?

Treatment for anovulation is guided by the goals of therapy. Since anovulation is an endocrine abnormality, medical treatment is first line [31].If secondary causes are diagnosed, these should be treated first. Other goals of treatment can include reducing amount and irregularity of menstruation, provide contraception, increasing ovulation in women with desired fertility, and reducing androgenic sequelae such as acne and hirsutism.

When treating the irregular or heavy bleeding associated with anovulation, first-line treatment is exogenous hormone. This can be in the form of combined estrogen/progesterone formulations (pill, patch, and ring). Medroxyprogesterone (medroxyprogesterone acetate 5–10 mg daily) taken 10 to 14 days per month is another option. Standard consideration for medical eligibility in prescribing these agents should be considered (see U.S. medical eligibility criteria for contraceptive use available at www.cdc.gov/reproductivehealth/unintendedpregnancy/usmec.htm). Combined formulations offer contraception, while cyclic progesterone does not. Both offer cyclic withdrawal bleeding. A Cochrane review did not find any RCTs comparing one to the other and therefore either are reasonable options [36].The levonorgestrel IUD is effective at treating AUB as well [31].Women may still experience intermittent vaginal bleeding or amenorrhea so it is less likely to result in cyclic withdrawal bleeding.

All of the above treatments provide the additional benefit of thinning the endometrium and preventing unopposed estrogen effect. This provides further protection the endometrial hyperplasia with chronic anovulatory cycles and unopposed estrogen [31].

In women with PCOS and associated metabolic conditions, first-line treatment is weight loss and other lifestyle interventions to improve or prevent other sequelae of the condition. Weight loss has been shown to reduce circulating androgen levels and increase ovulation. It has been shown to reduce glucose and lipid levels and hirsutism. Pregnancy rates increase as well. Weight loss achieved through medications and gastric bypass has similar effects. There is no special diet that has been shown to be more effective than another [32]. As little as a 5% weight reduction from baseline can improve PCOS symptoms [34,35].

Metformin is also commonly added to lifestyle modifications in women with PCOS to reduce risks for developing diabetes. There is little high quality evidence of added benefit above lifestyle modifications [34].Statin therapy can be considered in women with hyperlipidemia and PCOS [32].

For women with PCOS who desire to conceive, treatment should target increased ovulation. Pre-conception counseling and lifestyle modifications are again first line [32].Ovulation induction interventions carry increased risk of multiple gestation. For ovulation induction, clomiphene citrate is first line therapy. Metformin is commonly used as noted above to improve comorbidities associated with PCOS and can increase ovulation compared to placebo [37].However, RCTs do not support its use as first-line treatment of infertility treatment in PCOS. Clomiphene is 3 times more effective than metformin alone [32].

Medications can improve but often do not resolve hirsutism in women with PCOS. Combined hormonal contraceptives are commonly used off-label and no one type of pill has been shown to be superior. Anti-androgens are also off-label but empirically used. They can also improve lipid and other metabolic variables. They are all teratogenic and therefore should not be used in women who desire conception, and be used with effective contraceptives. Spironolactone is an androgen receptor antagonist. It takes months for effect. Some women will have improved menstrual frequency with this medication as well. Often adjunctive therapy such as eflornithine facial cream or laser therapy or a combination is needed to further treat hirsutism [32,35,38].

Follow-up

After discussion, the patient decides to adopt therapeutic lifestyle changes. She desires to get pregnant and does not opt for hormonal contraceptives at this time. She sees a nutritionist and begins calorie restriction and exercise. Three months later she has lost 20 pounds and feels “healthier.” Her lipid panel shows LDL of 125 and HDL of 43. Her triglycerides are now 160. Her blood pressure in the office is 118/78 mm Hg. She has lost “inches” around her middle. She has had more regular periods as well. She is still not pregnant so the physician asks her to begin tracking ovulation with cervical mucus evaluation and basal body temperature prior to considering further infertility evaluations. Three months after that she misses a period but is pleased to report a positive home pregnancy test.

Case 3—Breakthough Bleeding On Combined Hormonal Contraceptives 

A 28-year-old G0P0 in a monogamous relationship presents to her physician. She has been on oral contraceptive pills for 8 years. For the last 3 years she has been taking the pills on an extended cycle schedule. She normally takes an active pill daily for 3 cycles of pills (9 weeks), and then takes a 7-day pill-free week when she gets a menstrual period. This had been working fine until the last 6 months. She has noticed breakthrough spotting up to 2 weeks at a time during the 2nd and 3rd pack of pills.

• What is the approach to evaluation and treatment in this patient?

Bleeding in Women on Combined Hormonal Contraception

Many women are now using combined hormonal contraceptives on different schedules. Extended-cycle contraception has been shown to be as effective as the traditional 21/7 schedule of active pills/pill-free week. The FDA has approved several packaged extended-cycle contraceptives. Extended-cycle contraception decreases overall number of bleeding days and improves many menstrual-related symptoms [39].Breakthrough bleeding is the most common side effect of extended cycle contraception. It is classified as AUB-I (abnormal uterine bleeding—iatrogenic). It is most common in the first few months of use, and decreases as use continues. Up to 86% of women will have unscheduled bleeding during the first 3 months of use of extended cycle contraception, but this bleedingdecreases as use continues [40].

There is no consensus as to the underlying mechanism causing this abnormal bleeding. Most clinicians believe that it is related to the balance of estrogen/progestin in each combined hormonal contraceptive. Each woman reacts differently to this combination, making it difficult to predict who will have abnormal bleeding. In women who are beginning an extended-cycle regimen, reassurance is sufficient. Most abnormal bleeding will normalize within the first 2 to 3 months. Missed pills and smoking are consistently related to breakthrough bleeding in women who take combined oral contraceptive pills [41].In women who have previously had stable bleeding patterns and who present with new breakthrough bleeding, evaluation for secondary causes of bleeding may be considered (ie, urine hCG, TSH, STI cultures, evaluation for cervical cancer screening). A pelvic examination may help determine a possible secondary cause of bleeding, but is not necessary.

Treatment of unscheduled bleeding in women on extended-cycle contraception includes shortening the hormone-free interval and adding medications for prevention/treatment of bleeding episodes. The 7-day hormone-free interval in the context of low-dose hormonal contraception may be too long. One study demonstrated that a 7-day hormone-free interval was associated with a lack of pituitary-ovarian suppression, follicular development, and possible ovulation [42].A systematic review found that shortened hormone-free intervals decreased the amount of unscheduled bleeding [39].A small RCT (65 women) of continuous contraceptive ring users found that the group that removed the ring for 4 days during an episode of unscheduled bleeding, and then reinserted it had overall reduction in unscheduled bleeding [43].Some clinicians will also recommend trying a different pill formlation or a different schedule. There is no evidence to support this recommendation, but it can be helpful in some women.

Low-dose doxycycline (40 mg daily) for prevention of unscheduled bleeding shows promise [44].This low- dose doxycycline is also helpful to prevent more unscheduled bleeding in extended-cycle oral contraceptive users [44].However, an RCT found that traditional-dose doxycline (100 mg BID) taken for 5 days at the onset of a bleeding episode, did not decrease the amount or length of unscheduled bleeding [40].Neither estrogen dose [45]nor progestin dose [45]affected bleeding patterns. There is some suggestion based on a small study that women on pills with norethindrone may have less unscheduled bleeding than those who are on pills with levonorgestrel, but more research needs to be done before clinicians change practice [46].A Cochrane review looked at one small study that suggested third-generation progestins had more favorable bleeding profiles than second-generation progestins [47].

Follow-up

The physician investigates for secondary causes of the bleeding. The patient’s urine hCG, TSH, and prolactin levels are all normal. No fibroids or polyps are seen on ultrasound. The physician and patient discuss treatment options, including a low-dose doxycycline pill to help minimize bleeding, trying a different pill formulation, or use of naproxen during the bleeding episodes, but the patient does not want to take 2 pills every day. After further discussion, the patient decides she would like to change to the contraceptive ring with the plan of removing the ring for 4 days at the onset of any unscheduled bleeding. In a phone call 6 months later, the patient states that her unscheduled bleeding has been controlled.

Corresponding author: Sarina Schrager, MD, MS, Dept. of Family Medicine, University of Wisconsin School of Medicine and Public Health, 1100 Delaplaine Ct., Madison, WI 53715, sbschrag@wisc.edu.

From Novant Health and Novant Health Medical Group, Winston-Salem, NC.

Abstract

• Objective: To evaluate the effect of an educational intervention with regular audit and feedback on reporting of patient safety events in a nonacademic, community practice setting with an established reporting system.
• Methods: A quasi-experimental with comparator design was used to compare a 6-practice collaborative group with a 27-practice comparator group with regard to safety event reporting rates. Baseline data were collected for a 12-month period followed by recruitment of 6 practices (3 family medicine, 2 pediatric, and 1 general surgery). An educational intervention was carried out with each, and this was followed by monthly audit and regular written and in-person feedback. Practice-level comparisons were made with specialty- and size-matched practices for the 6 practices in the collaborative group.
• Results: In the 12-month period following the intervention in March 2013, the 6 practices reported 175 patient safety events compared with only 19 events in the previous 12-month period. Each practice at least doubled reporting rates, and 5 of the 6 significantly increased rates. In contrast, rates for comparator practices were unchanged, with 84 events reported for the pre-intervention period and 81 for the post-intervention period. Event classification and types of events reported were different in the collaborative practices compared with the comparators for the post-intervention period. For the collaborative group, near miss events predominated as did diagnostic testing and communication event types.
• Conclusion: An initial educational session stressing anonymous, voluntary safety event reporting together with monthly audit and feedback and a focus on developing a nonpunitive environment can significantly enhance reporting of safety events.

Multiple challenges in the outpatient setting make establishing a culture of safety and improving care delivery more difficult than for inpatient settings. In the outpatient setting, care is often inaccessible, not well coordinated between providers and between facilities and providers, and delivered in many locations. It may also involve multiple sites and providers for a single patient, may require multiple visits in a single location, and can be provided by phone, email, mail, video, or in person [1]. Errors and adverse events may take long periods of time to become apparent and are more often errors of omission compared with those in the inpatient setting [2].

Incident reporting systems are considered important in improving patient safety [3], and their limitations and value have recently been reviewed [4]. However, limited research has been conducted on medical errors in ambulatory care, and even less is available on optimal monitoring and reporting strategies [5–12].Reporting in our system is time-consuming (about 15 minutes for entry of a single  report), is not tailored for outpatient practices, may be considered potentially punitive (staff may believe that reporting may place themselves at risk for performance downgrade or other actions), and marked under-reporting of safety events was suspected. Most but not all of the suggested characteristics considered important for hospital-based reporting systems are fulfilled in our ambulatory reporting system [13].

Several academic groups have reported much improved reporting and a much better understanding of the types of errors occurring in their respective outpatient settings [14–16]. The most compelling model includes a voluntary, nonpunitive, anonymous reporting approach and a multidisciplinary practice-specific team to analyze reported errors and to enact change through a continuous quality improvement process [14,15].

We implemented a project to significantly improve reporting of safety events in an outpatient, nonacademic 6-practice collaborative by using education, monthly audit, and regular feedback.

Methods

Setting

Novant Health Medical Group is a consortium of over 380 clinic sites, nearly 1300 physicians, and over 500 advanced practice clinicians. Clinic locations are found in Virginia, North Carolina, and South Carolina. Medical group members partner with physicians and staff in 15 hospitals in these geographic locations. Novant Health utilizes Epic (Epic Systems, Verona, WI) as an electronic health record. Safety event reporting is accomplished electronically in a single software program (VIncident, Verge Solutions, Mt. Pleasant, SC), used for all patients in our integrated care system (inpatient and outpatient facilities).

Intervention

Two of the authors (HWC and TC) met in March 2013 with the lead physician, practice manager, and patient safety coach at each clinic for approximately 1 hour. We discussed current reporting practice, delivered education for the safety event compendium, and detailed an anonymous, voluntary, and nonpunitive approach (stressing the use of the term “safety event” and not “error”) to reporting using a single page, 8-question paper report about the event. The report was not to be signed by the person completing the event data with placement in a drop box for later collection and electronic reporting as per usual practice in the clinic. We agreed that clinic leaders would stress to staff and providers that  the initiative was nonpunitive and anonymous and that the goal was to report all known safety events, as an improvement project.

Patient safety coaches were selected for each of the 6 practices by the manager. Patient safety coaches are volunteer clinical or nonclinical staff members whose role is to observe, model, and reinforce pre-established patient safety behaviors and use of error prevention tools among peers and providers. Training requirements include an initial 2-hour training session in which they learn fundamentals of patient safety science, high reliability principles, coaching techniques for team accountability, and concepts for continuous quality improvement. Additionally, they attend monthly meetings where patient safety concepts are discussed in greater detail and best practices are shared. Following this training, each clinic’s staff was educated on the project, a process improvement team (lead physician, manager, and patient safety coach) was constituted, and the project was begun in April 2013. In quarter 3 of 2013, each practice team selected a quality improvement project based upon reported safety events in their clinic. We asked our medical group risk managers to continue event discussion with practice managers as usual, as each event is discussed briefly after a report is made.

We audited reports monthly and provided feedback to the practice team with a written report at the end of each 3-month period starting in June 2013 and ending in June 2014 (5 reports). Individual on-site visits to meet and discuss progress were completed in September 2013 and March 2014, in addition to the initial visit in March 2013.

Evaluation

We compared reported monthly safety events for each of the 6 practices and for the 6-practice collaborative in the aggregate for the 12-month pre-intervention period (April 2012 through March 2013) and post-intervention period (April 2013 through March 2014). Each practice was compared with 3 specialty- and size (number of providers)-matched practices, none of whom received education or feedback on reporting or had patient safety coaches in the practice. In addition, for each of the 3 family medicine practices in the collaborative, we matched 1:3 other family medicine practices for specialty, size, and presence of a designated and trained patient safety coach. For the duration of the project, only 50 of 380 practices in the medical group had a trained patient safety coach.

The rate of safety events reported (ie, number of safety events reported/number of patient encounters) was compared for the 2 time periods using Poisson regression or zero-inflated Poisson regression. SASenterprise guide5.1 was used for all analyses. A P value of < 0.05 was considered statistically significant. The protocol was reviewed by the institutional review board of Novant Health Presbyterian Medical Center and a waiver for informed written consent was granted.

Results

To control for the presence of patient safety coaches in practices, the 3 family medicine clinics (clinics 4 through 6, Figure 2) were each matched 1:3 for size (number of providers) and specialty (other family medicine clinics), also with a patient safety coach. While the rates were significantly increased for the 3 collaborative family medicine clinics (P < 0.001), only 1 of the comparators clinic’s rate changed significantly (0.2 or 1/44,580 to 1.3 or 6/45,157), and this change was marginally significant (P = 0.048). This practice was the only one of the 27 comparator clinics to demonstrate any increased rate.

Discussion

In our nonacademic community practices, patient safety reporting rates improved following an initial educational session stressing anonymous, voluntary safety event reporting together with monthly audit and feedback. Our findings corroborate those of others in academic ambulatory settings, who found that an emphasis on patient safety reporting, particularly if an anonymous approach is taken in a nonpunitive atmosphere, can significantly increase the reporting of patient safety events [14–16]. We demonstrated marked under-reporting and stability of patient safety event reporting throughout our ambulatory practice group and a 10-fold increase in reporting among the 6-practice collaborative.

An unexpected finding was that with the exception of 1 practice, we found no increased reporting in comparator practices that had a patient safety coach. Additionally, we noted that general surgery practices report (or experience) very few ambulatory safety events, as a total of 4 events were reported for all 4 general surgery practices in 18 months.

We chose a quasi-experimental with a comparison group and pre-test/post-test design since randomization of practices was not feasible [17]. We used a 2-year period to control for any seasonal trends and to allow time after the intervention to see if meaningful improvement in reporting over time would continue. We attempted to address the potential for nonequivalence in the comparison group by matching for specialty and size of practice.

There are several  limitations to this study. Bias in the selection of collaborative practices may have occurred since each had a proven leader, and this may have led to more rapid adoption and utilization of this reporting approach. Also, our findings may not be generalizable to other integrated health systems given the unique approaches to patient safety culture development and the disparate nature of reporting systems. In addition, with our study design we could not be certain that anonymous reporting was a key factor in the increase in reporting rates, but de-briefing interviews indicated that both anonymous reporting and declaring a nonpunitive, supportive approach in each practice was important to enhanced reporting.

We expect increased reporting to decline over time without consistent feedback, as has been demonstrated in other studies [18], and we will continue to monitor rates over time.

As our current reporting system requires considerable reporter time for data input and discussion with risk managers, is not specifically configured for ambulatory reporting, is considered by staff and providers potentially punitive, and marked under-reporting is clear, we have proposed moving to a new system that is more user-friendly, ambulatory-focused, and has a provision for anonymous reporting.

Presented in part at the Institute for Healthcare Improvement 15th Annual International Summit on Improving Patient Care in the Office Practice and the Community, Washington DC, March 2014.

Acknowledgements: We gratefully acknowledge the work of collaborative practice team members, including Christopher Isenhour MD, Janet White, Shelby Carlyle, Mark Tillotson MD, Maria Migliaccio, Melanie Trapp, Jennifer Ochs, Gary DeRosa MD, Margarete Hinkle, Scott Wagner, Kelly Schetselaar, Timothy Eichenbrenner MD, Sandy Hite, Jamie Shelton, Raymond Swetenburg MD, James Lye MD, Kelly Morrison, Jan Rapisardo, Jane Moss, Rhett Brown MD, Dorothy Hedrick, Camille Farmer, and William Anderson, MS, for assistance with analysis.

Corresponding author: Herbert Clegg, MD, 108 Providence Road, Charlotte NC, 28207, hwclegg@novanthealth.org.

Financial disclosures: None.

From Novant Health and Novant Health Medical Group, Winston-Salem, NC.

Abstract

• Objective: To evaluate the effect of an educational intervention with regular audit and feedback on reporting of patient safety events in a nonacademic, community practice setting with an established reporting system.
• Methods: A quasi-experimental with comparator design was used to compare a 6-practice collaborative group with a 27-practice comparator group with regard to safety event reporting rates. Baseline data were collected for a 12-month period followed by recruitment of 6 practices (3 family medicine, 2 pediatric, and 1 general surgery). An educational intervention was carried out with each, and this was followed by monthly audit and regular written and in-person feedback. Practice-level comparisons were made with specialty- and size-matched practices for the 6 practices in the collaborative group.
• Results: In the 12-month period following the intervention in March 2013, the 6 practices reported 175 patient safety events compared with only 19 events in the previous 12-month period. Each practice at least doubled reporting rates, and 5 of the 6 significantly increased rates. In contrast, rates for comparator practices were unchanged, with 84 events reported for the pre-intervention period and 81 for the post-intervention period. Event classification and types of events reported were different in the collaborative practices compared with the comparators for the post-intervention period. For the collaborative group, near miss events predominated as did diagnostic testing and communication event types.
• Conclusion: An initial educational session stressing anonymous, voluntary safety event reporting together with monthly audit and feedback and a focus on developing a nonpunitive environment can significantly enhance reporting of safety events.

Multiple challenges in the outpatient setting make establishing a culture of safety and improving care delivery more difficult than for inpatient settings. In the outpatient setting, care is often inaccessible, not well coordinated between providers and between facilities and providers, and delivered in many locations. It may also involve multiple sites and providers for a single patient, may require multiple visits in a single location, and can be provided by phone, email, mail, video, or in person [1]. Errors and adverse events may take long periods of time to become apparent and are more often errors of omission compared with those in the inpatient setting [2].

Incident reporting systems are considered important in improving patient safety [3], and their limitations and value have recently been reviewed [4]. However, limited research has been conducted on medical errors in ambulatory care, and even less is available on optimal monitoring and reporting strategies [5–12].Reporting in our system is time-consuming (about 15 minutes for entry of a single  report), is not tailored for outpatient practices, may be considered potentially punitive (staff may believe that reporting may place themselves at risk for performance downgrade or other actions), and marked under-reporting of safety events was suspected. Most but not all of the suggested characteristics considered important for hospital-based reporting systems are fulfilled in our ambulatory reporting system [13].

Several academic groups have reported much improved reporting and a much better understanding of the types of errors occurring in their respective outpatient settings [14–16]. The most compelling model includes a voluntary, nonpunitive, anonymous reporting approach and a multidisciplinary practice-specific team to analyze reported errors and to enact change through a continuous quality improvement process [14,15].

We implemented a project to significantly improve reporting of safety events in an outpatient, nonacademic 6-practice collaborative by using education, monthly audit, and regular feedback.

Methods

Setting

Novant Health Medical Group is a consortium of over 380 clinic sites, nearly 1300 physicians, and over 500 advanced practice clinicians. Clinic locations are found in Virginia, North Carolina, and South Carolina. Medical group members partner with physicians and staff in 15 hospitals in these geographic locations. Novant Health utilizes Epic (Epic Systems, Verona, WI) as an electronic health record. Safety event reporting is accomplished electronically in a single software program (VIncident, Verge Solutions, Mt. Pleasant, SC), used for all patients in our integrated care system (inpatient and outpatient facilities).

Intervention

Two of the authors (HWC and TC) met in March 2013 with the lead physician, practice manager, and patient safety coach at each clinic for approximately 1 hour. We discussed current reporting practice, delivered education for the safety event compendium, and detailed an anonymous, voluntary, and nonpunitive approach (stressing the use of the term “safety event” and not “error”) to reporting using a single page, 8-question paper report about the event. The report was not to be signed by the person completing the event data with placement in a drop box for later collection and electronic reporting as per usual practice in the clinic. We agreed that clinic leaders would stress to staff and providers that  the initiative was nonpunitive and anonymous and that the goal was to report all known safety events, as an improvement project.

Patient safety coaches were selected for each of the 6 practices by the manager. Patient safety coaches are volunteer clinical or nonclinical staff members whose role is to observe, model, and reinforce pre-established patient safety behaviors and use of error prevention tools among peers and providers. Training requirements include an initial 2-hour training session in which they learn fundamentals of patient safety science, high reliability principles, coaching techniques for team accountability, and concepts for continuous quality improvement. Additionally, they attend monthly meetings where patient safety concepts are discussed in greater detail and best practices are shared. Following this training, each clinic’s staff was educated on the project, a process improvement team (lead physician, manager, and patient safety coach) was constituted, and the project was begun in April 2013. In quarter 3 of 2013, each practice team selected a quality improvement project based upon reported safety events in their clinic. We asked our medical group risk managers to continue event discussion with practice managers as usual, as each event is discussed briefly after a report is made.

We audited reports monthly and provided feedback to the practice team with a written report at the end of each 3-month period starting in June 2013 and ending in June 2014 (5 reports). Individual on-site visits to meet and discuss progress were completed in September 2013 and March 2014, in addition to the initial visit in March 2013.

Evaluation

We compared reported monthly safety events for each of the 6 practices and for the 6-practice collaborative in the aggregate for the 12-month pre-intervention period (April 2012 through March 2013) and post-intervention period (April 2013 through March 2014). Each practice was compared with 3 specialty- and size (number of providers)-matched practices, none of whom received education or feedback on reporting or had patient safety coaches in the practice. In addition, for each of the 3 family medicine practices in the collaborative, we matched 1:3 other family medicine practices for specialty, size, and presence of a designated and trained patient safety coach. For the duration of the project, only 50 of 380 practices in the medical group had a trained patient safety coach.

The rate of safety events reported (ie, number of safety events reported/number of patient encounters) was compared for the 2 time periods using Poisson regression or zero-inflated Poisson regression. SASenterprise guide5.1 was used for all analyses. A P value of < 0.05 was considered statistically significant. The protocol was reviewed by the institutional review board of Novant Health Presbyterian Medical Center and a waiver for informed written consent was granted.

Results

To control for the presence of patient safety coaches in practices, the 3 family medicine clinics (clinics 4 through 6, Figure 2) were each matched 1:3 for size (number of providers) and specialty (other family medicine clinics), also with a patient safety coach. While the rates were significantly increased for the 3 collaborative family medicine clinics (P < 0.001), only 1 of the comparators clinic’s rate changed significantly (0.2 or 1/44,580 to 1.3 or 6/45,157), and this change was marginally significant (P = 0.048). This practice was the only one of the 27 comparator clinics to demonstrate any increased rate.

Discussion

In our nonacademic community practices, patient safety reporting rates improved following an initial educational session stressing anonymous, voluntary safety event reporting together with monthly audit and feedback. Our findings corroborate those of others in academic ambulatory settings, who found that an emphasis on patient safety reporting, particularly if an anonymous approach is taken in a nonpunitive atmosphere, can significantly increase the reporting of patient safety events [14–16]. We demonstrated marked under-reporting and stability of patient safety event reporting throughout our ambulatory practice group and a 10-fold increase in reporting among the 6-practice collaborative.

An unexpected finding was that with the exception of 1 practice, we found no increased reporting in comparator practices that had a patient safety coach. Additionally, we noted that general surgery practices report (or experience) very few ambulatory safety events, as a total of 4 events were reported for all 4 general surgery practices in 18 months.

We chose a quasi-experimental with a comparison group and pre-test/post-test design since randomization of practices was not feasible [17]. We used a 2-year period to control for any seasonal trends and to allow time after the intervention to see if meaningful improvement in reporting over time would continue. We attempted to address the potential for nonequivalence in the comparison group by matching for specialty and size of practice.

There are several  limitations to this study. Bias in the selection of collaborative practices may have occurred since each had a proven leader, and this may have led to more rapid adoption and utilization of this reporting approach. Also, our findings may not be generalizable to other integrated health systems given the unique approaches to patient safety culture development and the disparate nature of reporting systems. In addition, with our study design we could not be certain that anonymous reporting was a key factor in the increase in reporting rates, but de-briefing interviews indicated that both anonymous reporting and declaring a nonpunitive, supportive approach in each practice was important to enhanced reporting.

We expect increased reporting to decline over time without consistent feedback, as has been demonstrated in other studies [18], and we will continue to monitor rates over time.

As our current reporting system requires considerable reporter time for data input and discussion with risk managers, is not specifically configured for ambulatory reporting, is considered by staff and providers potentially punitive, and marked under-reporting is clear, we have proposed moving to a new system that is more user-friendly, ambulatory-focused, and has a provision for anonymous reporting.

Presented in part at the Institute for Healthcare Improvement 15th Annual International Summit on Improving Patient Care in the Office Practice and the Community, Washington DC, March 2014.

Acknowledgements: We gratefully acknowledge the work of collaborative practice team members, including Christopher Isenhour MD, Janet White, Shelby Carlyle, Mark Tillotson MD, Maria Migliaccio, Melanie Trapp, Jennifer Ochs, Gary DeRosa MD, Margarete Hinkle, Scott Wagner, Kelly Schetselaar, Timothy Eichenbrenner MD, Sandy Hite, Jamie Shelton, Raymond Swetenburg MD, James Lye MD, Kelly Morrison, Jan Rapisardo, Jane Moss, Rhett Brown MD, Dorothy Hedrick, Camille Farmer, and William Anderson, MS, for assistance with analysis.

Corresponding author: Herbert Clegg, MD, 108 Providence Road, Charlotte NC, 28207, hwclegg@novanthealth.org.

Financial disclosures: None.

From Novant Health and Novant Health Medical Group, Winston-Salem, NC.

Abstract

• Objective: To evaluate the effect of an educational intervention with regular audit and feedback on reporting of patient safety events in a nonacademic, community practice setting with an established reporting system.
• Methods: A quasi-experimental with comparator design was used to compare a 6-practice collaborative group with a 27-practice comparator group with regard to safety event reporting rates. Baseline data were collected for a 12-month period followed by recruitment of 6 practices (3 family medicine, 2 pediatric, and 1 general surgery). An educational intervention was carried out with each, and this was followed by monthly audit and regular written and in-person feedback. Practice-level comparisons were made with specialty- and size-matched practices for the 6 practices in the collaborative group.
• Results: In the 12-month period following the intervention in March 2013, the 6 practices reported 175 patient safety events compared with only 19 events in the previous 12-month period. Each practice at least doubled reporting rates, and 5 of the 6 significantly increased rates. In contrast, rates for comparator practices were unchanged, with 84 events reported for the pre-intervention period and 81 for the post-intervention period. Event classification and types of events reported were different in the collaborative practices compared with the comparators for the post-intervention period. For the collaborative group, near miss events predominated as did diagnostic testing and communication event types.
• Conclusion: An initial educational session stressing anonymous, voluntary safety event reporting together with monthly audit and feedback and a focus on developing a nonpunitive environment can significantly enhance reporting of safety events.

Multiple challenges in the outpatient setting make establishing a culture of safety and improving care delivery more difficult than for inpatient settings. In the outpatient setting, care is often inaccessible, not well coordinated between providers and between facilities and providers, and delivered in many locations. It may also involve multiple sites and providers for a single patient, may require multiple visits in a single location, and can be provided by phone, email, mail, video, or in person [1]. Errors and adverse events may take long periods of time to become apparent and are more often errors of omission compared with those in the inpatient setting [2].

Incident reporting systems are considered important in improving patient safety [3], and their limitations and value have recently been reviewed [4]. However, limited research has been conducted on medical errors in ambulatory care, and even less is available on optimal monitoring and reporting strategies [5–12].Reporting in our system is time-consuming (about 15 minutes for entry of a single  report), is not tailored for outpatient practices, may be considered potentially punitive (staff may believe that reporting may place themselves at risk for performance downgrade or other actions), and marked under-reporting of safety events was suspected. Most but not all of the suggested characteristics considered important for hospital-based reporting systems are fulfilled in our ambulatory reporting system [13].

Several academic groups have reported much improved reporting and a much better understanding of the types of errors occurring in their respective outpatient settings [14–16]. The most compelling model includes a voluntary, nonpunitive, anonymous reporting approach and a multidisciplinary practice-specific team to analyze reported errors and to enact change through a continuous quality improvement process [14,15].

We implemented a project to significantly improve reporting of safety events in an outpatient, nonacademic 6-practice collaborative by using education, monthly audit, and regular feedback.

Methods

Setting

Novant Health Medical Group is a consortium of over 380 clinic sites, nearly 1300 physicians, and over 500 advanced practice clinicians. Clinic locations are found in Virginia, North Carolina, and South Carolina. Medical group members partner with physicians and staff in 15 hospitals in these geographic locations. Novant Health utilizes Epic (Epic Systems, Verona, WI) as an electronic health record. Safety event reporting is accomplished electronically in a single software program (VIncident, Verge Solutions, Mt. Pleasant, SC), used for all patients in our integrated care system (inpatient and outpatient facilities).

Intervention

Two of the authors (HWC and TC) met in March 2013 with the lead physician, practice manager, and patient safety coach at each clinic for approximately 1 hour. We discussed current reporting practice, delivered education for the safety event compendium, and detailed an anonymous, voluntary, and nonpunitive approach (stressing the use of the term “safety event” and not “error”) to reporting using a single page, 8-question paper report about the event. The report was not to be signed by the person completing the event data with placement in a drop box for later collection and electronic reporting as per usual practice in the clinic. We agreed that clinic leaders would stress to staff and providers that  the initiative was nonpunitive and anonymous and that the goal was to report all known safety events, as an improvement project.

Patient safety coaches were selected for each of the 6 practices by the manager. Patient safety coaches are volunteer clinical or nonclinical staff members whose role is to observe, model, and reinforce pre-established patient safety behaviors and use of error prevention tools among peers and providers. Training requirements include an initial 2-hour training session in which they learn fundamentals of patient safety science, high reliability principles, coaching techniques for team accountability, and concepts for continuous quality improvement. Additionally, they attend monthly meetings where patient safety concepts are discussed in greater detail and best practices are shared. Following this training, each clinic’s staff was educated on the project, a process improvement team (lead physician, manager, and patient safety coach) was constituted, and the project was begun in April 2013. In quarter 3 of 2013, each practice team selected a quality improvement project based upon reported safety events in their clinic. We asked our medical group risk managers to continue event discussion with practice managers as usual, as each event is discussed briefly after a report is made.

We audited reports monthly and provided feedback to the practice team with a written report at the end of each 3-month period starting in June 2013 and ending in June 2014 (5 reports). Individual on-site visits to meet and discuss progress were completed in September 2013 and March 2014, in addition to the initial visit in March 2013.

Evaluation

We compared reported monthly safety events for each of the 6 practices and for the 6-practice collaborative in the aggregate for the 12-month pre-intervention period (April 2012 through March 2013) and post-intervention period (April 2013 through March 2014). Each practice was compared with 3 specialty- and size (number of providers)-matched practices, none of whom received education or feedback on reporting or had patient safety coaches in the practice. In addition, for each of the 3 family medicine practices in the collaborative, we matched 1:3 other family medicine practices for specialty, size, and presence of a designated and trained patient safety coach. For the duration of the project, only 50 of 380 practices in the medical group had a trained patient safety coach.

The rate of safety events reported (ie, number of safety events reported/number of patient encounters) was compared for the 2 time periods using Poisson regression or zero-inflated Poisson regression. SASenterprise guide5.1 was used for all analyses. A P value of < 0.05 was considered statistically significant. The protocol was reviewed by the institutional review board of Novant Health Presbyterian Medical Center and a waiver for informed written consent was granted.

Results

To control for the presence of patient safety coaches in practices, the 3 family medicine clinics (clinics 4 through 6, Figure 2) were each matched 1:3 for size (number of providers) and specialty (other family medicine clinics), also with a patient safety coach. While the rates were significantly increased for the 3 collaborative family medicine clinics (P < 0.001), only 1 of the comparators clinic’s rate changed significantly (0.2 or 1/44,580 to 1.3 or 6/45,157), and this change was marginally significant (P = 0.048). This practice was the only one of the 27 comparator clinics to demonstrate any increased rate.

Discussion

In our nonacademic community practices, patient safety reporting rates improved following an initial educational session stressing anonymous, voluntary safety event reporting together with monthly audit and feedback. Our findings corroborate those of others in academic ambulatory settings, who found that an emphasis on patient safety reporting, particularly if an anonymous approach is taken in a nonpunitive atmosphere, can significantly increase the reporting of patient safety events [14–16]. We demonstrated marked under-reporting and stability of patient safety event reporting throughout our ambulatory practice group and a 10-fold increase in reporting among the 6-practice collaborative.

An unexpected finding was that with the exception of 1 practice, we found no increased reporting in comparator practices that had a patient safety coach. Additionally, we noted that general surgery practices report (or experience) very few ambulatory safety events, as a total of 4 events were reported for all 4 general surgery practices in 18 months.

We chose a quasi-experimental with a comparison group and pre-test/post-test design since randomization of practices was not feasible [17]. We used a 2-year period to control for any seasonal trends and to allow time after the intervention to see if meaningful improvement in reporting over time would continue. We attempted to address the potential for nonequivalence in the comparison group by matching for specialty and size of practice.

There are several  limitations to this study. Bias in the selection of collaborative practices may have occurred since each had a proven leader, and this may have led to more rapid adoption and utilization of this reporting approach. Also, our findings may not be generalizable to other integrated health systems given the unique approaches to patient safety culture development and the disparate nature of reporting systems. In addition, with our study design we could not be certain that anonymous reporting was a key factor in the increase in reporting rates, but de-briefing interviews indicated that both anonymous reporting and declaring a nonpunitive, supportive approach in each practice was important to enhanced reporting.

We expect increased reporting to decline over time without consistent feedback, as has been demonstrated in other studies [18], and we will continue to monitor rates over time.

As our current reporting system requires considerable reporter time for data input and discussion with risk managers, is not specifically configured for ambulatory reporting, is considered by staff and providers potentially punitive, and marked under-reporting is clear, we have proposed moving to a new system that is more user-friendly, ambulatory-focused, and has a provision for anonymous reporting.

Presented in part at the Institute for Healthcare Improvement 15th Annual International Summit on Improving Patient Care in the Office Practice and the Community, Washington DC, March 2014.

Acknowledgements: We gratefully acknowledge the work of collaborative practice team members, including Christopher Isenhour MD, Janet White, Shelby Carlyle, Mark Tillotson MD, Maria Migliaccio, Melanie Trapp, Jennifer Ochs, Gary DeRosa MD, Margarete Hinkle, Scott Wagner, Kelly Schetselaar, Timothy Eichenbrenner MD, Sandy Hite, Jamie Shelton, Raymond Swetenburg MD, James Lye MD, Kelly Morrison, Jan Rapisardo, Jane Moss, Rhett Brown MD, Dorothy Hedrick, Camille Farmer, and William Anderson, MS, for assistance with analysis.

Corresponding author: Herbert Clegg, MD, 108 Providence Road, Charlotte NC, 28207, hwclegg@novanthealth.org.

Financial disclosures: None.

From Summa Health System, Akron, OH.

Abstract

• Background: Ischemic stroke is a major cause of morbidity and mortality for patients ≥ 80 years old. The use of intravenous recombinant tissue plasminogen activator (tPA) in patients ≥ 80 years for treatment of ischemic stroke remains controversial.
• Objective: To examine outcomes in patients ≥ 80 years old who received tPA in our institution.
• Methods: This was a retrospective cohort study at a community-based certified acute stroke center. Individuals age ≥ 80 years evaluated emergently for acute neurologic changes consistent with ischemic stroke were included (n = 184). The comparison groups within this sample were patients who received tPA versus with those who did not because they came to the ED outside of the treatment window. Outcome measures included length of stay, symptomatic intracerebral hemorrhage (ICH), discharge disposition, and in-hospital death
• Results: 38 patients (20.7%) received tPA. 50 patients (27.2%) presented outside of treatment windows and were included in comparative analysis. There was no difference between groups in age (P = 0.26) or initial National Institute of Health Stroke Scale (P = 0.598). One patient (2.6%) who received tPA developed symptomatic ICH. Those receiving tPA were more likely to be discharged to acute rehabilitation hospitals (P = 0.012) and less likely to experience in hospital death (P = 0.048).
• Conclusion: At this institution, the use of tPA in patients ≥ 80 years old is not associated with increased mortality or risk of symptomatic ICH. Those who received tPA were more likely to be discharged to acute rehabilitation hospitals, suggesting greater potential for functional recovery.

Acute ischemic stroke is a major cause of morbidity and mortality in patients 80 years or older. Though less than 5% of the United States population is over the age of 80 [1], studies have shown that up to one-third of patients presenting with ischemic stroke are ≥ 80 years old [2] and among first-time strokes, a third occur in those ≥ 80 [3]. Older adults present with worse symptoms associated with ischemic stroke as measured by the National Institutes of Health Stroke Scale (NIHSS) compared with younger (< 80 years) counterparts [4]. Older patients are more likely to be discharged to a location other than home [5]. Older age is associated with higher hospital, 30-day, and 1-year mortality [3,5,6]. Patients ≥ 80 are significantly more likely to die in the hospital compared to younger patients, 11.7% to 23.6% vs 5.1%, respectively [3,7].

The Food and Drug Administration (FDA) approved the use of intravenous recombinant tissue plasminogen activator (tPA) in 1996 for the treatment of ischemic stroke [8]. Studies evaluating the safety and efficacy of tPA in ischemic stroke excluded or underrepresented patients ≥ 80 [8,9]. The use of tPA in those ≥ 80 has not been shown consistently to improve outcomes [6,10,11]. Post-hoc analysis of the National Institute of Neurologic Disorders and Stroke (NINDS) study did not show worse outcomes or harms to older adults treated with tPA [12]. Likewise, data from the International Stroke Treatment (IST-3) collaborative group show that treatment with tPA up to 6 hours from the onset of symptoms improves outcomes in the elderly [13]. Use of tPA in the oldest adults remains controversial due to perceived higher risk of symptomatic intracerebral hemorrhage (ICH). Published data suggest overall ICH risk of 4.3% to 6.4% across all age-groups [9,14,15].Studies have failed to demonstrate an increased risk in the oldest adults [4,10,16,17], though they may have higher mortality rates associated with ICH [15]. Despite this, trends suggest increasing use of tPA in those ≥ 80 over the past decade [2]. Along with primary data from NINDS [12] and IST-3 [13], a meta-analysis conducted in 2014 suggests that regardless of age, patients have improved outcomes with tPA [18].With the increasing age of the population, effective treatment of strokes in patients ≥ 80 will continue to be an important clinical and research endeavor.

This study evaluates the outcomes of clinical use of tPA for treatment of patients ≥ 80 years old who present to a community-based certified stroke center with ischemic stroke.

Methods

The study setting was a 540-bed acute care hospital that is a community-based certified stroke center. This study was deemed nonhuman subjects research by the institutional review board as the goal was to evaluate processes and outcomes of this institution’s stroke team in treating a subgroup of patients according to clinically accepted practice (quality improvement initiative). All patients presenting to the emergency department (ED) between 1 January 2011 and 30 November 2013 with the onset of stroke-like neurological deficits underwent evaluation and treatment by a neurologist and/or specially trained stroke team. This team consists of the attending neurologist, ED physician, resident physicians, advanced practice nurses, and ED staff nurses and emergency medicine technicians. Team members involved in the evaluation and treatment of these patients undergo routine clinical education and testing to ensure standardization. Patients undergo emergent evaluation including the National Institutes of Health Stroke Scale (NIHSS) and obtain brain imaging with computed tomography (CT).

Patients ≥ 80 years were identified among all those who presented to the ED with ischemic stroke. Patients were included if they were subsequently diagnosed with ischemic stroke or transient ischemic attacks (TIA). They were excluded from analysis if neurological changes were due to primary hemorrhagic stroke, intracranial hemorrhage, subarachnoid hemorrhage, seizure, conversion disorder, or metabolic derangements. They were also excluded from analysis if the acute ischemic stroke treatment included intra-arterial administration of tPA or endovascular revascularization.

Patient data collected included age, NIHSS at presentation to ED, time to presentation at ED, treatment with tPA, contraindications to tPA, discharge disposition, length of stay and in-hospital mortality. Raw NIHSS values were collected at the time of presentation. NIHSS were categorized into mild symptoms (NIHSS < 6), moderate symptoms (NIHSS 6–19), or severe symptoms (NIHSS ≥ 20). Clinical indications for receiving tPA include NIHSS > 4, focal neurological deficit onset < 3 hours (for those ≥ 80 years old), and no evidence of acute hemorrhage or acute infarct on CT. Contraindications include rapidly improving symptoms (repeat NIHSS < 4), active or history of intracranial hemorrhage, history of stroke or head trauma in past 3 months, gastrointestinal or genitourinary hemorrhage within 21 days, major surgery within 14 days, arterial puncture at a noncompressible site in past 7 days, treatment with anticoagulation with therapeutic indices, systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg and not responding to treatment, or platelet count < 100,000/mm³. Patients who were not eligible for tPA based on contraindications with the exception of being outside the treatment window (3 hours) were excluded from comparative analysis. Patient length of stay was rounded to nearest full day. Discharge disposition was categorized as home, acute rehabilitation hospital, skilled nursing facility, home or facility with hospice services, other hospital setting, or death.

Statistics were calculated using SPSS statistical software. Variables were reported as means and percentages. Group means were compared using t tests and differences in proportions were compared using the chi square test. Correlations were performed using Pearson’s correlation. A 2-tailed P < 0.05 was considered statistically significant.

Results

Discussion

Ischemic stroke remains a major cause of morbidity and mortality for very old patients. Though less than 5% of the United States population is over the age of 80 [1], at this community-based hospital 18% of those presenting to the ED with ischemic stroke were in this age-group. With a population of increasing age, more people in this age-group will present with ischemic stroke and need effective treatment to limit the associated morbidity and mortality. Being able to quickly and safely treat acute ischemic stroke may help very old adults maintain independence or prevent institutionalization. While the original studies demonstrating the effectiveness of tPA for acute ischemic stroke excluded or underrepresented those ≥ 80 years, retrospective analysis has not been conclusive regarding its use in very old patients [4–6,10,12,13].However, post-hoc analysis of NINDS and IST-3 data demonstrate efficacy and safety of treatment [12,13].

This study explored the use of tPA at a community-based certified stroke center. Similar to previous studies, it demonstrates the large proportion of patients presenting with acute neurological findings consistent with ischemic stroke are ≥ 80 years old [3,6]. Our incidence of acute ischemic stroke in the oldest patients may be slightly lower than reported elsewhere, which may reflect community differences, with higher rates of younger patients with multiple comorbidities presenting with stroke-like symptoms. Amongst this very old cohort, age was positively correlated with stroke severity. Mortality in patients ≥ 80 years old who present with acute ischemic stroke approaches 25%.

The majority of patients who did not receive tPA had documented contraindications to receiving the medication. The most common reason was rapidly improving symptoms with repeat NIHSS often ≤ 4. The second most common reason was presentation outside the treatment window of 3 hours. We compared those who either arrived too late to receive treatment with tPA or already had ischemic changes on CT to those who received tPA as this suggests the natural history of stroke progression and outcome without effective, early treatment. The outcomes at this institution support this trend. Very old patients who received tPA did not experience harm as evidenced by similar lengths of stay and rates of discharge to home. Also, rates of symptomatic ICH were lower than those reported in the literature. In fact, patients who received tPA were less likely to experience in-hospital death and more likely to be discharged to acute rehabilitation hospitals, suggesting more functional ability to tolerate aggressive recovery efforts.

Very few people who presented with acute ischemic stroke and were eligible for treatment with tPA failed to receive it. This suggests that despite the perceived increased risk to treating these patients with tPA, the specialized stroke team aggressively treats patients age ≥ 80 years who present with acute ischemic stroke. However, those who did not receive tPA were more likely to have presented with mild or severe strokes. This may suggest that treatment time frames are more strongly held, or that treatment teams are more likely to use time frames as a reason to not treat with tPA for patients with mild or severe strokes. Also, very few patients and families who were eligible to receive tPA declined treatment despite the associated risks. This suggests that patients and families are eager for aggressive treatment in attempt to prevent death or disability associated with ischemic stroke.

There are several limitations associated with this evaluation. First, this is a retrospective analysis of a single institution’s acute stroke procedures. Data was collected in an effort to evaluate the processes and outcomes of the specialized stroke team in evaluating and treating this very old cohort who present to a community-based hospital. It involved individualized clinical evaluation and decision making by multiple care providers who may offer different perspectives on the risk of treating patients ≥ 80 years old with tPA, which may result in selection bias. While comparing those who arrived outside treatment windows offers a comparison group who represents the natural course of untreated strokes, patient characteristics that prevented timely evaluation may also impact their outcomes including baseline mobility, care giving availability and underlying medical comorbidities. The similarity in mean presenting NIHSS scores of the two groups, however, argues against this possibility. Lastly, exclusion criteria to receiving tPA may represent intrinsic characteristics that impart higher risk of negative outcomes.

Conculsion

Although there have been no randomized controlled trials that evaluate the safety and efficacy of tPA in the treatment of acute ischemic stroke in very old patients, use at the community-based stroke center was not associated with worse outcomes including symptomatic ICH, hospital length of stay, and in-hospital mortality. In fact, there were trends towards better outcomes in older patients who received tPA, including a significant reduction in in-hospital mortality. This evaluation supports the benefits of using tPA to treat acute ischemic stroke as seen in prior randomized controlled trials that included the treatment of very old patients. Though ongoing research is needed, a growing body of evidence supports the use of tPA to treat acute ischemic stroke in patients ≥ 80 years.

Corresponding author: Jennifer C. Drost, DO, MPH, Summa Health System, 75 Arch St., Ste. G1, Akron, OH 44304, DrostJ@summahealth.org.

Financial disclosures: None.

Author contributions: Conception and design, JCD, SMB; analysis and interpretation of data, JCD, SMB; drafting of article, JCD; critical revision of the article, JCD, SMB; provision of study materials or patients, SMB; collection and assembly of data, JCD.

From Summa Health System, Akron, OH.

Abstract

• Background: Ischemic stroke is a major cause of morbidity and mortality for patients ≥ 80 years old. The use of intravenous recombinant tissue plasminogen activator (tPA) in patients ≥ 80 years for treatment of ischemic stroke remains controversial.
• Objective: To examine outcomes in patients ≥ 80 years old who received tPA in our institution.
• Methods: This was a retrospective cohort study at a community-based certified acute stroke center. Individuals age ≥ 80 years evaluated emergently for acute neurologic changes consistent with ischemic stroke were included (n = 184). The comparison groups within this sample were patients who received tPA versus with those who did not because they came to the ED outside of the treatment window. Outcome measures included length of stay, symptomatic intracerebral hemorrhage (ICH), discharge disposition, and in-hospital death
• Results: 38 patients (20.7%) received tPA. 50 patients (27.2%) presented outside of treatment windows and were included in comparative analysis. There was no difference between groups in age (P = 0.26) or initial National Institute of Health Stroke Scale (P = 0.598). One patient (2.6%) who received tPA developed symptomatic ICH. Those receiving tPA were more likely to be discharged to acute rehabilitation hospitals (P = 0.012) and less likely to experience in hospital death (P = 0.048).
• Conclusion: At this institution, the use of tPA in patients ≥ 80 years old is not associated with increased mortality or risk of symptomatic ICH. Those who received tPA were more likely to be discharged to acute rehabilitation hospitals, suggesting greater potential for functional recovery.

Acute ischemic stroke is a major cause of morbidity and mortality in patients 80 years or older. Though less than 5% of the United States population is over the age of 80 [1], studies have shown that up to one-third of patients presenting with ischemic stroke are ≥ 80 years old [2] and among first-time strokes, a third occur in those ≥ 80 [3]. Older adults present with worse symptoms associated with ischemic stroke as measured by the National Institutes of Health Stroke Scale (NIHSS) compared with younger (< 80 years) counterparts [4]. Older patients are more likely to be discharged to a location other than home [5]. Older age is associated with higher hospital, 30-day, and 1-year mortality [3,5,6]. Patients ≥ 80 are significantly more likely to die in the hospital compared to younger patients, 11.7% to 23.6% vs 5.1%, respectively [3,7].

The Food and Drug Administration (FDA) approved the use of intravenous recombinant tissue plasminogen activator (tPA) in 1996 for the treatment of ischemic stroke [8]. Studies evaluating the safety and efficacy of tPA in ischemic stroke excluded or underrepresented patients ≥ 80 [8,9]. The use of tPA in those ≥ 80 has not been shown consistently to improve outcomes [6,10,11]. Post-hoc analysis of the National Institute of Neurologic Disorders and Stroke (NINDS) study did not show worse outcomes or harms to older adults treated with tPA [12]. Likewise, data from the International Stroke Treatment (IST-3) collaborative group show that treatment with tPA up to 6 hours from the onset of symptoms improves outcomes in the elderly [13]. Use of tPA in the oldest adults remains controversial due to perceived higher risk of symptomatic intracerebral hemorrhage (ICH). Published data suggest overall ICH risk of 4.3% to 6.4% across all age-groups [9,14,15].Studies have failed to demonstrate an increased risk in the oldest adults [4,10,16,17], though they may have higher mortality rates associated with ICH [15]. Despite this, trends suggest increasing use of tPA in those ≥ 80 over the past decade [2]. Along with primary data from NINDS [12] and IST-3 [13], a meta-analysis conducted in 2014 suggests that regardless of age, patients have improved outcomes with tPA [18].With the increasing age of the population, effective treatment of strokes in patients ≥ 80 will continue to be an important clinical and research endeavor.

This study evaluates the outcomes of clinical use of tPA for treatment of patients ≥ 80 years old who present to a community-based certified stroke center with ischemic stroke.

Methods

The study setting was a 540-bed acute care hospital that is a community-based certified stroke center. This study was deemed nonhuman subjects research by the institutional review board as the goal was to evaluate processes and outcomes of this institution’s stroke team in treating a subgroup of patients according to clinically accepted practice (quality improvement initiative). All patients presenting to the emergency department (ED) between 1 January 2011 and 30 November 2013 with the onset of stroke-like neurological deficits underwent evaluation and treatment by a neurologist and/or specially trained stroke team. This team consists of the attending neurologist, ED physician, resident physicians, advanced practice nurses, and ED staff nurses and emergency medicine technicians. Team members involved in the evaluation and treatment of these patients undergo routine clinical education and testing to ensure standardization. Patients undergo emergent evaluation including the National Institutes of Health Stroke Scale (NIHSS) and obtain brain imaging with computed tomography (CT).

Patients ≥ 80 years were identified among all those who presented to the ED with ischemic stroke. Patients were included if they were subsequently diagnosed with ischemic stroke or transient ischemic attacks (TIA). They were excluded from analysis if neurological changes were due to primary hemorrhagic stroke, intracranial hemorrhage, subarachnoid hemorrhage, seizure, conversion disorder, or metabolic derangements. They were also excluded from analysis if the acute ischemic stroke treatment included intra-arterial administration of tPA or endovascular revascularization.

Patient data collected included age, NIHSS at presentation to ED, time to presentation at ED, treatment with tPA, contraindications to tPA, discharge disposition, length of stay and in-hospital mortality. Raw NIHSS values were collected at the time of presentation. NIHSS were categorized into mild symptoms (NIHSS < 6), moderate symptoms (NIHSS 6–19), or severe symptoms (NIHSS ≥ 20). Clinical indications for receiving tPA include NIHSS > 4, focal neurological deficit onset < 3 hours (for those ≥ 80 years old), and no evidence of acute hemorrhage or acute infarct on CT. Contraindications include rapidly improving symptoms (repeat NIHSS < 4), active or history of intracranial hemorrhage, history of stroke or head trauma in past 3 months, gastrointestinal or genitourinary hemorrhage within 21 days, major surgery within 14 days, arterial puncture at a noncompressible site in past 7 days, treatment with anticoagulation with therapeutic indices, systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg and not responding to treatment, or platelet count < 100,000/mm³. Patients who were not eligible for tPA based on contraindications with the exception of being outside the treatment window (3 hours) were excluded from comparative analysis. Patient length of stay was rounded to nearest full day. Discharge disposition was categorized as home, acute rehabilitation hospital, skilled nursing facility, home or facility with hospice services, other hospital setting, or death.

Statistics were calculated using SPSS statistical software. Variables were reported as means and percentages. Group means were compared using t tests and differences in proportions were compared using the chi square test. Correlations were performed using Pearson’s correlation. A 2-tailed P < 0.05 was considered statistically significant.

Results

Discussion

Ischemic stroke remains a major cause of morbidity and mortality for very old patients. Though less than 5% of the United States population is over the age of 80 [1], at this community-based hospital 18% of those presenting to the ED with ischemic stroke were in this age-group. With a population of increasing age, more people in this age-group will present with ischemic stroke and need effective treatment to limit the associated morbidity and mortality. Being able to quickly and safely treat acute ischemic stroke may help very old adults maintain independence or prevent institutionalization. While the original studies demonstrating the effectiveness of tPA for acute ischemic stroke excluded or underrepresented those ≥ 80 years, retrospective analysis has not been conclusive regarding its use in very old patients [4–6,10,12,13].However, post-hoc analysis of NINDS and IST-3 data demonstrate efficacy and safety of treatment [12,13].

This study explored the use of tPA at a community-based certified stroke center. Similar to previous studies, it demonstrates the large proportion of patients presenting with acute neurological findings consistent with ischemic stroke are ≥ 80 years old [3,6]. Our incidence of acute ischemic stroke in the oldest patients may be slightly lower than reported elsewhere, which may reflect community differences, with higher rates of younger patients with multiple comorbidities presenting with stroke-like symptoms. Amongst this very old cohort, age was positively correlated with stroke severity. Mortality in patients ≥ 80 years old who present with acute ischemic stroke approaches 25%.

The majority of patients who did not receive tPA had documented contraindications to receiving the medication. The most common reason was rapidly improving symptoms with repeat NIHSS often ≤ 4. The second most common reason was presentation outside the treatment window of 3 hours. We compared those who either arrived too late to receive treatment with tPA or already had ischemic changes on CT to those who received tPA as this suggests the natural history of stroke progression and outcome without effective, early treatment. The outcomes at this institution support this trend. Very old patients who received tPA did not experience harm as evidenced by similar lengths of stay and rates of discharge to home. Also, rates of symptomatic ICH were lower than those reported in the literature. In fact, patients who received tPA were less likely to experience in-hospital death and more likely to be discharged to acute rehabilitation hospitals, suggesting more functional ability to tolerate aggressive recovery efforts.

Very few people who presented with acute ischemic stroke and were eligible for treatment with tPA failed to receive it. This suggests that despite the perceived increased risk to treating these patients with tPA, the specialized stroke team aggressively treats patients age ≥ 80 years who present with acute ischemic stroke. However, those who did not receive tPA were more likely to have presented with mild or severe strokes. This may suggest that treatment time frames are more strongly held, or that treatment teams are more likely to use time frames as a reason to not treat with tPA for patients with mild or severe strokes. Also, very few patients and families who were eligible to receive tPA declined treatment despite the associated risks. This suggests that patients and families are eager for aggressive treatment in attempt to prevent death or disability associated with ischemic stroke.

There are several limitations associated with this evaluation. First, this is a retrospective analysis of a single institution’s acute stroke procedures. Data was collected in an effort to evaluate the processes and outcomes of the specialized stroke team in evaluating and treating this very old cohort who present to a community-based hospital. It involved individualized clinical evaluation and decision making by multiple care providers who may offer different perspectives on the risk of treating patients ≥ 80 years old with tPA, which may result in selection bias. While comparing those who arrived outside treatment windows offers a comparison group who represents the natural course of untreated strokes, patient characteristics that prevented timely evaluation may also impact their outcomes including baseline mobility, care giving availability and underlying medical comorbidities. The similarity in mean presenting NIHSS scores of the two groups, however, argues against this possibility. Lastly, exclusion criteria to receiving tPA may represent intrinsic characteristics that impart higher risk of negative outcomes.

Conculsion

Although there have been no randomized controlled trials that evaluate the safety and efficacy of tPA in the treatment of acute ischemic stroke in very old patients, use at the community-based stroke center was not associated with worse outcomes including symptomatic ICH, hospital length of stay, and in-hospital mortality. In fact, there were trends towards better outcomes in older patients who received tPA, including a significant reduction in in-hospital mortality. This evaluation supports the benefits of using tPA to treat acute ischemic stroke as seen in prior randomized controlled trials that included the treatment of very old patients. Though ongoing research is needed, a growing body of evidence supports the use of tPA to treat acute ischemic stroke in patients ≥ 80 years.

Corresponding author: Jennifer C. Drost, DO, MPH, Summa Health System, 75 Arch St., Ste. G1, Akron, OH 44304, DrostJ@summahealth.org.

Financial disclosures: None.

Author contributions: Conception and design, JCD, SMB; analysis and interpretation of data, JCD, SMB; drafting of article, JCD; critical revision of the article, JCD, SMB; provision of study materials or patients, SMB; collection and assembly of data, JCD.

From Summa Health System, Akron, OH.

Abstract

• Background: Ischemic stroke is a major cause of morbidity and mortality for patients ≥ 80 years old. The use of intravenous recombinant tissue plasminogen activator (tPA) in patients ≥ 80 years for treatment of ischemic stroke remains controversial.
• Objective: To examine outcomes in patients ≥ 80 years old who received tPA in our institution.
• Methods: This was a retrospective cohort study at a community-based certified acute stroke center. Individuals age ≥ 80 years evaluated emergently for acute neurologic changes consistent with ischemic stroke were included (n = 184). The comparison groups within this sample were patients who received tPA versus with those who did not because they came to the ED outside of the treatment window. Outcome measures included length of stay, symptomatic intracerebral hemorrhage (ICH), discharge disposition, and in-hospital death
• Results: 38 patients (20.7%) received tPA. 50 patients (27.2%) presented outside of treatment windows and were included in comparative analysis. There was no difference between groups in age (P = 0.26) or initial National Institute of Health Stroke Scale (P = 0.598). One patient (2.6%) who received tPA developed symptomatic ICH. Those receiving tPA were more likely to be discharged to acute rehabilitation hospitals (P = 0.012) and less likely to experience in hospital death (P = 0.048).
• Conclusion: At this institution, the use of tPA in patients ≥ 80 years old is not associated with increased mortality or risk of symptomatic ICH. Those who received tPA were more likely to be discharged to acute rehabilitation hospitals, suggesting greater potential for functional recovery.

Acute ischemic stroke is a major cause of morbidity and mortality in patients 80 years or older. Though less than 5% of the United States population is over the age of 80 [1], studies have shown that up to one-third of patients presenting with ischemic stroke are ≥ 80 years old [2] and among first-time strokes, a third occur in those ≥ 80 [3]. Older adults present with worse symptoms associated with ischemic stroke as measured by the National Institutes of Health Stroke Scale (NIHSS) compared with younger (< 80 years) counterparts [4]. Older patients are more likely to be discharged to a location other than home [5]. Older age is associated with higher hospital, 30-day, and 1-year mortality [3,5,6]. Patients ≥ 80 are significantly more likely to die in the hospital compared to younger patients, 11.7% to 23.6% vs 5.1%, respectively [3,7].

The Food and Drug Administration (FDA) approved the use of intravenous recombinant tissue plasminogen activator (tPA) in 1996 for the treatment of ischemic stroke [8]. Studies evaluating the safety and efficacy of tPA in ischemic stroke excluded or underrepresented patients ≥ 80 [8,9]. The use of tPA in those ≥ 80 has not been shown consistently to improve outcomes [6,10,11]. Post-hoc analysis of the National Institute of Neurologic Disorders and Stroke (NINDS) study did not show worse outcomes or harms to older adults treated with tPA [12]. Likewise, data from the International Stroke Treatment (IST-3) collaborative group show that treatment with tPA up to 6 hours from the onset of symptoms improves outcomes in the elderly [13]. Use of tPA in the oldest adults remains controversial due to perceived higher risk of symptomatic intracerebral hemorrhage (ICH). Published data suggest overall ICH risk of 4.3% to 6.4% across all age-groups [9,14,15].Studies have failed to demonstrate an increased risk in the oldest adults [4,10,16,17], though they may have higher mortality rates associated with ICH [15]. Despite this, trends suggest increasing use of tPA in those ≥ 80 over the past decade [2]. Along with primary data from NINDS [12] and IST-3 [13], a meta-analysis conducted in 2014 suggests that regardless of age, patients have improved outcomes with tPA [18].With the increasing age of the population, effective treatment of strokes in patients ≥ 80 will continue to be an important clinical and research endeavor.

This study evaluates the outcomes of clinical use of tPA for treatment of patients ≥ 80 years old who present to a community-based certified stroke center with ischemic stroke.

Methods

The study setting was a 540-bed acute care hospital that is a community-based certified stroke center. This study was deemed nonhuman subjects research by the institutional review board as the goal was to evaluate processes and outcomes of this institution’s stroke team in treating a subgroup of patients according to clinically accepted practice (quality improvement initiative). All patients presenting to the emergency department (ED) between 1 January 2011 and 30 November 2013 with the onset of stroke-like neurological deficits underwent evaluation and treatment by a neurologist and/or specially trained stroke team. This team consists of the attending neurologist, ED physician, resident physicians, advanced practice nurses, and ED staff nurses and emergency medicine technicians. Team members involved in the evaluation and treatment of these patients undergo routine clinical education and testing to ensure standardization. Patients undergo emergent evaluation including the National Institutes of Health Stroke Scale (NIHSS) and obtain brain imaging with computed tomography (CT).

Patients ≥ 80 years were identified among all those who presented to the ED with ischemic stroke. Patients were included if they were subsequently diagnosed with ischemic stroke or transient ischemic attacks (TIA). They were excluded from analysis if neurological changes were due to primary hemorrhagic stroke, intracranial hemorrhage, subarachnoid hemorrhage, seizure, conversion disorder, or metabolic derangements. They were also excluded from analysis if the acute ischemic stroke treatment included intra-arterial administration of tPA or endovascular revascularization.

Patient data collected included age, NIHSS at presentation to ED, time to presentation at ED, treatment with tPA, contraindications to tPA, discharge disposition, length of stay and in-hospital mortality. Raw NIHSS values were collected at the time of presentation. NIHSS were categorized into mild symptoms (NIHSS < 6), moderate symptoms (NIHSS 6–19), or severe symptoms (NIHSS ≥ 20). Clinical indications for receiving tPA include NIHSS > 4, focal neurological deficit onset < 3 hours (for those ≥ 80 years old), and no evidence of acute hemorrhage or acute infarct on CT. Contraindications include rapidly improving symptoms (repeat NIHSS < 4), active or history of intracranial hemorrhage, history of stroke or head trauma in past 3 months, gastrointestinal or genitourinary hemorrhage within 21 days, major surgery within 14 days, arterial puncture at a noncompressible site in past 7 days, treatment with anticoagulation with therapeutic indices, systolic blood pressure > 185 mm Hg or diastolic blood pressure > 110 mm Hg and not responding to treatment, or platelet count < 100,000/mm³. Patients who were not eligible for tPA based on contraindications with the exception of being outside the treatment window (3 hours) were excluded from comparative analysis. Patient length of stay was rounded to nearest full day. Discharge disposition was categorized as home, acute rehabilitation hospital, skilled nursing facility, home or facility with hospice services, other hospital setting, or death.

Statistics were calculated using SPSS statistical software. Variables were reported as means and percentages. Group means were compared using t tests and differences in proportions were compared using the chi square test. Correlations were performed using Pearson’s correlation. A 2-tailed P < 0.05 was considered statistically significant.

Results

Discussion

Ischemic stroke remains a major cause of morbidity and mortality for very old patients. Though less than 5% of the United States population is over the age of 80 [1], at this community-based hospital 18% of those presenting to the ED with ischemic stroke were in this age-group. With a population of increasing age, more people in this age-group will present with ischemic stroke and need effective treatment to limit the associated morbidity and mortality. Being able to quickly and safely treat acute ischemic stroke may help very old adults maintain independence or prevent institutionalization. While the original studies demonstrating the effectiveness of tPA for acute ischemic stroke excluded or underrepresented those ≥ 80 years, retrospective analysis has not been conclusive regarding its use in very old patients [4–6,10,12,13].However, post-hoc analysis of NINDS and IST-3 data demonstrate efficacy and safety of treatment [12,13].

This study explored the use of tPA at a community-based certified stroke center. Similar to previous studies, it demonstrates the large proportion of patients presenting with acute neurological findings consistent with ischemic stroke are ≥ 80 years old [3,6]. Our incidence of acute ischemic stroke in the oldest patients may be slightly lower than reported elsewhere, which may reflect community differences, with higher rates of younger patients with multiple comorbidities presenting with stroke-like symptoms. Amongst this very old cohort, age was positively correlated with stroke severity. Mortality in patients ≥ 80 years old who present with acute ischemic stroke approaches 25%.

The majority of patients who did not receive tPA had documented contraindications to receiving the medication. The most common reason was rapidly improving symptoms with repeat NIHSS often ≤ 4. The second most common reason was presentation outside the treatment window of 3 hours. We compared those who either arrived too late to receive treatment with tPA or already had ischemic changes on CT to those who received tPA as this suggests the natural history of stroke progression and outcome without effective, early treatment. The outcomes at this institution support this trend. Very old patients who received tPA did not experience harm as evidenced by similar lengths of stay and rates of discharge to home. Also, rates of symptomatic ICH were lower than those reported in the literature. In fact, patients who received tPA were less likely to experience in-hospital death and more likely to be discharged to acute rehabilitation hospitals, suggesting more functional ability to tolerate aggressive recovery efforts.

Very few people who presented with acute ischemic stroke and were eligible for treatment with tPA failed to receive it. This suggests that despite the perceived increased risk to treating these patients with tPA, the specialized stroke team aggressively treats patients age ≥ 80 years who present with acute ischemic stroke. However, those who did not receive tPA were more likely to have presented with mild or severe strokes. This may suggest that treatment time frames are more strongly held, or that treatment teams are more likely to use time frames as a reason to not treat with tPA for patients with mild or severe strokes. Also, very few patients and families who were eligible to receive tPA declined treatment despite the associated risks. This suggests that patients and families are eager for aggressive treatment in attempt to prevent death or disability associated with ischemic stroke.

There are several limitations associated with this evaluation. First, this is a retrospective analysis of a single institution’s acute stroke procedures. Data was collected in an effort to evaluate the processes and outcomes of the specialized stroke team in evaluating and treating this very old cohort who present to a community-based hospital. It involved individualized clinical evaluation and decision making by multiple care providers who may offer different perspectives on the risk of treating patients ≥ 80 years old with tPA, which may result in selection bias. While comparing those who arrived outside treatment windows offers a comparison group who represents the natural course of untreated strokes, patient characteristics that prevented timely evaluation may also impact their outcomes including baseline mobility, care giving availability and underlying medical comorbidities. The similarity in mean presenting NIHSS scores of the two groups, however, argues against this possibility. Lastly, exclusion criteria to receiving tPA may represent intrinsic characteristics that impart higher risk of negative outcomes.

Conculsion

Although there have been no randomized controlled trials that evaluate the safety and efficacy of tPA in the treatment of acute ischemic stroke in very old patients, use at the community-based stroke center was not associated with worse outcomes including symptomatic ICH, hospital length of stay, and in-hospital mortality. In fact, there were trends towards better outcomes in older patients who received tPA, including a significant reduction in in-hospital mortality. This evaluation supports the benefits of using tPA to treat acute ischemic stroke as seen in prior randomized controlled trials that included the treatment of very old patients. Though ongoing research is needed, a growing body of evidence supports the use of tPA to treat acute ischemic stroke in patients ≥ 80 years.

Corresponding author: Jennifer C. Drost, DO, MPH, Summa Health System, 75 Arch St., Ste. G1, Akron, OH 44304, DrostJ@summahealth.org.

Financial disclosures: None.

Author contributions: Conception and design, JCD, SMB; analysis and interpretation of data, JCD, SMB; drafting of article, JCD; critical revision of the article, JCD, SMB; provision of study materials or patients, SMB; collection and assembly of data, JCD.

Study Overview

Objective. To determine the efficacy, both short and long term, of a behavioral intervention targeting overweight parents and their children simultaneously versus an intervention focused on weight management only for the child within the patient-centered medical home (PCMH).

Design. 4-center, 2-arm, randomized controlled trial.

Setting and participants. Study participants were recruited from 4 urban/suburban pediatric practices. Primary care providers (PCPs) recruited patients at the time of well or sick visits based on body mass index (BMI) flagged prior to the visit by Patient Enhancement Assistants (PEAs). 171 parent/child dyads were assessed for eligibility and 105 were randomized in blocks of 12 dyads using a random number generator and stratified by child’s gender. Pediatricians were blind to their patient’s group assignments. Inclusion criteria were as follows: children aged 2–5 with a BMI higher than the 85th percentile for both age and gender, and 1 parent with a BMI greater than 25. Exclusion criteria were limited to children who were small for gestational age and/or short stature, and child or parent inability to perform physical activity. Specific precautions were taken to prevent contamination between intervention and information control (IC) groups [1].

Intervention. Three PEAs who held a masters or bachelors degree in psychology, nutrition, exercise science, or equivalent, or were registered dietitians, were embedded within each PCMH practice. For both the intervention and IC groups, parents attended 13 one-hour group sessions led by a PEA over a 12-month period, followed by a 12-month follow-up period with 3 additional meetings. The PEA telephoned parents between scheduled meetings. Pediatricians reviewed child’s weight changes every 6 months during scheduled appointments and the PEA sent progress notes in between these visits [2]. Dietary, physical, and sedentary activity guidelines were given based on the recommendations of a national multi-organizational expert committee [3]. Parents were given specific goals for their child, including a 0.5- to 1-pound per week loss, 60 minutes per day of physical activity, and limiting TV and screen time to less than 2 hours per day.

In addition, the intervention group received parenting and behavior change strategies to promote both parent and child weight loss. Parents were instructed to weigh themselves and their child once per week and monitor physical activity and diet. They received individual meetings with the PEA before or after group meetings to review goal setting and food/physical activity diaries. Parents were also given a weight loss goal of 1 to 2 pounds per week and were advised to model physical activity by engaging in active play with their child for at least 10 minutes per day.

Main outcome measures. The main outcome measures were %0BMI and z-BMI. Percent 0BMI is defined as [(child’s BMI – 50th percentile BMI)/50th percentile BMI] x 100 [2]. The authors chose %0BMI as the primary outcome measure because z-BMI can diminish the effect of weight change in heavier children [4]. Both measures were expressed as mean ± standard error (SEM). Parent weight change was measured using BMI alone.

The child’s weight was measured at each session and height was measured at baseline, 3, 6, 12, 18, and 24 months. Parent weight was measured every session in the intervention group, but only at baseline, 6, 12, 18, and 24 months in the IC group. A standardized protocol was followed for all height and weight measurements. An intention to treat analysis (ITT) was conducted on all parent/child dyads, regardless of whether or not they completed the study (n = 96).

Results. Research assistants assessed 171 parent/child dyads for eligibility. 66 were excluded for either not meeting inclusion criteria (n = 24) or declining to participate (n = 42). 105 dyads were randomized, but 9 did not receive the allocated intervention because they did not start the study, resulting in a total of 96 dyads included in analysis: 46 in the intervention group and 50 in the IC. Twelve- and 24-month completion rates were 83% and 73% respectively; there was no difference in attrition between intervention and IC groups.

The mean child ages of the intervention and IC groups were 4.6 ± 0.2 and 4.4 ± 0.2 years, respectively. 33 of the 46 children in the intervention group and 37 of the 50 children in the IC group were identified as non-Hispanic white. The mean yearly income of all families was $65,729 ± $3068, with only 8.3% of families below $20,000.

The intervention group had greater decreases in child %0BMI from baseline to 6, 12, 18, and 24 months than the IC group. Similar trends were seen with child z-BMI. A slower increase in height was observed in the intervention group when compared with the IC at both 18 months (P < 0.001) and at 24 months (P < 0.02). Parents showed greater overall BMI reduction in the intervention group as opposed to the IC group at all time points (P < 0.001). BMI changes achieved at 6 months were maintained at 24 months. %0BMI and parent BMI changes were correlated from baseline to 12, 18, and 24 months. No significant baseline moderators were found among the children in either group.

Conclusion. This study demonstrated that within the PCMH model of pediatric primary care, an intervention focused on joint behavior change and weight modification treatment of parents and children led to better initial and sustained improvements in %0BMI and z-BMI (in children) and BMI (in parents) than a child-focused IC.

Commentary

Over one-third of children and adolescents are considered to be overweight or have obesity, a number that has doubled in the past 30 years [5]. Pediatrician and primary care physician visits are optimal places to identify overweight children who are at risk for obesity and begin prevention measures, although identifying overweight and obese younger children can be difficult [6]. This study used PEAs to aid physicians in identification, implementation, and delivery. With increasing evidence to support pediatrician involvement in intensive weight management in a primary versus specialty care setting, embedding PEAs within the PCMH model may be an important way to help deliver care for overweight/obese children [7].

Although many approaches have been considered to target childhood obesity, this study represents an important contribution to the literature because it demonstrates that a primary care–based intervention targeting parents as well as their young children is more efficacious for weight management than a more traditional, child-only focused intervention. In addition, the intervention included many different evidence-based components such as teaching behavior modification techniques to parents, consideration of parenting styles and techniques, and encouraging simultaneous parental weight modification. While the U.S. Preventive Services Task Force (USPSTF) recommends intensive interventions with 30 sessions over 2 years [8], this study was able to accomplish significant weight change in 13 sessions.

This intervention is unique in its integration of parenting techniques with other evidence-based strategies for child weight management. Although it has been shown in the literature that certain parenting styles can positively impact children’s health behaviors [9], namely the use of positive reinforcement and monitoring children’s health practices [10], only a few studies have looked at the impact of parenting interventions on childhood obesity. Mazzeo et al demonstrated a significant reduction in child BMI with a parenting-only intervention in the NOURISH trial [11], Slusser et al found a significant child BMI reduction using parent training for low-income, 2- to 4-year-old children [12], and Brotman et al conducted a longitudinal study demonstrating that a family intervention could decrease BMI and improve overall child health behaviors [13]. Despite these aforementioned studies, there is a lack of longitudinal data on the association between general parenting style and weight [14], and this study addresses this gap in literature by providing 2-year follow-up and demonstrating sustained impact on the intervention group.

This study had many additional strengths, including randomized design, primary care physician blinding, use of intention to treat analysis, standardization of measurement tools, clear justification of sample size, long-term follow-up, and the use of child-appropriate BMI measures (eg, %0BMI vs. z-BMI as primary outcome measure). In addition, the intervention setting in a PCMH follows the trend of increasing interest in exploring this model of health care delivery [15,16]. It is also important to note that the intervention and IC groups received the same number of group visits and phone calls, the only difference being the content and the extra 1:1 PEA sessions received by the intervention group.

The few weaknesses include that the PEAs could not be blinded to treatment allocation, and generalizability is limited by the mostly non-Hispanic white population and that only 8.3% of the study population had an annual household income of less than $20,000. All parents included in this study were on the high end of the obese range (BMI 30–39.9), with baseline BMI values of 37.2 and 36.2 in the intervention and IC groups respectively. In addition, the age of the children included in the study were on the high end of the designated 2- to 5-year-old range: 4.6 years (IC) and 4.4 years (intervention). Although findings were promising within this specific population, further research in younger and more diverse populations is necessary [11].

Finally, it is unclear whether this intervention is scalable, and a cost-effectiveness analysis of this intervention is needed. This study was designed to limit the PCP’s role and simplify the process of identifying and intervening on overweight children and their parents, yet this required 3 part-time PEAs and a project coordinator responsible for delivering all of the group sessions and providing follow-up counseling to both intervention and IC groups.

Applications for Clinical Practice

This study demonstrates that in a mostly white, urban/suburban population, a parenting and behavior modification intervention focused on both parent and child leads to greater improvements in %0BMI and z-BMI in the child and BMI reduction in parents compared with an intervention focused on the child alone within pediatric PCMH practices. This intervention should be tested in more diverse populations. This study also suggests further exploration of the use of PEAs to help clinicians address obesity within the PCMH model of primary care.

—Natalie Berner, BA, and Melanie Jay, MD, MS

Study Overview

Objective. To determine the efficacy, both short and long term, of a behavioral intervention targeting overweight parents and their children simultaneously versus an intervention focused on weight management only for the child within the patient-centered medical home (PCMH).

Design. 4-center, 2-arm, randomized controlled trial.

Setting and participants. Study participants were recruited from 4 urban/suburban pediatric practices. Primary care providers (PCPs) recruited patients at the time of well or sick visits based on body mass index (BMI) flagged prior to the visit by Patient Enhancement Assistants (PEAs). 171 parent/child dyads were assessed for eligibility and 105 were randomized in blocks of 12 dyads using a random number generator and stratified by child’s gender. Pediatricians were blind to their patient’s group assignments. Inclusion criteria were as follows: children aged 2–5 with a BMI higher than the 85th percentile for both age and gender, and 1 parent with a BMI greater than 25. Exclusion criteria were limited to children who were small for gestational age and/or short stature, and child or parent inability to perform physical activity. Specific precautions were taken to prevent contamination between intervention and information control (IC) groups [1].

Intervention. Three PEAs who held a masters or bachelors degree in psychology, nutrition, exercise science, or equivalent, or were registered dietitians, were embedded within each PCMH practice. For both the intervention and IC groups, parents attended 13 one-hour group sessions led by a PEA over a 12-month period, followed by a 12-month follow-up period with 3 additional meetings. The PEA telephoned parents between scheduled meetings. Pediatricians reviewed child’s weight changes every 6 months during scheduled appointments and the PEA sent progress notes in between these visits [2]. Dietary, physical, and sedentary activity guidelines were given based on the recommendations of a national multi-organizational expert committee [3]. Parents were given specific goals for their child, including a 0.5- to 1-pound per week loss, 60 minutes per day of physical activity, and limiting TV and screen time to less than 2 hours per day.

In addition, the intervention group received parenting and behavior change strategies to promote both parent and child weight loss. Parents were instructed to weigh themselves and their child once per week and monitor physical activity and diet. They received individual meetings with the PEA before or after group meetings to review goal setting and food/physical activity diaries. Parents were also given a weight loss goal of 1 to 2 pounds per week and were advised to model physical activity by engaging in active play with their child for at least 10 minutes per day.

Main outcome measures. The main outcome measures were %0BMI and z-BMI. Percent 0BMI is defined as [(child’s BMI – 50th percentile BMI)/50th percentile BMI] x 100 [2]. The authors chose %0BMI as the primary outcome measure because z-BMI can diminish the effect of weight change in heavier children [4]. Both measures were expressed as mean ± standard error (SEM). Parent weight change was measured using BMI alone.

The child’s weight was measured at each session and height was measured at baseline, 3, 6, 12, 18, and 24 months. Parent weight was measured every session in the intervention group, but only at baseline, 6, 12, 18, and 24 months in the IC group. A standardized protocol was followed for all height and weight measurements. An intention to treat analysis (ITT) was conducted on all parent/child dyads, regardless of whether or not they completed the study (n = 96).

Results. Research assistants assessed 171 parent/child dyads for eligibility. 66 were excluded for either not meeting inclusion criteria (n = 24) or declining to participate (n = 42). 105 dyads were randomized, but 9 did not receive the allocated intervention because they did not start the study, resulting in a total of 96 dyads included in analysis: 46 in the intervention group and 50 in the IC. Twelve- and 24-month completion rates were 83% and 73% respectively; there was no difference in attrition between intervention and IC groups.

The mean child ages of the intervention and IC groups were 4.6 ± 0.2 and 4.4 ± 0.2 years, respectively. 33 of the 46 children in the intervention group and 37 of the 50 children in the IC group were identified as non-Hispanic white. The mean yearly income of all families was $65,729 ± $3068, with only 8.3% of families below $20,000.

The intervention group had greater decreases in child %0BMI from baseline to 6, 12, 18, and 24 months than the IC group. Similar trends were seen with child z-BMI. A slower increase in height was observed in the intervention group when compared with the IC at both 18 months (P < 0.001) and at 24 months (P < 0.02). Parents showed greater overall BMI reduction in the intervention group as opposed to the IC group at all time points (P < 0.001). BMI changes achieved at 6 months were maintained at 24 months. %0BMI and parent BMI changes were correlated from baseline to 12, 18, and 24 months. No significant baseline moderators were found among the children in either group.

Conclusion. This study demonstrated that within the PCMH model of pediatric primary care, an intervention focused on joint behavior change and weight modification treatment of parents and children led to better initial and sustained improvements in %0BMI and z-BMI (in children) and BMI (in parents) than a child-focused IC.

Commentary

Over one-third of children and adolescents are considered to be overweight or have obesity, a number that has doubled in the past 30 years [5]. Pediatrician and primary care physician visits are optimal places to identify overweight children who are at risk for obesity and begin prevention measures, although identifying overweight and obese younger children can be difficult [6]. This study used PEAs to aid physicians in identification, implementation, and delivery. With increasing evidence to support pediatrician involvement in intensive weight management in a primary versus specialty care setting, embedding PEAs within the PCMH model may be an important way to help deliver care for overweight/obese children [7].

Although many approaches have been considered to target childhood obesity, this study represents an important contribution to the literature because it demonstrates that a primary care–based intervention targeting parents as well as their young children is more efficacious for weight management than a more traditional, child-only focused intervention. In addition, the intervention included many different evidence-based components such as teaching behavior modification techniques to parents, consideration of parenting styles and techniques, and encouraging simultaneous parental weight modification. While the U.S. Preventive Services Task Force (USPSTF) recommends intensive interventions with 30 sessions over 2 years [8], this study was able to accomplish significant weight change in 13 sessions.

This intervention is unique in its integration of parenting techniques with other evidence-based strategies for child weight management. Although it has been shown in the literature that certain parenting styles can positively impact children’s health behaviors [9], namely the use of positive reinforcement and monitoring children’s health practices [10], only a few studies have looked at the impact of parenting interventions on childhood obesity. Mazzeo et al demonstrated a significant reduction in child BMI with a parenting-only intervention in the NOURISH trial [11], Slusser et al found a significant child BMI reduction using parent training for low-income, 2- to 4-year-old children [12], and Brotman et al conducted a longitudinal study demonstrating that a family intervention could decrease BMI and improve overall child health behaviors [13]. Despite these aforementioned studies, there is a lack of longitudinal data on the association between general parenting style and weight [14], and this study addresses this gap in literature by providing 2-year follow-up and demonstrating sustained impact on the intervention group.

This study had many additional strengths, including randomized design, primary care physician blinding, use of intention to treat analysis, standardization of measurement tools, clear justification of sample size, long-term follow-up, and the use of child-appropriate BMI measures (eg, %0BMI vs. z-BMI as primary outcome measure). In addition, the intervention setting in a PCMH follows the trend of increasing interest in exploring this model of health care delivery [15,16]. It is also important to note that the intervention and IC groups received the same number of group visits and phone calls, the only difference being the content and the extra 1:1 PEA sessions received by the intervention group.

The few weaknesses include that the PEAs could not be blinded to treatment allocation, and generalizability is limited by the mostly non-Hispanic white population and that only 8.3% of the study population had an annual household income of less than $20,000. All parents included in this study were on the high end of the obese range (BMI 30–39.9), with baseline BMI values of 37.2 and 36.2 in the intervention and IC groups respectively. In addition, the age of the children included in the study were on the high end of the designated 2- to 5-year-old range: 4.6 years (IC) and 4.4 years (intervention). Although findings were promising within this specific population, further research in younger and more diverse populations is necessary [11].

Finally, it is unclear whether this intervention is scalable, and a cost-effectiveness analysis of this intervention is needed. This study was designed to limit the PCP’s role and simplify the process of identifying and intervening on overweight children and their parents, yet this required 3 part-time PEAs and a project coordinator responsible for delivering all of the group sessions and providing follow-up counseling to both intervention and IC groups.

Applications for Clinical Practice

This study demonstrates that in a mostly white, urban/suburban population, a parenting and behavior modification intervention focused on both parent and child leads to greater improvements in %0BMI and z-BMI in the child and BMI reduction in parents compared with an intervention focused on the child alone within pediatric PCMH practices. This intervention should be tested in more diverse populations. This study also suggests further exploration of the use of PEAs to help clinicians address obesity within the PCMH model of primary care.

—Natalie Berner, BA, and Melanie Jay, MD, MS

Study Overview

Objective. To determine the efficacy, both short and long term, of a behavioral intervention targeting overweight parents and their children simultaneously versus an intervention focused on weight management only for the child within the patient-centered medical home (PCMH).

Design. 4-center, 2-arm, randomized controlled trial.

Setting and participants. Study participants were recruited from 4 urban/suburban pediatric practices. Primary care providers (PCPs) recruited patients at the time of well or sick visits based on body mass index (BMI) flagged prior to the visit by Patient Enhancement Assistants (PEAs). 171 parent/child dyads were assessed for eligibility and 105 were randomized in blocks of 12 dyads using a random number generator and stratified by child’s gender. Pediatricians were blind to their patient’s group assignments. Inclusion criteria were as follows: children aged 2–5 with a BMI higher than the 85th percentile for both age and gender, and 1 parent with a BMI greater than 25. Exclusion criteria were limited to children who were small for gestational age and/or short stature, and child or parent inability to perform physical activity. Specific precautions were taken to prevent contamination between intervention and information control (IC) groups [1].

Intervention. Three PEAs who held a masters or bachelors degree in psychology, nutrition, exercise science, or equivalent, or were registered dietitians, were embedded within each PCMH practice. For both the intervention and IC groups, parents attended 13 one-hour group sessions led by a PEA over a 12-month period, followed by a 12-month follow-up period with 3 additional meetings. The PEA telephoned parents between scheduled meetings. Pediatricians reviewed child’s weight changes every 6 months during scheduled appointments and the PEA sent progress notes in between these visits [2]. Dietary, physical, and sedentary activity guidelines were given based on the recommendations of a national multi-organizational expert committee [3]. Parents were given specific goals for their child, including a 0.5- to 1-pound per week loss, 60 minutes per day of physical activity, and limiting TV and screen time to less than 2 hours per day.

In addition, the intervention group received parenting and behavior change strategies to promote both parent and child weight loss. Parents were instructed to weigh themselves and their child once per week and monitor physical activity and diet. They received individual meetings with the PEA before or after group meetings to review goal setting and food/physical activity diaries. Parents were also given a weight loss goal of 1 to 2 pounds per week and were advised to model physical activity by engaging in active play with their child for at least 10 minutes per day.

Main outcome measures. The main outcome measures were %0BMI and z-BMI. Percent 0BMI is defined as [(child’s BMI – 50th percentile BMI)/50th percentile BMI] x 100 [2]. The authors chose %0BMI as the primary outcome measure because z-BMI can diminish the effect of weight change in heavier children [4]. Both measures were expressed as mean ± standard error (SEM). Parent weight change was measured using BMI alone.

The child’s weight was measured at each session and height was measured at baseline, 3, 6, 12, 18, and 24 months. Parent weight was measured every session in the intervention group, but only at baseline, 6, 12, 18, and 24 months in the IC group. A standardized protocol was followed for all height and weight measurements. An intention to treat analysis (ITT) was conducted on all parent/child dyads, regardless of whether or not they completed the study (n = 96).

Results. Research assistants assessed 171 parent/child dyads for eligibility. 66 were excluded for either not meeting inclusion criteria (n = 24) or declining to participate (n = 42). 105 dyads were randomized, but 9 did not receive the allocated intervention because they did not start the study, resulting in a total of 96 dyads included in analysis: 46 in the intervention group and 50 in the IC. Twelve- and 24-month completion rates were 83% and 73% respectively; there was no difference in attrition between intervention and IC groups.

The mean child ages of the intervention and IC groups were 4.6 ± 0.2 and 4.4 ± 0.2 years, respectively. 33 of the 46 children in the intervention group and 37 of the 50 children in the IC group were identified as non-Hispanic white. The mean yearly income of all families was $65,729 ± $3068, with only 8.3% of families below $20,000.

The intervention group had greater decreases in child %0BMI from baseline to 6, 12, 18, and 24 months than the IC group. Similar trends were seen with child z-BMI. A slower increase in height was observed in the intervention group when compared with the IC at both 18 months (P < 0.001) and at 24 months (P < 0.02). Parents showed greater overall BMI reduction in the intervention group as opposed to the IC group at all time points (P < 0.001). BMI changes achieved at 6 months were maintained at 24 months. %0BMI and parent BMI changes were correlated from baseline to 12, 18, and 24 months. No significant baseline moderators were found among the children in either group.

Conclusion. This study demonstrated that within the PCMH model of pediatric primary care, an intervention focused on joint behavior change and weight modification treatment of parents and children led to better initial and sustained improvements in %0BMI and z-BMI (in children) and BMI (in parents) than a child-focused IC.

Commentary

Over one-third of children and adolescents are considered to be overweight or have obesity, a number that has doubled in the past 30 years [5]. Pediatrician and primary care physician visits are optimal places to identify overweight children who are at risk for obesity and begin prevention measures, although identifying overweight and obese younger children can be difficult [6]. This study used PEAs to aid physicians in identification, implementation, and delivery. With increasing evidence to support pediatrician involvement in intensive weight management in a primary versus specialty care setting, embedding PEAs within the PCMH model may be an important way to help deliver care for overweight/obese children [7].

Although many approaches have been considered to target childhood obesity, this study represents an important contribution to the literature because it demonstrates that a primary care–based intervention targeting parents as well as their young children is more efficacious for weight management than a more traditional, child-only focused intervention. In addition, the intervention included many different evidence-based components such as teaching behavior modification techniques to parents, consideration of parenting styles and techniques, and encouraging simultaneous parental weight modification. While the U.S. Preventive Services Task Force (USPSTF) recommends intensive interventions with 30 sessions over 2 years [8], this study was able to accomplish significant weight change in 13 sessions.

This intervention is unique in its integration of parenting techniques with other evidence-based strategies for child weight management. Although it has been shown in the literature that certain parenting styles can positively impact children’s health behaviors [9], namely the use of positive reinforcement and monitoring children’s health practices [10], only a few studies have looked at the impact of parenting interventions on childhood obesity. Mazzeo et al demonstrated a significant reduction in child BMI with a parenting-only intervention in the NOURISH trial [11], Slusser et al found a significant child BMI reduction using parent training for low-income, 2- to 4-year-old children [12], and Brotman et al conducted a longitudinal study demonstrating that a family intervention could decrease BMI and improve overall child health behaviors [13]. Despite these aforementioned studies, there is a lack of longitudinal data on the association between general parenting style and weight [14], and this study addresses this gap in literature by providing 2-year follow-up and demonstrating sustained impact on the intervention group.

This study had many additional strengths, including randomized design, primary care physician blinding, use of intention to treat analysis, standardization of measurement tools, clear justification of sample size, long-term follow-up, and the use of child-appropriate BMI measures (eg, %0BMI vs. z-BMI as primary outcome measure). In addition, the intervention setting in a PCMH follows the trend of increasing interest in exploring this model of health care delivery [15,16]. It is also important to note that the intervention and IC groups received the same number of group visits and phone calls, the only difference being the content and the extra 1:1 PEA sessions received by the intervention group.

The few weaknesses include that the PEAs could not be blinded to treatment allocation, and generalizability is limited by the mostly non-Hispanic white population and that only 8.3% of the study population had an annual household income of less than $20,000. All parents included in this study were on the high end of the obese range (BMI 30–39.9), with baseline BMI values of 37.2 and 36.2 in the intervention and IC groups respectively. In addition, the age of the children included in the study were on the high end of the designated 2- to 5-year-old range: 4.6 years (IC) and 4.4 years (intervention). Although findings were promising within this specific population, further research in younger and more diverse populations is necessary [11].

Finally, it is unclear whether this intervention is scalable, and a cost-effectiveness analysis of this intervention is needed. This study was designed to limit the PCP’s role and simplify the process of identifying and intervening on overweight children and their parents, yet this required 3 part-time PEAs and a project coordinator responsible for delivering all of the group sessions and providing follow-up counseling to both intervention and IC groups.

Applications for Clinical Practice

This study demonstrates that in a mostly white, urban/suburban population, a parenting and behavior modification intervention focused on both parent and child leads to greater improvements in %0BMI and z-BMI in the child and BMI reduction in parents compared with an intervention focused on the child alone within pediatric PCMH practices. This intervention should be tested in more diverse populations. This study also suggests further exploration of the use of PEAs to help clinicians address obesity within the PCMH model of primary care.

—Natalie Berner, BA, and Melanie Jay, MD, MS

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Pier Luigi Zinzani, MD, PhD

Photo by Larry Young

SAN FRANCISCO—Two phase 2 studies testing mogamulizumab in peripheral T-cell lymphomas (PTCLs) suggest that higher response rates don’t necessarily translate to an improvement in progression-free survival (PFS).

The anti-CCR4 antibody produced a higher overall response rate (ORR) in a Japanese study than in a European study—34% and 11%, respectively.

However, median PFS times were similar—about 2 months in both studies.

This similarity is all the more interesting because the studies enrolled different types of patients and followed different dosing schedules, according to Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy.

Dr Zinzani discussed details of the European experience testing mogamulizumab in PTCL, comparing it to the Japanese experience, in a presentation at the 7th Annual T-cell Lymphoma Forum.

Kensei Tobinai, MD, PhD, of the National Cancer Center Hospital in Tokyo, Japan, also reviewed the Japanese experience (TCLF 2013, JCO 2014) during the meeting’s keynote address and presented data from an ancillary analysis of this study (which is unpublished).

All of the research was sponsored by Kyowa Hakko Kirin Co., Ltd., the company developing mogamulizumab.

The Japanese experience

The Japanese study included 29 patients with PTCL and 8 with cutaneous T-cell lymphoma (CTCL). All patients had relapsed after their last chemotherapy regimen, and none had received an allogeneic stem cell transplant (allo-SCT). The PTCL patients had a median age of 67, and 69% were male.

All patients received mogamulizumab at 1.0 mg/kg/day weekly for 8 weeks. The ORR was 35%—34% for PTCL patients and 38% for CTCL patients.

Among PTCL patients, there were 5 complete responses (CRs) and 5 partial responses (PRs). Nine patients had stable disease (SD), and 10 progressed.

Of the 16 patients with PTCL-not otherwise specified (PTCL-NOS), 1 had a CR, 2 had a PR, 6 had SD, and 7 progressed. Of the 12 patients with angioimmunoblastic T-cell lymphoma (AITL), 3 had a CR, 3 had a PR, 3 had SD, and 3 progressed. The only patient with ALK- anaplastic large-cell lymphoma (ALCL) had an unconfirmed CR.

The ancillary analysis showed that tumor shrinkage of the target lesions occurred in 72% (21/29) of patients with PTCL. The patients’ median duration of response was 6.4 months, and the median time to response was 1.9 months.

Overall, the median PFS was 3.0 months—2.0 months in patients with PTCL and 3.4 months in patients with CTCL.

Common adverse events (for both PTCL and CTCL patients) included lymphopenia (81%), skin disorders (51%), leukopenia (43%), neutropenia (38%), thrombocytopenia (38%), pyrexia (30%), acute infusion reactions (24%), and anemia (14%).

Dr Tobinai noted that these results are not as favorable as those observed when patients with adult T-cell leukemia-lymphoma receive mogamulizumab.

“But compared to the efficacy rate of other approved agents—pralatrexate and romidepsin—this antibody has promising efficacy,” he said.

In fact, the results of this study prompted the December approval of mogamulizumab to treat PTCL and CTCL patients in Japan.

The European experience

The European study differed from the Japanese study in a few ways, Dr Zinzani pointed out. The European study only enrolled patients with PTCL. And it included patients with relapsed (49%) or refractory (51%) disease, whereas the Japanese study only included relapsed patients.

Furthermore, the Japanese study did not include any patients with an ECOG performance status of 2, while the European study did (39%). And the dosing schedule differed between the 2 studies.

In the European study, patients received mogamulizumab at 1 mg/kg once weekly for 4 weeks and then once every 2 weeks until they progressed or developed unacceptable toxicity.

There were 38 patients in the safety analysis. They had a median age of 58.5 years, and 61% were male.

Thirty-five of these patients were included in the efficacy analysis. They had a median of 2 prior treatments (range, 1-8), and 17 patients (49%) had responded to their last therapy.

The patients had PTCL-NOS (43%, 15/35), AITL (34%, 12), transformed mycosis fungoides (9%, 3), ALK- ALCL (11%, 4), and ALK+ ALCL (3%, 1).

The ORR was 11% (n=4), and 46% of patients (n=16) had SD or better. Two patients with PTCL-NOS responded, as did 2 with AITL.

Six patients with PTCL-NOS had SD, as did 3 with AITL, 1 with transformed mycosis fungoides, and 2 with ALK- ALCL.

The median duration of response (including SD) was 2.9 months. And the median PFS was 2.1 months. Two patients (1 with ALK- ALCL and 1 with PTCL-NOS) went on to allo-SCT.

The most frequent adverse events (occurring in at least 10% of patients) were drug eruption (n=12), pyrexia (n=9), pruritus (n=7), diarrhea (n=7), cough (n=6), vomiting (n=6), thrombocytopenia (n=6), hypotension (n=4), headache (n=4), peripheral edema (n=4), asthenia (n=4), nausea (n=4), anemia (n=4), and neutropenia (n=4).

“For the European experience, there were some differences from the Japanese experience,” Dr Zinzani said in closing. “It was worse in terms of overall response rate—only 11%—but roughly 50% of patients attained at least stable disease. And there was an acceptable safety profile in these really heavily pretreated, relapsed/refractory PTCL patients.”

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

Drugs in vials

Photo by Bill Branson

A new analysis indicates that certain high-cost therapies for hematologic malignancies provide reasonable value for money spent.

Most cost-effectiveness ratios were lower than thresholds commonly used to establish cost-effectiveness in the US—$50,000 or $100,000 per quality-adjusted life year (QALY) gained.

The median cost-effectiveness ratio was highest for chronic myeloid leukemia (CML), at $55,000/QALY, and lowest for non-Hodgkin lymphoma (NHL), at $21,500/QALY.

Researchers presented these data in Blood.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said study author Peter J. Neumann, ScD, of Tufts Medical Center in Boston.

“Our analysis had a small sample size and included both industry- and non-industry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in healthcare should consider the value of breakthrough drugs and not just costs.”

With that issue in mind, Dr Neumann and his colleagues had conducted a systematic review of studies published between 1996 and 2012 that examined the cost utility of agents for hematologic malignancies. The cost utility of a drug was depicted as a ratio of a drug’s total cost per patient QALY gained.

The researchers identified 29 studies, 22 of which were industry-funded. Nine studies were conducted from a US perspective, 6 from the UK, 3 from Norway, 3 from Sweden, 2 from France, 1 from Canada, 1 from Finland, and 4 from “other” countries.

The team grouped studies according to malignancy—CML, chronic lymphocytic leukemia (CLL), NHL, and multiple myeloma (MM)—as well as by treatment—α interferon, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide.

The studies reported 44 cost-effectiveness ratios, most concerning interventions for NHL (41%) or CML (30%). Most ratios pertained to rituximab (43%), α interferon (18%), or imatinib (16%), and the most common intervention-disease combination was rituximab (alone or in combination) for NHL (36%).

The median cost-effectiveness ratios fluctuated over time, rising from $35,000/QALY (1996-2002) to $52,000/QALY (2003-2006), then falling to $22,000/QALY (2007-2012).

The median cost-effectiveness ratio reported by industry-funded studies was lower ($26,000/QALY) than for non-industry-funded studies ($33,000/QALY).

Four cost-effectiveness ratios, 1 from an industry-funded study, exceeded $100,000/QALY. This included 2 studies of bortezomib in MM, 1 of α interferon in CML, and 1 of imatinib in CML.

The researchers said these results suggest that many new treatments for hematologic malignancies may confer reasonable value for money spent. The distribution of cost-effectiveness ratios is comparable to those for cancers overall and for other healthcare fields, they said.

This study was funded by internal resources at the Center for the Evaluation of Value and Risk in Health. The center receives funding from federal, private foundation, and pharmaceutical industry sources.

The three most exposed areas of the body that give away a person’s age are the face, neck, and hands. Rejuvenation of the hands is an often simple and nice addition to facial and neck aesthetic rejuvenation.

When examining aging hands, the three most prominent features are decreased volume in the interosseous spaces (leading to increased crepiness of the skin and increased show of extensor tendons), lentigines, and prominent veins. Therefore, the treatment for hands is quite simple: Restore volume, treat the pigmented lesions, and if needed, treat the prominent veins.

The anatomy of the dorsal hand can be divided into three major compartments. First, the skin, which on the dorsal hand is quite pliable. Second, the subcutaneous tissue, which consists of a loose areolar tissue where the lymphatics and veins lie. Third, beneath the subcutaneous tissue is the dorsal fascia of the hand, which is contiguous with extensor tendons and underlying compartments. It is in the subcutaneous layer (or loose areolar tissue) where fillers or fat are placed to treat volume loss.

While several fillers are currently used off label for hand rejuvenation, the Food and Drug Administration is meeting in February to consider officially approving Radiesse for this indication. Currently, hyaluronic acid (HA) fillers, calcium- hydroxylapatite (Radiesse), poly-L-lactic acid, and autologous fat are all utilized. I tend to use HAs in this location because of the reversibility, if needed, and decreased risk of nodule formation. Several techniques exist, including injecting between each tendon space vs. a bolus technique. I tend to use a bolus technique, where one or two boluses are injected while tenting the skin up to ensure injection into the correct plane and to avoid the vessels. Subsequently, the boluses are massaged into place while the patient makes a fist.

Once the interosseous spaces have been treated, the veins often appear less prominent and often don’t require direct treatment. I typically do not treat the dorsal hand veins, but sclerotherapy can be performed. Lentigines may be treated with a variety of devices including intense pulse light, Q-switched lasers, and fractionated nonablative lasers. Chemical peels and topical antipigment agents also may help to a lesser degree or also may be used for maintenance to keep the lentigines away.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley.

The three most exposed areas of the body that give away a person’s age are the face, neck, and hands. Rejuvenation of the hands is an often simple and nice addition to facial and neck aesthetic rejuvenation.

When examining aging hands, the three most prominent features are decreased volume in the interosseous spaces (leading to increased crepiness of the skin and increased show of extensor tendons), lentigines, and prominent veins. Therefore, the treatment for hands is quite simple: Restore volume, treat the pigmented lesions, and if needed, treat the prominent veins.

The anatomy of the dorsal hand can be divided into three major compartments. First, the skin, which on the dorsal hand is quite pliable. Second, the subcutaneous tissue, which consists of a loose areolar tissue where the lymphatics and veins lie. Third, beneath the subcutaneous tissue is the dorsal fascia of the hand, which is contiguous with extensor tendons and underlying compartments. It is in the subcutaneous layer (or loose areolar tissue) where fillers or fat are placed to treat volume loss.

While several fillers are currently used off label for hand rejuvenation, the Food and Drug Administration is meeting in February to consider officially approving Radiesse for this indication. Currently, hyaluronic acid (HA) fillers, calcium- hydroxylapatite (Radiesse), poly-L-lactic acid, and autologous fat are all utilized. I tend to use HAs in this location because of the reversibility, if needed, and decreased risk of nodule formation. Several techniques exist, including injecting between each tendon space vs. a bolus technique. I tend to use a bolus technique, where one or two boluses are injected while tenting the skin up to ensure injection into the correct plane and to avoid the vessels. Subsequently, the boluses are massaged into place while the patient makes a fist.

Once the interosseous spaces have been treated, the veins often appear less prominent and often don’t require direct treatment. I typically do not treat the dorsal hand veins, but sclerotherapy can be performed. Lentigines may be treated with a variety of devices including intense pulse light, Q-switched lasers, and fractionated nonablative lasers. Chemical peels and topical antipigment agents also may help to a lesser degree or also may be used for maintenance to keep the lentigines away.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley.

The three most exposed areas of the body that give away a person’s age are the face, neck, and hands. Rejuvenation of the hands is an often simple and nice addition to facial and neck aesthetic rejuvenation.

When examining aging hands, the three most prominent features are decreased volume in the interosseous spaces (leading to increased crepiness of the skin and increased show of extensor tendons), lentigines, and prominent veins. Therefore, the treatment for hands is quite simple: Restore volume, treat the pigmented lesions, and if needed, treat the prominent veins.

The anatomy of the dorsal hand can be divided into three major compartments. First, the skin, which on the dorsal hand is quite pliable. Second, the subcutaneous tissue, which consists of a loose areolar tissue where the lymphatics and veins lie. Third, beneath the subcutaneous tissue is the dorsal fascia of the hand, which is contiguous with extensor tendons and underlying compartments. It is in the subcutaneous layer (or loose areolar tissue) where fillers or fat are placed to treat volume loss.

While several fillers are currently used off label for hand rejuvenation, the Food and Drug Administration is meeting in February to consider officially approving Radiesse for this indication. Currently, hyaluronic acid (HA) fillers, calcium- hydroxylapatite (Radiesse), poly-L-lactic acid, and autologous fat are all utilized. I tend to use HAs in this location because of the reversibility, if needed, and decreased risk of nodule formation. Several techniques exist, including injecting between each tendon space vs. a bolus technique. I tend to use a bolus technique, where one or two boluses are injected while tenting the skin up to ensure injection into the correct plane and to avoid the vessels. Subsequently, the boluses are massaged into place while the patient makes a fist.

Once the interosseous spaces have been treated, the veins often appear less prominent and often don’t require direct treatment. I typically do not treat the dorsal hand veins, but sclerotherapy can be performed. Lentigines may be treated with a variety of devices including intense pulse light, Q-switched lasers, and fractionated nonablative lasers. Chemical peels and topical antipigment agents also may help to a lesser degree or also may be used for maintenance to keep the lentigines away.

Dr. Talakoub and Dr. Wesley are co-contributors to a monthly Aesthetic Dermatology column in Dermatology News. Dr. Talakoub is in private practice in McLean, Va. Dr. Wesley practices dermatology in Beverly Hills, Calif. This month’s column is by Dr. Wesley.

Velcade (bortezomib)

Photo courtesy of Millennium

The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.

Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).

Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.

The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.

This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.

About bortezomib

Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.

In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.

Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.

And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.

Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.

The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.

Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.

Velcade (bortezomib)

Photo courtesy of Millennium

The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.

Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).

Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.

The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.

This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.

About bortezomib

Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.

In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.

Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.

And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.

Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.

The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.

Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.

Velcade (bortezomib)

Photo courtesy of Millennium

The European Commission (EC) has approved bortezomib (Velcade) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) to treat adults with previously untreated mantle cell lymphoma (MCL) in whom hematopoietic stem cell transplant (HSCT) is considered unsuitable.

Now, bortezomib can be marketed for this indication in all 28 countries of the European Union (EU).

Bortezomib is already approved in the EU to treat multiple myeloma (MM), either as monotherapy or in combination with other agents.

The EC’s approval of bortezomib in MCL is based on data from a phase 3 study known as LYM-3002.

This randomized trial included 487 patients with newly diagnosed MCL who were ineligible, or not considered, for HSCT. Patients were randomized to receive VR-CAP or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

The VR-CAP regimen significantly improved progression-free survival (PFS), the primary endpoint, when compared to R-CHOP.

According to an independent review committee, there was a 59% improvement in PFS for the VR-CAP arm compared to the R-CHOP arm, with median times of 24.7 months and 14.4 months, respectively (hazard ratio=0.63; P<0.001).

Study investigators reported a 96% increase in PFS with VR-CAP compared to R-CHOP, with median times of 30.7 months and 16.1 months, respectively (hazard ratio=0.51, P<0.001).

VR-CAP was associated with additional, but manageable, toxicity when compared to R-CHOP. Serious adverse events (AEs) were reported in 38% and 30% of patients, respectively. And grade 3 or higher AEs were reported in 93% and 85% of patients, respectively.

Treatment discontinuation due to AEs occurred in 9% of patients in the VR-CAP arm and 7% in the R-CHOP arm. On-treatment, drug-related deaths occurred in 2% and 3% of patients, respectively.

About bortezomib

Bortezomib works by reversibly interrupting the normal working of cell proteasomes, inducing cancerous cells to stop growing and die.

In addition to the new MCL indication, the drug is approved in the EU to treat various stages of MM. It’s approved in combination with melphalan and prednisone to treat previously untreated adults with MM who are unsuitable for high-dose chemotherapy with HSCT.

Bortezomib is also approved in combination with dexamethasone, or with dexamethasone plus thalidomide, to treat previously untreated MM patients set to receive high-dose chemotherapy followed by HSCT.

And the drug is approved as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone to treat adults with MM whose disease has progressed after at least one other treatment and who have already had, or cannot undergo, HSCT.

Bortezomib is approved in more than 90 countries and has been used to treat more than 550,000 patients worldwide.

The product is co-developed by Millennium, the Takeda Oncology Company, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, and Janssen Pharmaceutical Companies.

Millennium is responsible for commercialization in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote the drug in Japan.

NEW YORK– The REACH Institute trains primary care clinicians to include more mental health assessment and management in their practices, Dr. Lawrence V. Amsel said during an interview at the psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Many primary care clinicians don’t feel adequately trained to interview patients, guage their mental status, and then act on the findings by treatment or referral. But over the past decade, psychiatrists have developed and validated several tools that are appropriate for a primary care practice, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York, and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. The program also tries to make clinicians comfortable prescribing psychiatric medications and links them with psychiatrists who can provide consultations when needed.

“It’s kind of like a psychiatrist extender,” when a psychiatrist consults with several primary care clinicians, which allows for improved psychiatric care of many more patients, he said.

Dr. Amsel is on the faculty of the REACH Institute.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

NEW YORK– The REACH Institute trains primary care clinicians to include more mental health assessment and management in their practices, Dr. Lawrence V. Amsel said during an interview at the psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Many primary care clinicians don’t feel adequately trained to interview patients, guage their mental status, and then act on the findings by treatment or referral. But over the past decade, psychiatrists have developed and validated several tools that are appropriate for a primary care practice, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York, and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. The program also tries to make clinicians comfortable prescribing psychiatric medications and links them with psychiatrists who can provide consultations when needed.

“It’s kind of like a psychiatrist extender,” when a psychiatrist consults with several primary care clinicians, which allows for improved psychiatric care of many more patients, he said.

Dr. Amsel is on the faculty of the REACH Institute.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

NEW YORK– The REACH Institute trains primary care clinicians to include more mental health assessment and management in their practices, Dr. Lawrence V. Amsel said during an interview at the psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

Many primary care clinicians don’t feel adequately trained to interview patients, guage their mental status, and then act on the findings by treatment or referral. But over the past decade, psychiatrists have developed and validated several tools that are appropriate for a primary care practice, said Dr. Amsel, a clinical psychiatrist at Columbia University in New York, and a faculty member of the REACH Institute, a New York–based nonprofit focused on disseminating mental health skills to primary care clinicians, teachers, parents, and others. The program also tries to make clinicians comfortable prescribing psychiatric medications and links them with psychiatrists who can provide consultations when needed.

“It’s kind of like a psychiatrist extender,” when a psychiatrist consults with several primary care clinicians, which allows for improved psychiatric care of many more patients, he said.

Dr. Amsel is on the faculty of the REACH Institute.

mzoler@frontlinemedcom.com

On Twitter@mitchelzoler

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.

Rudolph Virchow clearly demonstrated the association between malignancy and venous thromboembolic events. VTE – deep vein thrombosis and pulmonary embolism – affect between 15% and 38% of patients with gynecologic malignancies after surgery.

The rate of pulmonary embolism (PE) in this patient population can be as high as 6.8%, with the case fatality rate being 11%-12% (Obstet. Gynecol. 2012;119:155-67). Other factors associated with the development of VTE include prior VTE, older age, African American race, prolonged operative time, obesity, and prior radiation therapy (Obstet. Gynecol. 1987;69:146-50). The risk of VTE in women undergoing gynecologic surgery is quadrupled in the presence of malignancy(Obstet. Gynecol. 2006;107:666-71) and these patients are twice as likely to die from a VTE compared to matched controls (Gynecol. Oncol. 2007;106:439-45).

Additionally, cancer patients are typically older, have longer and more complex surgeries, and the presence of a pelvic mass further contributes to venous stasis (Obstet. Gynecol. 2012;119:155-67).

Although the treatment of VTE is fairly similar between patients with malignancy and those without cancer, treatment of a VTE in patients with cancer can be further complicated by higher VTE recurrence rates and increased risk of bleeding. Furthermore, issues related to the malignant disease process such as prognosis, presence and location of metastasis, and life expectancy should be taken into consideration when managing VTE in this patient population.

Generally, in the setting of an acute or recurrent VTE, initial therapy with a parenteral anticoagulant (heparin or low-molecular-weight heparins [LMWH]) should be immediately instituted in patients with a gynecologic malignancy, unless there is evidence of active bleeding or any other contraindication for the use of an anticoagulant.

Other factors associated with cancer such as immobilization, the presence of metastases, and impaired renal function with a creatinine clearance less than 30 mL/min, may increase the risk of bleeding complications but are not absolute contraindications to anticoagulation (Thromb. Haemost. 2008;100:435-9). The initial treatment phase, which last for 5-10 days, is then followed by a longer treatment phase lasting 3-6 months.

In the majority of cases, LMWH is the preferred agent for both the initial and prolonged treatment phase assuming adequate renal function. Based on evidence from a meta-analysis of 16 randomized controlled trials in cancer patients receiving initial anticoagulation for VTE, LMWH is associated with a 30% reduction in mortality without an increased risk of bleeding in comparison to unfractionated heparin (Cochrane Database. Syst. Rev. 2014;6:CD006649).

When compared with the vitamin K antagonist warfarin, LMWH appears to be associated with a significantly reduced rate of recurrent VTE (hazard ratio, 0.47; 95% confidence interval 0.32-0.71). However, this was not associated with a survival advantage (N. Engl. J. Med. 2003;349:146-53).

There are no trials comparing the different formulations of LMWH. In our practice, we routinely use the LMWH enoxaparin dosed at 1 mg/kg subcutaneously twice daily. Other well-studied LMWHs include dalteparin and tinzaparin.

LMWHs are primarily renally excreted, thus, in patients with compromised renal function, the biological half-life of the medication may be prolonged, leading to potential bleeding complications. The majority of LMWH trials excluded patients with creatinine clearance less than 30 mL/min, therefore, in patients with compromised renal function, one option would be to decrease the daily dose by as much as 50% and closely monitor antifactor XA levels. Alternatively, the use of unfractionated heparin in the acute setting followed by warfarin with close monitoring of the patient’s international normalized ratio could prove less cumbersome and ultimately safer for these patients. However, given the limitations of the currently available data we would not recommend the routine use of newer oral anticoagulation agents.

Patients with a malignancy are at increased risk for the development of a recurrent VTE even in the setting of anticoagulation. Some of the risks factors for this phenomenon include presence of central venous catheters, interruption of therapy for procedures, and immobilization. In cases of recurrent VTE, consideration should be given to extending the duration of treatment beyond the initial planned 3-6 months. Other patients that may benefit from extended therapy include those with continued immobility or active cancer burden.

LMWH is also the preferred agent for extended therapy based on very limited evidence from experimental studies suggesting that LMWH may have antineoplastic effects and thus a survival advantage. However, in the setting of a recurrent VTE, there is very limited data on which to base the choice of extended treatment. Options include switching the therapeutic agent, increasing the dose or frequency of administration, or placement of an inferior vena cava filter. Consultation with a hematologist may also be warranted in this and more complicated scenarios.

Ultimately, LMWH appears to be the best available therapy for patients with a gynecologic malignancy. However, the decision to anticoagulate should be carefully planned out, taking into consideration the individual patient’s disease burden and associated comorbidities in order to select the most appropriate treatment option.

Dr. Roque is a fellow in the gynecologic oncology program at the University of North Carolina at Chapel Hill. Dr. Clarke-Pearson is the chair and the Robert A. Ross Distinguished Professor of Obstetrics and Gynecology and a professor in the division of gynecologic oncology at the university. Dr. Roque and Dr. Clarke-Pearson said they had no relevant financial disclosures.