THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

The plasma cell disorders are a spectrum of conditions that include asymptomatic precursor conditions—monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)—as well as symptomatic multiple myeloma (MM) and solitary plasmacytoma. Other plasma cell disorders include immunoglobulin light chain amyloidosis and POEMS syndrome, which are characterized by a unique set of end-organ manifestations. There are other related plasma cell and B-cell proliferations, such as light chain deposition disease and cryoglobulinemia, that are beyond the scope of this review but are relevant to the hematologist/oncologist and have been reviewed in detail elsewhere.

To read the full article in PDF:

Click here

The plasma cell disorders are a spectrum of conditions that include asymptomatic precursor conditions—monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)—as well as symptomatic multiple myeloma (MM) and solitary plasmacytoma. Other plasma cell disorders include immunoglobulin light chain amyloidosis and POEMS syndrome, which are characterized by a unique set of end-organ manifestations. There are other related plasma cell and B-cell proliferations, such as light chain deposition disease and cryoglobulinemia, that are beyond the scope of this review but are relevant to the hematologist/oncologist and have been reviewed in detail elsewhere.

To read the full article in PDF:

Click here

The plasma cell disorders are a spectrum of conditions that include asymptomatic precursor conditions—monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)—as well as symptomatic multiple myeloma (MM) and solitary plasmacytoma. Other plasma cell disorders include immunoglobulin light chain amyloidosis and POEMS syndrome, which are characterized by a unique set of end-organ manifestations. There are other related plasma cell and B-cell proliferations, such as light chain deposition disease and cryoglobulinemia, that are beyond the scope of this review but are relevant to the hematologist/oncologist and have been reviewed in detail elsewhere.

To read the full article in PDF:

Click here

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.

This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.

The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).

Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.

Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.

Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.

At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.

About obinutuzumab

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.

The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.

The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.

Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.

Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.

This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.

The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).

Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.

Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.

Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.

At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.

About obinutuzumab

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.

The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.

The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.

Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.

Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.

This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.

The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).

Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.

Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.

Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.

At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.

About obinutuzumab

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.

The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.

The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.

Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.

Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.

Stroke in a Young Man

A 26-year-old man presented to the ED with the chief complaint of mild right-sided weakness, paresthesias, and slurred speech. He stated the onset was sudden—approximately 30 minutes prior to arrival to the ED. The patient denied any previous similar symptoms and was otherwise in good health; he denied taking any medications. He drank alcohol socially, but denied smoking or illicit drug use.

On physical examination, his vital signs and oxygen saturation were normal. Pulmonary, cardiovascular, and abdominal examinations were also normal. The patient thought his speech was somewhat slurred, but the triage nurse and treating emergency physician (EP) had difficulty detecting any altered speech. He was noted to have mild (4+/5) right upper and lower extremity weakness; no facial droop was detected. The patient did have a mild pronator drift of the right upper extremity. Gait testing revealed a mild limp of the right lower extremity.

The EP consulted the hospitalist, and the patient was admitted to a monitored bed. The following morning, a brain magnetic resonance image revealed an ischemic stroke in the distribution of the left middle cerebral artery. The patient’s hospital course was uncomplicated, but at the time of discharge, he continued to have mild right-sided weakness and required the use of a cane.

The patient sued the hospital and the EP for negligence in failing to treat his condition in a timely manner and for not consulting a neurologist. The plaintiff’s attorneys argued the patient should have been given tissue plasminogen activator (tPA), which would have avoided the residual right-sided weakness. The defense denied negligence and argued the patient’s symptoms could have been due to several things for which tPA would have been an inappropriate treatment. A defense verdict was returned.

Discussion

Stroke in young patients is relatively rare. With “young” defined as aged 18 to 45 years, this population accounts for approximately 2% to 12% of cerebral infarcts.¹ In one nationwide US study of stroke in young adults, Ellis² found that 4.9% of individuals experiencing a stroke in 2007 were between ages 18 and 44 years. Among this group, 78% experienced an ischemic stroke; 11.2% experienced a subarachnoid hemorrhage (SAH); and 10.8% had an intracerebral hemorrhage.²

While the clinical presentation of stroke in young adults is similar to that of older patients, the etiologies and risk factors are very different. In older patients, atherosclerosis is the major cause of ischemic stroke. In studies of young adults with ischemic stroke, cardioembolism was found to be the leading cause. Under this category, a patent foramen ovale (PFO) was considered a common cause, followed by atrial fibrillation, bacterial endocarditis, rheumatic heart disease, and atrial myxoma. There is, however, increasing controversy over the role of PFO as an etiology of stroke. Many investigators think its role has been overstated and is probably more of an incidental finding than a causal relationship.³ Patients with a suspected cardioembolic etiology will usually require an echocardiogram (with saline contrast or a “bubble study” for suspected PFO), cardiac monitoring, and a possible Holter monitor at the time of discharge (to detect paroxysmal arrhythmias).

Following cardioembolic etiologies, arterial dissection is the next most common category.⁴ In one study of patients aged 31 to 45 years old, arterial dissection was the most common cause of ischemic stroke.⁴  Clinical features suggesting dissection include a history of head or neck trauma (even minor trauma), headache or neck pain, and local neurological findings (eg, cranial nerve palsy or Horner syndrome).³ Unfortunately, only about 25% of patients volunteer a history of recent neck trauma. If a cervical or vertebral artery dissection is suspected, contrast enhanced magnetic resonance angiography (MRA) is the most sensitive and specific test, followed by carotid ultrasound and CT angiography.³

Traditional risk factors for stroke include hypertension and diabetes mellitus (DM). This is not true for younger adults that experience an ischemic stroke. Cigarette smoking is a very important risk factor for cerebrovascular accident in young adults; in addition, the more one smokes, the greater the risk. Other risk factors in young adults include history of migraine headaches (especially migraine with aura), pregnancy and the postpartum period, and illicit drug use.³

The defense’s argument that there are many causes of stroke in young adults that would be inappropriate for treatment with tPA, such as a PFO, carotid dissection or bacterial endocarditis, is absolutely true. Young patients need to be aggressively worked up for the etiology of their stroke, and may require additional testing, such as an MRA, echocardiogram, or Holter monitoring to determine the underlying cause of their stroke.

Obstruction Following Gastric Bypass Surgery

A 47-year-old woman presented to the ED complaining of severe back and abdominal pain. Onset had been gradual and began approximately 4 hours prior to arrival. She described the pain as crampy and constant. The patient had vomited twice; she denied diarrhea and had a normal bowel movement the previous day. She denied any vaginal or urinary complaints. Her past medical history was significant for hypertension and status post gastric bypass surgery 6 months prior. She had lost 42 pounds to date. She denied smoking or alcohol use.

The patient’s vital signs on physical examination were: blood pressure, 154/92 mm Hg; pulse, 106 beats/minute; respiratory rate, 18 breaths/minute; and temperature, 99˚F. Oxygen saturation was 96% on room air. The patient’s lungs were clear to auscultation bilaterally. The heart was mildly tachycardic, with a regular rhythm and without murmurs, rubs, or gallops. The abdominal examination revealed diffuse tenderness and involuntary guarding. There was no distention or rebound. Bowel sounds were present but hypoactive. Examination of the back revealed bilateral paraspinal muscle tenderness without costovertebral angle tenderness.

The EP ordered a CBC, BMP, serum lipase, and a urinalysis. The patient was given an intravenous (IV) bolus of 250 cc normal saline in addition to IV morphine 4 mg and IV ondansetron 4 mg. Her white blood cell (WBC) count was slightly elevated at 12.2 g/dL, with a normal differential. The remainder of the laboratory studies were normal, except for a serum bicarbonate of 22 mmol/L.

The patient stated she felt somewhat improved, but continued to have abdominal and back pain. The EP admitted her to the hospital for observation and pain control. She died the following day from a bowel obstruction. The family sued the EP for negligence in failing to order appropriate testing and for not consulting with specialists to diagnose the bowel obstruction, which is a known complication of gastric bypass surgery. The jury returned a verdict of $2.4 million against the EP.

Discussion

The frequency of bariatric surgery in the United States continues to increase, primarily due to its success with regard to weight loss, but also because of its demonstrated improvement in hypertension, obstructive sleep apnea, hyperlipidemia, and type 2 DM.¹

Frequently, the term “gastric bypass surgery” is used interchangeably with bariatric surgery. However, the EP must realize these terms encompass multiple different operations. The four most common types of bariatric surgery in the United Stated are (1) adjustable gastric banding (AGB); (2) the Roux-en-Y gastric bypass (RYGB);  (3) biliopancreatic diversion with duodenal switch (BPD-DS); and (4) vertical sleeve gastrectomy (VSG).² (See the Table for a brief explanation of each type of procedure.)

Since each procedure has its own respective associated complications, it is important for the EP to know which the type of gastric bypass surgery the patient had. For example, leakage is much more frequent following RYGB than in gastric banding, while slippage and obstruction are the most common complications of gastric banding.^3,4 It is also very helpful to know the specific type of procedure when discussing the case with the surgical consultant.

Based on a recent review of over 800,000 bariatric surgery patients, seven serious common complications following the surgery were identified.³ These included bleeding, leakage, obstruction, stomal ulceration, pulmonary embolism and respiratory complications, blood sugar disturbances (usually hypoglycemia and/or metabolic acidosis), and nutritional disturbances. While not all-inclusive, this list represents the most common serious complications of gastric bypass surgery.

The complaint of abdominal pain in a patient that has undergone bariatric surgery should be taken very seriously. In addition to determining the specific procedure performed and date, the patient should be questioned about vomiting, bowel movements, and the presence of blood in stool or vomit. Depending upon the degree of pain present, the patient may need to be given IV opioid analgesia to facilitate a thorough abdominal examination. A rectal examination should be performed to identify occult gastrointestinal bleeding.

These patients require laboratory testing, including CBC, BMP, and other laboratory evaluation as indicated by the history and physical examination. Early consultation with the bariatric surgeon is recommended. Many, if not most, patients with abdominal pain and vomiting will require imaging, usually a CT scan with contrast of the abdomen and pelvis. Because of the difficulty in interpreting the CT scan results in these patients, the bariatric surgeon will often want to personally review the films rather than rely solely on the interpretation by radiology services.

Unfortunately, the EP in this case did not appreciate the seriousness of the situation. The presence of severe abdominal pain, tenderness, guarding, mild tachycardia with leukocytosis, and metabolic acidosis all pointed to a more serious etiology than muscle spasm. This patient required IV fluids, analgesia, and imaging, as well as consultation with the bariatric surgeon.

Stroke in a Young Man

A 26-year-old man presented to the ED with the chief complaint of mild right-sided weakness, paresthesias, and slurred speech. He stated the onset was sudden—approximately 30 minutes prior to arrival to the ED. The patient denied any previous similar symptoms and was otherwise in good health; he denied taking any medications. He drank alcohol socially, but denied smoking or illicit drug use.

On physical examination, his vital signs and oxygen saturation were normal. Pulmonary, cardiovascular, and abdominal examinations were also normal. The patient thought his speech was somewhat slurred, but the triage nurse and treating emergency physician (EP) had difficulty detecting any altered speech. He was noted to have mild (4+/5) right upper and lower extremity weakness; no facial droop was detected. The patient did have a mild pronator drift of the right upper extremity. Gait testing revealed a mild limp of the right lower extremity.

The EP consulted the hospitalist, and the patient was admitted to a monitored bed. The following morning, a brain magnetic resonance image revealed an ischemic stroke in the distribution of the left middle cerebral artery. The patient’s hospital course was uncomplicated, but at the time of discharge, he continued to have mild right-sided weakness and required the use of a cane.

The patient sued the hospital and the EP for negligence in failing to treat his condition in a timely manner and for not consulting a neurologist. The plaintiff’s attorneys argued the patient should have been given tissue plasminogen activator (tPA), which would have avoided the residual right-sided weakness. The defense denied negligence and argued the patient’s symptoms could have been due to several things for which tPA would have been an inappropriate treatment. A defense verdict was returned.

Discussion

Stroke in young patients is relatively rare. With “young” defined as aged 18 to 45 years, this population accounts for approximately 2% to 12% of cerebral infarcts.¹ In one nationwide US study of stroke in young adults, Ellis² found that 4.9% of individuals experiencing a stroke in 2007 were between ages 18 and 44 years. Among this group, 78% experienced an ischemic stroke; 11.2% experienced a subarachnoid hemorrhage (SAH); and 10.8% had an intracerebral hemorrhage.²

While the clinical presentation of stroke in young adults is similar to that of older patients, the etiologies and risk factors are very different. In older patients, atherosclerosis is the major cause of ischemic stroke. In studies of young adults with ischemic stroke, cardioembolism was found to be the leading cause. Under this category, a patent foramen ovale (PFO) was considered a common cause, followed by atrial fibrillation, bacterial endocarditis, rheumatic heart disease, and atrial myxoma. There is, however, increasing controversy over the role of PFO as an etiology of stroke. Many investigators think its role has been overstated and is probably more of an incidental finding than a causal relationship.³ Patients with a suspected cardioembolic etiology will usually require an echocardiogram (with saline contrast or a “bubble study” for suspected PFO), cardiac monitoring, and a possible Holter monitor at the time of discharge (to detect paroxysmal arrhythmias).

Following cardioembolic etiologies, arterial dissection is the next most common category.⁴ In one study of patients aged 31 to 45 years old, arterial dissection was the most common cause of ischemic stroke.⁴  Clinical features suggesting dissection include a history of head or neck trauma (even minor trauma), headache or neck pain, and local neurological findings (eg, cranial nerve palsy or Horner syndrome).³ Unfortunately, only about 25% of patients volunteer a history of recent neck trauma. If a cervical or vertebral artery dissection is suspected, contrast enhanced magnetic resonance angiography (MRA) is the most sensitive and specific test, followed by carotid ultrasound and CT angiography.³

Traditional risk factors for stroke include hypertension and diabetes mellitus (DM). This is not true for younger adults that experience an ischemic stroke. Cigarette smoking is a very important risk factor for cerebrovascular accident in young adults; in addition, the more one smokes, the greater the risk. Other risk factors in young adults include history of migraine headaches (especially migraine with aura), pregnancy and the postpartum period, and illicit drug use.³

The defense’s argument that there are many causes of stroke in young adults that would be inappropriate for treatment with tPA, such as a PFO, carotid dissection or bacterial endocarditis, is absolutely true. Young patients need to be aggressively worked up for the etiology of their stroke, and may require additional testing, such as an MRA, echocardiogram, or Holter monitoring to determine the underlying cause of their stroke.

Obstruction Following Gastric Bypass Surgery

A 47-year-old woman presented to the ED complaining of severe back and abdominal pain. Onset had been gradual and began approximately 4 hours prior to arrival. She described the pain as crampy and constant. The patient had vomited twice; she denied diarrhea and had a normal bowel movement the previous day. She denied any vaginal or urinary complaints. Her past medical history was significant for hypertension and status post gastric bypass surgery 6 months prior. She had lost 42 pounds to date. She denied smoking or alcohol use.

The patient’s vital signs on physical examination were: blood pressure, 154/92 mm Hg; pulse, 106 beats/minute; respiratory rate, 18 breaths/minute; and temperature, 99˚F. Oxygen saturation was 96% on room air. The patient’s lungs were clear to auscultation bilaterally. The heart was mildly tachycardic, with a regular rhythm and without murmurs, rubs, or gallops. The abdominal examination revealed diffuse tenderness and involuntary guarding. There was no distention or rebound. Bowel sounds were present but hypoactive. Examination of the back revealed bilateral paraspinal muscle tenderness without costovertebral angle tenderness.

The EP ordered a CBC, BMP, serum lipase, and a urinalysis. The patient was given an intravenous (IV) bolus of 250 cc normal saline in addition to IV morphine 4 mg and IV ondansetron 4 mg. Her white blood cell (WBC) count was slightly elevated at 12.2 g/dL, with a normal differential. The remainder of the laboratory studies were normal, except for a serum bicarbonate of 22 mmol/L.

The patient stated she felt somewhat improved, but continued to have abdominal and back pain. The EP admitted her to the hospital for observation and pain control. She died the following day from a bowel obstruction. The family sued the EP for negligence in failing to order appropriate testing and for not consulting with specialists to diagnose the bowel obstruction, which is a known complication of gastric bypass surgery. The jury returned a verdict of $2.4 million against the EP.

Discussion

The frequency of bariatric surgery in the United States continues to increase, primarily due to its success with regard to weight loss, but also because of its demonstrated improvement in hypertension, obstructive sleep apnea, hyperlipidemia, and type 2 DM.¹

Frequently, the term “gastric bypass surgery” is used interchangeably with bariatric surgery. However, the EP must realize these terms encompass multiple different operations. The four most common types of bariatric surgery in the United Stated are (1) adjustable gastric banding (AGB); (2) the Roux-en-Y gastric bypass (RYGB);  (3) biliopancreatic diversion with duodenal switch (BPD-DS); and (4) vertical sleeve gastrectomy (VSG).² (See the Table for a brief explanation of each type of procedure.)

Since each procedure has its own respective associated complications, it is important for the EP to know which the type of gastric bypass surgery the patient had. For example, leakage is much more frequent following RYGB than in gastric banding, while slippage and obstruction are the most common complications of gastric banding.^3,4 It is also very helpful to know the specific type of procedure when discussing the case with the surgical consultant.

Based on a recent review of over 800,000 bariatric surgery patients, seven serious common complications following the surgery were identified.³ These included bleeding, leakage, obstruction, stomal ulceration, pulmonary embolism and respiratory complications, blood sugar disturbances (usually hypoglycemia and/or metabolic acidosis), and nutritional disturbances. While not all-inclusive, this list represents the most common serious complications of gastric bypass surgery.

The complaint of abdominal pain in a patient that has undergone bariatric surgery should be taken very seriously. In addition to determining the specific procedure performed and date, the patient should be questioned about vomiting, bowel movements, and the presence of blood in stool or vomit. Depending upon the degree of pain present, the patient may need to be given IV opioid analgesia to facilitate a thorough abdominal examination. A rectal examination should be performed to identify occult gastrointestinal bleeding.

These patients require laboratory testing, including CBC, BMP, and other laboratory evaluation as indicated by the history and physical examination. Early consultation with the bariatric surgeon is recommended. Many, if not most, patients with abdominal pain and vomiting will require imaging, usually a CT scan with contrast of the abdomen and pelvis. Because of the difficulty in interpreting the CT scan results in these patients, the bariatric surgeon will often want to personally review the films rather than rely solely on the interpretation by radiology services.

Unfortunately, the EP in this case did not appreciate the seriousness of the situation. The presence of severe abdominal pain, tenderness, guarding, mild tachycardia with leukocytosis, and metabolic acidosis all pointed to a more serious etiology than muscle spasm. This patient required IV fluids, analgesia, and imaging, as well as consultation with the bariatric surgeon.

Stroke in a Young Man

A 26-year-old man presented to the ED with the chief complaint of mild right-sided weakness, paresthesias, and slurred speech. He stated the onset was sudden—approximately 30 minutes prior to arrival to the ED. The patient denied any previous similar symptoms and was otherwise in good health; he denied taking any medications. He drank alcohol socially, but denied smoking or illicit drug use.

On physical examination, his vital signs and oxygen saturation were normal. Pulmonary, cardiovascular, and abdominal examinations were also normal. The patient thought his speech was somewhat slurred, but the triage nurse and treating emergency physician (EP) had difficulty detecting any altered speech. He was noted to have mild (4+/5) right upper and lower extremity weakness; no facial droop was detected. The patient did have a mild pronator drift of the right upper extremity. Gait testing revealed a mild limp of the right lower extremity.

The EP consulted the hospitalist, and the patient was admitted to a monitored bed. The following morning, a brain magnetic resonance image revealed an ischemic stroke in the distribution of the left middle cerebral artery. The patient’s hospital course was uncomplicated, but at the time of discharge, he continued to have mild right-sided weakness and required the use of a cane.

The patient sued the hospital and the EP for negligence in failing to treat his condition in a timely manner and for not consulting a neurologist. The plaintiff’s attorneys argued the patient should have been given tissue plasminogen activator (tPA), which would have avoided the residual right-sided weakness. The defense denied negligence and argued the patient’s symptoms could have been due to several things for which tPA would have been an inappropriate treatment. A defense verdict was returned.

Discussion

Stroke in young patients is relatively rare. With “young” defined as aged 18 to 45 years, this population accounts for approximately 2% to 12% of cerebral infarcts.¹ In one nationwide US study of stroke in young adults, Ellis² found that 4.9% of individuals experiencing a stroke in 2007 were between ages 18 and 44 years. Among this group, 78% experienced an ischemic stroke; 11.2% experienced a subarachnoid hemorrhage (SAH); and 10.8% had an intracerebral hemorrhage.²

While the clinical presentation of stroke in young adults is similar to that of older patients, the etiologies and risk factors are very different. In older patients, atherosclerosis is the major cause of ischemic stroke. In studies of young adults with ischemic stroke, cardioembolism was found to be the leading cause. Under this category, a patent foramen ovale (PFO) was considered a common cause, followed by atrial fibrillation, bacterial endocarditis, rheumatic heart disease, and atrial myxoma. There is, however, increasing controversy over the role of PFO as an etiology of stroke. Many investigators think its role has been overstated and is probably more of an incidental finding than a causal relationship.³ Patients with a suspected cardioembolic etiology will usually require an echocardiogram (with saline contrast or a “bubble study” for suspected PFO), cardiac monitoring, and a possible Holter monitor at the time of discharge (to detect paroxysmal arrhythmias).

Following cardioembolic etiologies, arterial dissection is the next most common category.⁴ In one study of patients aged 31 to 45 years old, arterial dissection was the most common cause of ischemic stroke.⁴  Clinical features suggesting dissection include a history of head or neck trauma (even minor trauma), headache or neck pain, and local neurological findings (eg, cranial nerve palsy or Horner syndrome).³ Unfortunately, only about 25% of patients volunteer a history of recent neck trauma. If a cervical or vertebral artery dissection is suspected, contrast enhanced magnetic resonance angiography (MRA) is the most sensitive and specific test, followed by carotid ultrasound and CT angiography.³

Traditional risk factors for stroke include hypertension and diabetes mellitus (DM). This is not true for younger adults that experience an ischemic stroke. Cigarette smoking is a very important risk factor for cerebrovascular accident in young adults; in addition, the more one smokes, the greater the risk. Other risk factors in young adults include history of migraine headaches (especially migraine with aura), pregnancy and the postpartum period, and illicit drug use.³

The defense’s argument that there are many causes of stroke in young adults that would be inappropriate for treatment with tPA, such as a PFO, carotid dissection or bacterial endocarditis, is absolutely true. Young patients need to be aggressively worked up for the etiology of their stroke, and may require additional testing, such as an MRA, echocardiogram, or Holter monitoring to determine the underlying cause of their stroke.

Obstruction Following Gastric Bypass Surgery

A 47-year-old woman presented to the ED complaining of severe back and abdominal pain. Onset had been gradual and began approximately 4 hours prior to arrival. She described the pain as crampy and constant. The patient had vomited twice; she denied diarrhea and had a normal bowel movement the previous day. She denied any vaginal or urinary complaints. Her past medical history was significant for hypertension and status post gastric bypass surgery 6 months prior. She had lost 42 pounds to date. She denied smoking or alcohol use.

The patient’s vital signs on physical examination were: blood pressure, 154/92 mm Hg; pulse, 106 beats/minute; respiratory rate, 18 breaths/minute; and temperature, 99˚F. Oxygen saturation was 96% on room air. The patient’s lungs were clear to auscultation bilaterally. The heart was mildly tachycardic, with a regular rhythm and without murmurs, rubs, or gallops. The abdominal examination revealed diffuse tenderness and involuntary guarding. There was no distention or rebound. Bowel sounds were present but hypoactive. Examination of the back revealed bilateral paraspinal muscle tenderness without costovertebral angle tenderness.

The EP ordered a CBC, BMP, serum lipase, and a urinalysis. The patient was given an intravenous (IV) bolus of 250 cc normal saline in addition to IV morphine 4 mg and IV ondansetron 4 mg. Her white blood cell (WBC) count was slightly elevated at 12.2 g/dL, with a normal differential. The remainder of the laboratory studies were normal, except for a serum bicarbonate of 22 mmol/L.

The patient stated she felt somewhat improved, but continued to have abdominal and back pain. The EP admitted her to the hospital for observation and pain control. She died the following day from a bowel obstruction. The family sued the EP for negligence in failing to order appropriate testing and for not consulting with specialists to diagnose the bowel obstruction, which is a known complication of gastric bypass surgery. The jury returned a verdict of $2.4 million against the EP.

Discussion

The frequency of bariatric surgery in the United States continues to increase, primarily due to its success with regard to weight loss, but also because of its demonstrated improvement in hypertension, obstructive sleep apnea, hyperlipidemia, and type 2 DM.¹

Frequently, the term “gastric bypass surgery” is used interchangeably with bariatric surgery. However, the EP must realize these terms encompass multiple different operations. The four most common types of bariatric surgery in the United Stated are (1) adjustable gastric banding (AGB); (2) the Roux-en-Y gastric bypass (RYGB);  (3) biliopancreatic diversion with duodenal switch (BPD-DS); and (4) vertical sleeve gastrectomy (VSG).² (See the Table for a brief explanation of each type of procedure.)

Since each procedure has its own respective associated complications, it is important for the EP to know which the type of gastric bypass surgery the patient had. For example, leakage is much more frequent following RYGB than in gastric banding, while slippage and obstruction are the most common complications of gastric banding.^3,4 It is also very helpful to know the specific type of procedure when discussing the case with the surgical consultant.

Based on a recent review of over 800,000 bariatric surgery patients, seven serious common complications following the surgery were identified.³ These included bleeding, leakage, obstruction, stomal ulceration, pulmonary embolism and respiratory complications, blood sugar disturbances (usually hypoglycemia and/or metabolic acidosis), and nutritional disturbances. While not all-inclusive, this list represents the most common serious complications of gastric bypass surgery.

The complaint of abdominal pain in a patient that has undergone bariatric surgery should be taken very seriously. In addition to determining the specific procedure performed and date, the patient should be questioned about vomiting, bowel movements, and the presence of blood in stool or vomit. Depending upon the degree of pain present, the patient may need to be given IV opioid analgesia to facilitate a thorough abdominal examination. A rectal examination should be performed to identify occult gastrointestinal bleeding.

These patients require laboratory testing, including CBC, BMP, and other laboratory evaluation as indicated by the history and physical examination. Early consultation with the bariatric surgeon is recommended. Many, if not most, patients with abdominal pain and vomiting will require imaging, usually a CT scan with contrast of the abdomen and pelvis. Because of the difficulty in interpreting the CT scan results in these patients, the bariatric surgeon will often want to personally review the films rather than rely solely on the interpretation by radiology services.

Unfortunately, the EP in this case did not appreciate the seriousness of the situation. The presence of severe abdominal pain, tenderness, guarding, mild tachycardia with leukocytosis, and metabolic acidosis all pointed to a more serious etiology than muscle spasm. This patient required IV fluids, analgesia, and imaging, as well as consultation with the bariatric surgeon.

We are pleased to introduce Curbside Consult with the Group for the Advancement of Psychiatry's (GAP) Family and Cultural committees. The column is inspired by the DSM-5's emphasis on developing a cultural formulation of patients' illnesses and addressing family dynamics and resilience in promoting care that fosters prevention and recovery.

What is GAP?

GAP was formed in 1946 under the leadership of Dr. William Menninger by a group of young psychiatrists who had served in World War II. They returned to the United States to find an inadequate system of civilian care. They were eager to professionalize the field and collaboratively develop new and creative thinking. They developed an organization that met as a whole twice a year, organized into committees of particular interest to the members and crucial to the needs of psychiatric care. The committees wrote monographs that formed a crucial role in the development of modern psychiatric thought.

Mission of GAP

• Bring together top psychiatrists of all disciplines
• Offer an objective, critical perspective on current issues facing psychiatry
• Develop smart analysis and recommendations
• Shape psychiatric thinking, clinical practice, and mental health programs
• Advocate for necessary changes in the psychiatric field
• Inspire the next generation of leading psychiatric thinkers

The Family and Cultural Psychiatry committees want to focus psychiatrists on the resilience inherent in the families and cultures of our patients in order to promote psychiatric care that focuses on prevention and recovery.

The Family and Cultural Psychiatry committees see every patient as connected to family members and belonging to a network of cultures that might include their national origin, race/ethnicity, religion/spirituality, language, occupation, age, sexual orientation and gender identity, or any other element of the person's background and collective life.

Over time, these family and cultural influences have shaped all aspects of the person’s response to adversity, experience of illness, and expectations of help seeking, even among patients who are currently living alone or do not recognize their background as explicitly cultural. This influence is highly individual; each person has his/her own combination of family and cultural experiences. How does the psychiatrist access this experience and use it to help develop resilience in our patients? How do we encourage them to use strengths/support from their family and culture, and to identify narratives that are helpful?

We see this column as one way to help answer these questions. We will bring to bear both family and cultural perspectives on the care of patients in everyday clinical practice through our comments on case vignettes sent in by readers. It can be challenging to integrate an understanding of family and culture into each patient encounter.

Our committees will work together to develop a coherent response that integrates both family and cultural perspectives and can be applied in real-world patient situations by clinicians who might not have access to specialized consultation. We aim to contribute to the growing awareness in our field of the cultural complexity of our patients, as developed and transmitted in the nexus of their families, which requires from us as clinicians a more inclusive and holistic approach to care.

This column helps to meet the goals of accreditation bodies such as The Joint Commission and the Accreditation Council for Graduate Medical Education (ACGME) for cultural and linguistic competence and patient- and family-centered care. Understanding how to think about, assess, and engage in treatment with the diversity of our patients’ cultural and family backgrounds constitutes important educational topics for all psychiatric trainees. In conjunction with formal didactics, these cases can be used as a focus for discussion in psychiatric residency training programs, ACGME Clinical Learning Environment Review (CLER), health care quality improvement activities, and faculty development programs.

Practicing clinicians also will find the DSM-5 Outline for Cultural Formulation and Cultural Formulation Interview to be a helpful clinical tool for eliciting and organizing cultural information, and in differential diagnosis and treatment planning.

The following is a list of the guiding principles we will use for assessment:

1. Heterogeneity and diversity exists within all families, cultures, and societies.

2. Avoid stereotyping, essentializing, and overgeneralizing.

3. Individualize and tailor diagnostic assessment, treatment, and care.

4. Address any language access barriers through the use of qualified medical interpreters and appropriately translated educational and informational materials.

5. Employ plain language in communicating with patients with limited health and mental health literacy.

6. Recognize the impact on both the patient and the clinician of our families of origin.

7. Engage in reflective, mindful practice and attend to cultural countertransference to provide insight into one’s own values, beliefs, and behaviors.

8. Cultivate cultural humility – the realization that our understanding of the other person’s background is always limited and incomplete.

9. Every encounter is a cross-cultural one.

10. Developing cultural competence is a lifelong journey and not a final destination.

Guidelines for Case Submission

We are requesting that you submit cases to cpnews@frontlinemedcom.com in which your understanding and treatment are affected by challenging cultural and family issues. We will then write back with our best answers about how one might proceed in such a case. Your case and our response will be published in Clinical Psychiatry News. Please limit your case description to 250 words and please include the following details:

1. Patient’s presenting problem or reason for the visit.

2. Patient’s age and gender.

3. Indicators of the patient’s identity – self-identified race/ethnicity, culture, religion/spirituality, socioeconomic status, education, among other variables.

4. Patient’s living situation, family composition, and genogram information (if available).

5. Patient’s geographic location (rural, suburban, urban) and occupation.

6. Patient’s and family’s degree of participation in their identified culture.

7. Questions of the individual submitting the case, including concerns about the role of the family and culture in the case, diagnosis, and treatment planning.

8. Please follow local ethical requirements, disguise the case to protect confidentiality and attend to HIPAA requirements, so that patients or family members reading the article would not recognize themselves.

Additional information might be requested, and editing of the case, questions, and commentary might be needed prior to final publication.

Please note that the opinions expressed in the case commentaries should not be seen as formal medical consultations and do not represent the opinions of GAP, CPN, or the institutions where the authors are employed or with which they are affiliated.

Contributors:

Michael S. Ascher, M.D. – University of Pennsylvania, Perelman School of Medicine

Alison M. Heru, M.D. – University of Colorado at Denver, Aurora

Roberto Lewis-Fernández, M.D. – Columbia University and New York State Psychiatric Institute

Robert C. Like, M.D., M.S. – Rutgers University, Robert Wood Johnson Medical School

Resources:

DSM-5 – Outline for Cultural Formulation and Cultural Formulation Interview: http://www.psychiatry.org/practice/dsm/dsm5/online-assessment-measures#Cultural

Clinical Manual of Couples and Family Therapy, Washington: American Psychiatric Publishing Inc., 2009.

Thinking Through Cultures: Expeditions in Cultural Psychology. Cambridge, Mass.: Harvard University Press, 1991.

Clinical Manual of Cultural Psychiatry, 2nd Edition, Washington: American Psychiatric Publishing Inc., 2015.

We are pleased to introduce Curbside Consult with the Group for the Advancement of Psychiatry's (GAP) Family and Cultural committees. The column is inspired by the DSM-5's emphasis on developing a cultural formulation of patients' illnesses and addressing family dynamics and resilience in promoting care that fosters prevention and recovery.

What is GAP?

GAP was formed in 1946 under the leadership of Dr. William Menninger by a group of young psychiatrists who had served in World War II. They returned to the United States to find an inadequate system of civilian care. They were eager to professionalize the field and collaboratively develop new and creative thinking. They developed an organization that met as a whole twice a year, organized into committees of particular interest to the members and crucial to the needs of psychiatric care. The committees wrote monographs that formed a crucial role in the development of modern psychiatric thought.

Mission of GAP

• Bring together top psychiatrists of all disciplines
• Offer an objective, critical perspective on current issues facing psychiatry
• Develop smart analysis and recommendations
• Shape psychiatric thinking, clinical practice, and mental health programs
• Advocate for necessary changes in the psychiatric field
• Inspire the next generation of leading psychiatric thinkers

The Family and Cultural Psychiatry committees want to focus psychiatrists on the resilience inherent in the families and cultures of our patients in order to promote psychiatric care that focuses on prevention and recovery.

The Family and Cultural Psychiatry committees see every patient as connected to family members and belonging to a network of cultures that might include their national origin, race/ethnicity, religion/spirituality, language, occupation, age, sexual orientation and gender identity, or any other element of the person's background and collective life.

Over time, these family and cultural influences have shaped all aspects of the person’s response to adversity, experience of illness, and expectations of help seeking, even among patients who are currently living alone or do not recognize their background as explicitly cultural. This influence is highly individual; each person has his/her own combination of family and cultural experiences. How does the psychiatrist access this experience and use it to help develop resilience in our patients? How do we encourage them to use strengths/support from their family and culture, and to identify narratives that are helpful?

We see this column as one way to help answer these questions. We will bring to bear both family and cultural perspectives on the care of patients in everyday clinical practice through our comments on case vignettes sent in by readers. It can be challenging to integrate an understanding of family and culture into each patient encounter.

Our committees will work together to develop a coherent response that integrates both family and cultural perspectives and can be applied in real-world patient situations by clinicians who might not have access to specialized consultation. We aim to contribute to the growing awareness in our field of the cultural complexity of our patients, as developed and transmitted in the nexus of their families, which requires from us as clinicians a more inclusive and holistic approach to care.

This column helps to meet the goals of accreditation bodies such as The Joint Commission and the Accreditation Council for Graduate Medical Education (ACGME) for cultural and linguistic competence and patient- and family-centered care. Understanding how to think about, assess, and engage in treatment with the diversity of our patients’ cultural and family backgrounds constitutes important educational topics for all psychiatric trainees. In conjunction with formal didactics, these cases can be used as a focus for discussion in psychiatric residency training programs, ACGME Clinical Learning Environment Review (CLER), health care quality improvement activities, and faculty development programs.

Practicing clinicians also will find the DSM-5 Outline for Cultural Formulation and Cultural Formulation Interview to be a helpful clinical tool for eliciting and organizing cultural information, and in differential diagnosis and treatment planning.

The following is a list of the guiding principles we will use for assessment:

1. Heterogeneity and diversity exists within all families, cultures, and societies.

2. Avoid stereotyping, essentializing, and overgeneralizing.

3. Individualize and tailor diagnostic assessment, treatment, and care.

4. Address any language access barriers through the use of qualified medical interpreters and appropriately translated educational and informational materials.

5. Employ plain language in communicating with patients with limited health and mental health literacy.

6. Recognize the impact on both the patient and the clinician of our families of origin.

7. Engage in reflective, mindful practice and attend to cultural countertransference to provide insight into one’s own values, beliefs, and behaviors.

8. Cultivate cultural humility – the realization that our understanding of the other person’s background is always limited and incomplete.

9. Every encounter is a cross-cultural one.

10. Developing cultural competence is a lifelong journey and not a final destination.

Guidelines for Case Submission

We are requesting that you submit cases to cpnews@frontlinemedcom.com in which your understanding and treatment are affected by challenging cultural and family issues. We will then write back with our best answers about how one might proceed in such a case. Your case and our response will be published in Clinical Psychiatry News. Please limit your case description to 250 words and please include the following details:

1. Patient’s presenting problem or reason for the visit.

2. Patient’s age and gender.

3. Indicators of the patient’s identity – self-identified race/ethnicity, culture, religion/spirituality, socioeconomic status, education, among other variables.

4. Patient’s living situation, family composition, and genogram information (if available).

5. Patient’s geographic location (rural, suburban, urban) and occupation.

6. Patient’s and family’s degree of participation in their identified culture.

7. Questions of the individual submitting the case, including concerns about the role of the family and culture in the case, diagnosis, and treatment planning.

8. Please follow local ethical requirements, disguise the case to protect confidentiality and attend to HIPAA requirements, so that patients or family members reading the article would not recognize themselves.

Additional information might be requested, and editing of the case, questions, and commentary might be needed prior to final publication.

Please note that the opinions expressed in the case commentaries should not be seen as formal medical consultations and do not represent the opinions of GAP, CPN, or the institutions where the authors are employed or with which they are affiliated.

Contributors:

Michael S. Ascher, M.D. – University of Pennsylvania, Perelman School of Medicine

Alison M. Heru, M.D. – University of Colorado at Denver, Aurora

Roberto Lewis-Fernández, M.D. – Columbia University and New York State Psychiatric Institute

Robert C. Like, M.D., M.S. – Rutgers University, Robert Wood Johnson Medical School

Resources:

DSM-5 – Outline for Cultural Formulation and Cultural Formulation Interview: http://www.psychiatry.org/practice/dsm/dsm5/online-assessment-measures#Cultural

Clinical Manual of Couples and Family Therapy, Washington: American Psychiatric Publishing Inc., 2009.

Thinking Through Cultures: Expeditions in Cultural Psychology. Cambridge, Mass.: Harvard University Press, 1991.

Clinical Manual of Cultural Psychiatry, 2nd Edition, Washington: American Psychiatric Publishing Inc., 2015.

We are pleased to introduce Curbside Consult with the Group for the Advancement of Psychiatry's (GAP) Family and Cultural committees. The column is inspired by the DSM-5's emphasis on developing a cultural formulation of patients' illnesses and addressing family dynamics and resilience in promoting care that fosters prevention and recovery.

What is GAP?

GAP was formed in 1946 under the leadership of Dr. William Menninger by a group of young psychiatrists who had served in World War II. They returned to the United States to find an inadequate system of civilian care. They were eager to professionalize the field and collaboratively develop new and creative thinking. They developed an organization that met as a whole twice a year, organized into committees of particular interest to the members and crucial to the needs of psychiatric care. The committees wrote monographs that formed a crucial role in the development of modern psychiatric thought.

Mission of GAP

• Bring together top psychiatrists of all disciplines
• Offer an objective, critical perspective on current issues facing psychiatry
• Develop smart analysis and recommendations
• Shape psychiatric thinking, clinical practice, and mental health programs
• Advocate for necessary changes in the psychiatric field
• Inspire the next generation of leading psychiatric thinkers

The Family and Cultural Psychiatry committees want to focus psychiatrists on the resilience inherent in the families and cultures of our patients in order to promote psychiatric care that focuses on prevention and recovery.

The Family and Cultural Psychiatry committees see every patient as connected to family members and belonging to a network of cultures that might include their national origin, race/ethnicity, religion/spirituality, language, occupation, age, sexual orientation and gender identity, or any other element of the person's background and collective life.

Over time, these family and cultural influences have shaped all aspects of the person’s response to adversity, experience of illness, and expectations of help seeking, even among patients who are currently living alone or do not recognize their background as explicitly cultural. This influence is highly individual; each person has his/her own combination of family and cultural experiences. How does the psychiatrist access this experience and use it to help develop resilience in our patients? How do we encourage them to use strengths/support from their family and culture, and to identify narratives that are helpful?

We see this column as one way to help answer these questions. We will bring to bear both family and cultural perspectives on the care of patients in everyday clinical practice through our comments on case vignettes sent in by readers. It can be challenging to integrate an understanding of family and culture into each patient encounter.

Our committees will work together to develop a coherent response that integrates both family and cultural perspectives and can be applied in real-world patient situations by clinicians who might not have access to specialized consultation. We aim to contribute to the growing awareness in our field of the cultural complexity of our patients, as developed and transmitted in the nexus of their families, which requires from us as clinicians a more inclusive and holistic approach to care.

This column helps to meet the goals of accreditation bodies such as The Joint Commission and the Accreditation Council for Graduate Medical Education (ACGME) for cultural and linguistic competence and patient- and family-centered care. Understanding how to think about, assess, and engage in treatment with the diversity of our patients’ cultural and family backgrounds constitutes important educational topics for all psychiatric trainees. In conjunction with formal didactics, these cases can be used as a focus for discussion in psychiatric residency training programs, ACGME Clinical Learning Environment Review (CLER), health care quality improvement activities, and faculty development programs.

Practicing clinicians also will find the DSM-5 Outline for Cultural Formulation and Cultural Formulation Interview to be a helpful clinical tool for eliciting and organizing cultural information, and in differential diagnosis and treatment planning.

The following is a list of the guiding principles we will use for assessment:

1. Heterogeneity and diversity exists within all families, cultures, and societies.

2. Avoid stereotyping, essentializing, and overgeneralizing.

3. Individualize and tailor diagnostic assessment, treatment, and care.

4. Address any language access barriers through the use of qualified medical interpreters and appropriately translated educational and informational materials.

5. Employ plain language in communicating with patients with limited health and mental health literacy.

6. Recognize the impact on both the patient and the clinician of our families of origin.

7. Engage in reflective, mindful practice and attend to cultural countertransference to provide insight into one’s own values, beliefs, and behaviors.

8. Cultivate cultural humility – the realization that our understanding of the other person’s background is always limited and incomplete.

9. Every encounter is a cross-cultural one.

10. Developing cultural competence is a lifelong journey and not a final destination.

Guidelines for Case Submission

We are requesting that you submit cases to cpnews@frontlinemedcom.com in which your understanding and treatment are affected by challenging cultural and family issues. We will then write back with our best answers about how one might proceed in such a case. Your case and our response will be published in Clinical Psychiatry News. Please limit your case description to 250 words and please include the following details:

1. Patient’s presenting problem or reason for the visit.

2. Patient’s age and gender.

3. Indicators of the patient’s identity – self-identified race/ethnicity, culture, religion/spirituality, socioeconomic status, education, among other variables.

4. Patient’s living situation, family composition, and genogram information (if available).

5. Patient’s geographic location (rural, suburban, urban) and occupation.

6. Patient’s and family’s degree of participation in their identified culture.

7. Questions of the individual submitting the case, including concerns about the role of the family and culture in the case, diagnosis, and treatment planning.

8. Please follow local ethical requirements, disguise the case to protect confidentiality and attend to HIPAA requirements, so that patients or family members reading the article would not recognize themselves.

Additional information might be requested, and editing of the case, questions, and commentary might be needed prior to final publication.

Please note that the opinions expressed in the case commentaries should not be seen as formal medical consultations and do not represent the opinions of GAP, CPN, or the institutions where the authors are employed or with which they are affiliated.

Contributors:

Michael S. Ascher, M.D. – University of Pennsylvania, Perelman School of Medicine

Alison M. Heru, M.D. – University of Colorado at Denver, Aurora

Roberto Lewis-Fernández, M.D. – Columbia University and New York State Psychiatric Institute

Robert C. Like, M.D., M.S. – Rutgers University, Robert Wood Johnson Medical School

Resources:

DSM-5 – Outline for Cultural Formulation and Cultural Formulation Interview: http://www.psychiatry.org/practice/dsm/dsm5/online-assessment-measures#Cultural

Clinical Manual of Couples and Family Therapy, Washington: American Psychiatric Publishing Inc., 2009.

Thinking Through Cultures: Expeditions in Cultural Psychology. Cambridge, Mass.: Harvard University Press, 1991.

Clinical Manual of Cultural Psychiatry, 2nd Edition, Washington: American Psychiatric Publishing Inc., 2015.

Sofosbuvir and ribavirin treatments should be administered to patients with hepatitis C virus who undergo liver transplantations in order to significantly decrease the risks of posttransplant HCV recurrence, according to two new studies published in the January issue of Gastroenterology (10.1053/j.gastro.2014.09.023 and 10.1053/j.gastro.2014.10.001).

“In clinical trials, administration of sofosbuvir with ribavirin was associated with rapid decreases of HCV RNA to undetectable levels in patients with HCV genotype 1, 2, 3, 4, and 6 infections,” wrote lead author Dr. Michael P. Curry of the Beth Israel Deaconess Medical Center in Boston, and his coauthors on the first of these two studies. “In more than 3,000 patients treated to date, sofosbuvir has been shown to be safe, viral breakthrough during treatment has been rare (and associated with nonadherence), and few drug interactions have been observed.”

In a phase II, open-label study, Dr. Curry and his coinvestigators enrolled 61 patients with HCV of any genotype, and cirrhosis with a Child-Turcotte-Pugh score no greater than 7, who were all wait-listed to receive liver transplantations. Subjects received up to 48 weeks of treatment with 400 mg of sofosbuvir, and a separate dose of ribavirin prior to liver transplantation, while 43 patients received transplantations alone. The primary outcome sought by investigators was HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients that had this level prior to the operation.

The investigators found that 43 subjects had the desired HCV-RNA levels; of that population, 49% had a posttransplantation virologic response, with the most frequent side effects reported by subjects being fatigue (38%), headache (23%), and anemia (21%). Of the 43 applicable subjects, 30 (70% of the population) had a posttransplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died.

“This study provides proof of concept that virologic suppression without interferon significantly can reduce the rate of recurrent HCV after liver transplantation,” the study says, adding that the results “compare favorably with those observed in other trials of pretransplantation antiviral therapy.”

In the second study, the authors ascertained that combination therapy consisting of sofosbuvir and ribavirin for 24 weeks is effective at preventing hepatitis C virus recurrence in patients who undergo liver transplantations.

“Recurrent HCV infection is the most common cause of mortality and graft loss following transplantation, and up to 30% of patients with recurrent infection develop cirrhosis within 5 years,” wrote the study’s authors, led by Dr. Michael Charlton of the Mayo Clinic in Rochester, Minn.

Using a prospective, multicenter, open-label pilot study, investigators enrolled and treated 40 patients with a 24-week regimen of 400 mg sofosbuvir and ribavirin starting at 400 mg, which was subsequently adjusted per patient based on individual creatinine clearance and hemoglobin levels. Subjects were 78% male and 85% white, with 83% having HCV genotype 1, 40% having cirrhosis, and 88% having been previously treated with interferon. The primary outcome investigators looked for was “sustained virologic response 12 weeks after treatment (SVR12).”

Data showed that SVR12 was achieved by 28 of the 40 subjects that received treatment, or 70%. The most commonly reported adverse effects were fatigue (30%), diarrhea (28%), headache (25%), and anemia (20%). No patients exhibited detectable viral resistance during or after treatment, and although two patients terminated their treatment because of adverse events, investigators reported no deaths, graft losses, or episodes of rejection.

“In contrast,” Dr. Charlton and his coauthors noted, “interferon-based treatments have been associated with posttreatment immunological dysfunction (particularly plasma cell hepatitis) and even hepatic decompensation in LT [liver transplant] recipients.”

The authors of the first study disclosed that Dr. Curry has received grants from and been affiliated with Gilead, which was a sponsor of the study. The authors of the second study reported no relevant financial disclosures.

dchitnis@frontlinemedcom.com

Sofosbuvir and ribavirin treatments should be administered to patients with hepatitis C virus who undergo liver transplantations in order to significantly decrease the risks of posttransplant HCV recurrence, according to two new studies published in the January issue of Gastroenterology (10.1053/j.gastro.2014.09.023 and 10.1053/j.gastro.2014.10.001).

“In clinical trials, administration of sofosbuvir with ribavirin was associated with rapid decreases of HCV RNA to undetectable levels in patients with HCV genotype 1, 2, 3, 4, and 6 infections,” wrote lead author Dr. Michael P. Curry of the Beth Israel Deaconess Medical Center in Boston, and his coauthors on the first of these two studies. “In more than 3,000 patients treated to date, sofosbuvir has been shown to be safe, viral breakthrough during treatment has been rare (and associated with nonadherence), and few drug interactions have been observed.”

In a phase II, open-label study, Dr. Curry and his coinvestigators enrolled 61 patients with HCV of any genotype, and cirrhosis with a Child-Turcotte-Pugh score no greater than 7, who were all wait-listed to receive liver transplantations. Subjects received up to 48 weeks of treatment with 400 mg of sofosbuvir, and a separate dose of ribavirin prior to liver transplantation, while 43 patients received transplantations alone. The primary outcome sought by investigators was HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients that had this level prior to the operation.

The investigators found that 43 subjects had the desired HCV-RNA levels; of that population, 49% had a posttransplantation virologic response, with the most frequent side effects reported by subjects being fatigue (38%), headache (23%), and anemia (21%). Of the 43 applicable subjects, 30 (70% of the population) had a posttransplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died.

“This study provides proof of concept that virologic suppression without interferon significantly can reduce the rate of recurrent HCV after liver transplantation,” the study says, adding that the results “compare favorably with those observed in other trials of pretransplantation antiviral therapy.”

In the second study, the authors ascertained that combination therapy consisting of sofosbuvir and ribavirin for 24 weeks is effective at preventing hepatitis C virus recurrence in patients who undergo liver transplantations.

“Recurrent HCV infection is the most common cause of mortality and graft loss following transplantation, and up to 30% of patients with recurrent infection develop cirrhosis within 5 years,” wrote the study’s authors, led by Dr. Michael Charlton of the Mayo Clinic in Rochester, Minn.

Using a prospective, multicenter, open-label pilot study, investigators enrolled and treated 40 patients with a 24-week regimen of 400 mg sofosbuvir and ribavirin starting at 400 mg, which was subsequently adjusted per patient based on individual creatinine clearance and hemoglobin levels. Subjects were 78% male and 85% white, with 83% having HCV genotype 1, 40% having cirrhosis, and 88% having been previously treated with interferon. The primary outcome investigators looked for was “sustained virologic response 12 weeks after treatment (SVR12).”

Data showed that SVR12 was achieved by 28 of the 40 subjects that received treatment, or 70%. The most commonly reported adverse effects were fatigue (30%), diarrhea (28%), headache (25%), and anemia (20%). No patients exhibited detectable viral resistance during or after treatment, and although two patients terminated their treatment because of adverse events, investigators reported no deaths, graft losses, or episodes of rejection.

“In contrast,” Dr. Charlton and his coauthors noted, “interferon-based treatments have been associated with posttreatment immunological dysfunction (particularly plasma cell hepatitis) and even hepatic decompensation in LT [liver transplant] recipients.”

The authors of the first study disclosed that Dr. Curry has received grants from and been affiliated with Gilead, which was a sponsor of the study. The authors of the second study reported no relevant financial disclosures.

dchitnis@frontlinemedcom.com

Sofosbuvir and ribavirin treatments should be administered to patients with hepatitis C virus who undergo liver transplantations in order to significantly decrease the risks of posttransplant HCV recurrence, according to two new studies published in the January issue of Gastroenterology (10.1053/j.gastro.2014.09.023 and 10.1053/j.gastro.2014.10.001).

“In clinical trials, administration of sofosbuvir with ribavirin was associated with rapid decreases of HCV RNA to undetectable levels in patients with HCV genotype 1, 2, 3, 4, and 6 infections,” wrote lead author Dr. Michael P. Curry of the Beth Israel Deaconess Medical Center in Boston, and his coauthors on the first of these two studies. “In more than 3,000 patients treated to date, sofosbuvir has been shown to be safe, viral breakthrough during treatment has been rare (and associated with nonadherence), and few drug interactions have been observed.”

In a phase II, open-label study, Dr. Curry and his coinvestigators enrolled 61 patients with HCV of any genotype, and cirrhosis with a Child-Turcotte-Pugh score no greater than 7, who were all wait-listed to receive liver transplantations. Subjects received up to 48 weeks of treatment with 400 mg of sofosbuvir, and a separate dose of ribavirin prior to liver transplantation, while 43 patients received transplantations alone. The primary outcome sought by investigators was HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients that had this level prior to the operation.

The investigators found that 43 subjects had the desired HCV-RNA levels; of that population, 49% had a posttransplantation virologic response, with the most frequent side effects reported by subjects being fatigue (38%), headache (23%), and anemia (21%). Of the 43 applicable subjects, 30 (70% of the population) had a posttransplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died.

“This study provides proof of concept that virologic suppression without interferon significantly can reduce the rate of recurrent HCV after liver transplantation,” the study says, adding that the results “compare favorably with those observed in other trials of pretransplantation antiviral therapy.”

In the second study, the authors ascertained that combination therapy consisting of sofosbuvir and ribavirin for 24 weeks is effective at preventing hepatitis C virus recurrence in patients who undergo liver transplantations.

“Recurrent HCV infection is the most common cause of mortality and graft loss following transplantation, and up to 30% of patients with recurrent infection develop cirrhosis within 5 years,” wrote the study’s authors, led by Dr. Michael Charlton of the Mayo Clinic in Rochester, Minn.

Using a prospective, multicenter, open-label pilot study, investigators enrolled and treated 40 patients with a 24-week regimen of 400 mg sofosbuvir and ribavirin starting at 400 mg, which was subsequently adjusted per patient based on individual creatinine clearance and hemoglobin levels. Subjects were 78% male and 85% white, with 83% having HCV genotype 1, 40% having cirrhosis, and 88% having been previously treated with interferon. The primary outcome investigators looked for was “sustained virologic response 12 weeks after treatment (SVR12).”

Data showed that SVR12 was achieved by 28 of the 40 subjects that received treatment, or 70%. The most commonly reported adverse effects were fatigue (30%), diarrhea (28%), headache (25%), and anemia (20%). No patients exhibited detectable viral resistance during or after treatment, and although two patients terminated their treatment because of adverse events, investigators reported no deaths, graft losses, or episodes of rejection.

“In contrast,” Dr. Charlton and his coauthors noted, “interferon-based treatments have been associated with posttreatment immunological dysfunction (particularly plasma cell hepatitis) and even hepatic decompensation in LT [liver transplant] recipients.”

The authors of the first study disclosed that Dr. Curry has received grants from and been affiliated with Gilead, which was a sponsor of the study. The authors of the second study reported no relevant financial disclosures.

dchitnis@frontlinemedcom.com

Antithrombotic therapy reduces the risk of systemic embolism in patients with atrial fibrillation, but one approach does not suit all patients. The decision whether to start this therapy—and which agent to use—must take into account the patient’s risk of thromboembolism as well as bleeding.

Antithrombotic therapy encompasses antiplatelet drugs such as aspirin and clopidogrel and anticoagulants such as warfarin and the target-specific oral anticoagulants (TSOACs). Oral anticoagulation is more effective than antiplatelet therapy and is preferred in all but those at lowest risk, in whom either antiplatelet therapy or no therapy is deemed adequate.

Patients with valvular atrial fibrillation, specifically those who have rheumatic mitral stenosis or a prosthetic heart valve, are at significantly higher risk of systemic embolization. Their overall risk-benefit profile is nearly always in favor of anticoagulation. But the same is not necessarily true for patients with nonvalvular atrial fibrillation.

The following discussion sets forth our rationale for clinical decision-making, based on recommendations in the 2014 guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society.¹ The second half of this review outlines the oral anticoagulants currently available.

ONE IN FOUR PEOPLE

Atrial fibrillation is common, with an incidence that increases with age. It affects more than 10% of people over age 80 and is often  associated with cardiovascular disease.² Based on Framingham Heart Study data, a person’s lifetime risk of developing it is about 25%.³

FIVEFOLD RISK OF STROKE

The most serious complication of atrial fibrillation is arterial thromboembolism, of which ischemic stroke is the most common and most feared manifestation. The risk of stroke is five times higher than normal in patients with atrial fibrillation.³ More than 15% of strokes may be attributable to atrial fibrillation, and the proportion increases with age.⁴

The risk of thromboembolism appears to be similar in patients with clinically manifest atrial fibrillation irrespective of the type (paroxysmal, persistent, or permanent). The Stroke Prevention in Atrial Fibrillation (SPAF) study⁵ and the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W)⁶ showed that patients who had paroxysmal atrial fibrillation and at least one risk factor for thromboembolism had stroke rates comparable to those of their counterparts who had persistent and permanent atrial fibrillation.

Subclinical atrial fibrillation may be an important cause of stroke. Clinically silent episodes can be detected by implantable electronic devices, which record episodes of atrial tachyarrhythmia (atrial high-rate events).  Subclinical episodes have been detected in 10% to 28% of monitored patients who did not have a history of atrial fibrillation.^7,8 Patients who have atrial high-rate events detected by implantable devices have a higher risk of future clinically manifest atrial fibrillation, thromboembolic events, or both.^7–9 Yet characteristics of atrial high-rate episodes that predict risk are not well defined and warrant further investigation.

CLINICAL RISK FACTORS FOR STROKE

To date, thousands of patients with nonvalvular atrial fibrillation have participated in randomized clinical trials of stroke prevention. The placebo groups from these trials provide a sizable database for retrospectively identifying clinical characteristics associated with thromboembolism. The Atrial Fibrillation Investigators¹⁰ pooled data from five large trials and found that risk factors consistently associated with stroke in multivariate analysis included diabetes mellitus, hypertension, prior systemic embolism, and advanced age.

Though the risk of stroke increases with age with no lower limit, most studies identify age 65 as a threshold, with further escalating risk after age 75. Moreover, women were observed to be at higher risk in some but not all studies. These risk factors have become components of commonly used risk-stratification schemes.

Hypertrophic cardiomyopathy. Maron et al¹¹ reported that atrial fibrillation in patients with hypertrophic cardiomyopathy was independently associated with thromboembolism. In 900 patients with hypertrophic cardiomyopathy, the prevalence of systemic embolism was 6%. Patients with hypertrophic cardiomyopathy and a thromboembolic complication were seven times more likely to have atrial fibrillation than matched counterparts free of thromboembolism. A notable subset of patients experienced a stroke or embolic event before age 50, and the authors advised that the risk of thromboembolism should be considered in patients of any age with hypertrophic cardiomyopathy and atrial fibrillation.

Olivotto et al¹² similarly found patients with hypertrophic cardiomyopathy and atrial fibrillation to be at significantly greater risk of stroke (odds ratio [OR] 17.7, 95% confidence interval [CI] 4.1–75.9, P < .001).

Chronic kidney disease is also associated with a higher risk of thromboembolism in patients with atrial fibrillation. A glomerular filtration rate of 60 mL/min or less is independently and inversely predictive of risk.^13,14

While patients with end-stage renal disease have been largely excluded from stroke prevention trials, Vázquez et al¹⁵ prospectively followed 190 dialysis patients for 12 months. In multivariate analysis, compared with matched controls without documented atrial fibrillation, patients receiving renal replacement therapy and having any form of atrial fibrillation were eight times more likely to have systemic embolization.

IMAGING-BASED RISK FACTORS

In addition to clinical factors, several imaging-based factors have been associated with stroke risk in patients with atrial fibrillation.

Complex aortic atheroma or markers of blood stasis within the left atrium, such as reduced left atrial appendage emptying flow (< 20 cm/second), dense spontaneous echo contrast, or left atrial appendage thrombus, seen on transesophageal echocardiography, were independently associated with increased systemic embolic risk in the third SPAF substudy.¹⁶ Moreover, multivariate analysis of SPAF data found both left ventricular dysfunction of any severity and increased left atrial size (diameter corrected for body surface area by M-mode > 2.5 cm/m2) to be independent predictors of thromboembolism.¹⁷

Although enlargement of the left atrium has not been incorporated into traditional risk stratification schemes, data from Osranek et al¹⁸ further implicate it as a marker of risk. The cohort was small (N = 46), but consisted of patients with lone atrial fibrillation followed for nearly 30 years. Patients with normal left atrial size enjoyed a benign course, while those with left atrial enlargement (> 32 mL/m²) at diagnosis or later during follow-up had significantly worse event-free survival (hazard ratio [HR] 4.46, 95% CI 1.56–12.74, P < .01). All embolic strokes occurred in the group with left atrial enlargement.

RISK STRATIFICATION SCHEMES

Several models for predicting systemic embolism risk in patients with nonvalvular atrial fibrillation have been proposed and validated.

The CHADS₂ score has been the most widely applied, being simple to use.^19,20 It assigns 1 point each for Congestive heart failure, Hypertension, Age 75 or older, and Diabetes, and 2 points for prior Stroke or systemic thromboembolism.

In patients with chronic nonvalvular atrial fibrillation, Gage et al¹⁹ reported that the stroke rate was lowest in those with a score of 0, with an annual adjusted stroke rate of 1.9% per year, and highest in those with the maximal possible score (ie, 6), with a rate of 18.2%. The rate increased by a factor of 1.5 with each point in the CHADS₂ score.

CHA₂DS₂-VASc. Endorsed for use in both the American and European guidelines,^1,21 CHA₂DS₂-VASc is an extension of CHADS₂. Points are assigned as follows:

• Congestive heart failure or left ventricular dysfunction (moderate to severe left ventricular dysfunction or recent heart failure exacerbation requiring hospitalization irrespective of ejection fraction): 1 point
• Hypertension: 1 point
• Age ≥ 75: 2 points; age 65–74: 1 point
• Diabetes mellitus: 1 point
• Stroke, transient ischemic attack, or thromboembolism: 2 points
• Vascular disease (prior myocardial infarction, peripheral arterial disease, or aortic plaque): 1 point
• Sex, female: 1 point
• Maximum score: 9 points.

Low risk is defined as a score of 0 for a man or, for a woman with no other risk factors, 1. A score of 1 for a man indicates moderate risk, and a score of 2 or more is high risk. Lip et al²² found that, in untreated patients with nonvalvular atrial fibrillation, rates of stroke ranged from 0 with a score of 0 to 15.2% per year with a score of 9 points.

In a large cohort with over 11,000 patient-years of follow-up, 98% of the thromboembolic events occurred in people with a CHA₂DS₂-VASc score of 2 or more. Moreover, more than 99% of patients with a score of less than 2 were free of stroke and thromboembolism.²³

Compared with CHADS₂, CHA₂DS₂-VASc has superior negative predictive power

Compared with the CHADS₂ score, CHA₂DS₂-VASc has superior negative predictive power. Of 1,084 patients from the European Heart Survey for Atrial Fibrillation, the newer scheme classified significantly fewer patients as being at either low risk (score of 0; 9% vs 20%) or intermediate risk (score of 1; 15% vs 35%).²³ Though the overall rate of stroke was low, those categorized as being at low or intermediate risk by CHA₂DS₂-VASc had significantly fewer thromboembolic events than their counterparts according to CHADS₂ (0.6% vs 3.3%).

Olesen et al²⁴ similarly showed that in patients with a CHADS₂ score of 0, reclassification by CHA₂DS₂-VASc yielded a range of annual stroke rates from 0.84% with a score of 0 up to 3.2% with a score of 3.

RISK-BASED ANTITHROMBOTIC THERAPY IN NONVALVULAR ATRIAL FIBRILLATION

The 2014 atrial fibrillation guidelines¹ state that the decision to give antithrombotic therapy for atrial fibrillation should be individualized, based on the absolute and relative risks of stroke and bleeding, and ought to take into consideration the patient’s preferences. For patients with nonvalvular atrial fibrillation, selection of antithrombotic therapy should take into account the risk of thromboembolism determined by the CHA₂DS₂-VASc score and be irrespective of the pattern of atrial fibrillation (paroxysmal, persistent, or permanent). Antithrombotic therapy is similarly recommended for patients with atrial flutter, according to the same risk profile used for atrial fibrillation.

Studies have consistently shown^24–27 that the risk of ischemic stroke without anticoagulation exceeds the risk of intracranial bleeding with anticoagulation in nearly all patients except those at lowest risk of thromboembolism. The CHA₂DS₂-VASc score better identified those at truly low risk, in whom treatment may offer more risk than benefit.^24–27

The HAS-BLED score²⁸ assigns points as follows:

• Hypertension (systolic blood pressure > 160 mm Hg): 1 point
• Abnormal renal function (dialysis, renal transplantation, or serum creatinine > 2.6 mg/mL) or liver function (cirrhosis, bilirubin more than two times the upper limit, or aminotransferase levels more than three times the upper limit): 1 or 2 points
• Stroke: 1 point
• Bleeding (prior major bleeding event or predisposition to bleeding): 1 point
• Labile international normalized ratio (INR) (supratherapeutic or time in therapeutic range < 60%): 1 point
• Elderly (age > 65): 1 point
• Drugs (antiplatelet, nonsteroidal anti-inflammatory) or alcohol (more than eight drinks per week): 1 or 2 points
• Maximum total: 9 points.

HAS-BLED is a practical and validated approach for estimating bleeding risk and is mentioned in the guidelines, but it is not recommended for use in guiding decisions about antithrombotic therapy. Specifically, it should not be used to exclude patients, but rather to identify those at high risk (score ≥ 3) who may require closer observation and more attentive monitoring of the INR.

ANTITHROMBOTIC THERAPY

Antithrombotic agents available for use in the United States include antiplatelet drugs (eg, aspirin and clopidogrel) and anticoagulants (unfractionated heparin and low-molecular-weight heparin, vitamin K antagonists such as warfarin, and direct thrombin and factor Xa inhibitors). Anticoagulation has been shown in randomized controlled trials to be superior to both placebo and antiplatelet agents used either alone or in combination.²⁹

Aspirin has been downgraded

Aspirin has been compared with placebo in seven randomized controlled trials. Only the original SPAF study, in which aspirin 325 mg/day was used, found that it was beneficial. This result alone accounted for the 19% reduction in relative risk (95% CI 1%–35%, P < .05) in a meta-analysis performed by Hart et al.²⁹ Even when combined with clopidogrel 75 mg/day, aspirin 75 to 100 mg/day is still inferior to warfarin.⁵ While dual antiplatelet therapy resulted in a 28% relative reduction in thromboembolism (95% CI 17%–38%, P < .01) compared with aspirin alone, major bleeding significantly increased by 57% (95% CI 29%–92%, P < .01).

Although aspirin may be beneficial, differences among patients may influence its efficacy. It may be more effective in preventing noncardioembolic stroke, particularly in diabetic and hypertensive patients.^30,31 To date, aspirin has not been shown to be beneficial in low-risk populations.

The 2014 guidelines downgraded the recommendation for aspirin therapy. For patients at low risk and for some at intermediate risk, it is permissible to forgo therapy altogether, including aspirin.¹

ORAL ANTICOAGULANTS

The rest of this paper reviews the oral anticoagulants that are approved for reducing the risk of thromboembolism in atrial fibrillation, focusing on each agent’s mechanism of action, pharmacokinetics, clinical efficacy, and safety.

WARFARIN, A VITAMIN K ANTAGONIST

Warfarin inhibits synthesis of vitamin K-dependent clotting factors (ie, factors II, VII, IX, and X) and proteins C and S by inhibiting the C1 subunit of vitamin K epoxide reductase, thereby interfering with production of vitamin K₁ epoxide and consequent regeneration of vitamin K.

Pharmacokinetics. Warfarin is nearly completely absorbed after oral administration. Its anticoagulant effect can be seen within 24 hours of administration, but its peak effect is typically apparent only after 72 hours. Elimination occurs predominantly through metabolism by cytochrome P450 enzymes, principally CYP2C9. Its effective half-life ranges from 20 to 60 hours, with a mean of 40 hours.³²

Warfarin’s effect, dosage, and bleeding risk are influenced by multiple factors, including vitamin K-containing foods such as green leafy vegetables, medications that either inhibit or induce hepatic cytochrome P450 enzymes, and polymorphisms in the VKORC1 and CYP2C9 genes.³²

Reversal. Warfarin’s anticoagulant effect is reversed with vitamin K, but this reversal may not become apparent for 6 to 24 hours. In contrast, fresh-frozen plasma and prothrombin protein concentrate, which contain clotting factors, reverse warfarin immediately. Currently, a three-factor prothrombin protein concentrate (factors II, IX, and X) and a four-factor concentrate (factors II, VII, IX, and X plus proteins C and S) are available in the United States. Although prothrombin protein concentrate works rapidly and has a lower volume of administration, available data do not indicate it is clinically superior to fresh-frozen plasma.^33,34 The ongoing randomized PROTECT trial (NCT00618098), comparing fresh-frozen plasma and four-factor prothrombin protein concentrate for reversal of vitamin K antagonist therapy, may provide further insight.

Efficacy and safety. Randomized controlled trials in patients with nonvalvular atrial fibrillation have shown that warfarin (in doses adjusted to maintain an INR greater than 2) is highly efficacious in preventing systemic embolism, with a relative risk reduction of 61% (95% CI 47%–71%, P < .05) compared with placebo.^29,35 An INR of 2 to 3 is recommended for patients with nonvalvular atrial fibrillation, and those with atrial fibrillation and either a bioprosthetic valve or rheumatic heart disease. In contrast, an INR of 2.5 to 3.5 is recommended for patients with atrial fibrillation and mechanical valves in the aortic or mitral positions.^1,36

An INR of 2 to 3 offers maximum protection with minimal risk of bleeding

Stroke prevention with warfarin is most effective when the achieved mean time in the therapeutic range is at least 70%. The risk of intracranial hemorrhage increases significantly at INRs higher than 3. An INR of 2 to 3 offers maximum protection with minimal risk of bleeding.^37,38 Systematic follow-up of patients through anticoagulation clinics produces better compliance and control and is encouraged.

TARGET-SPECIFIC ORAL ANTICOAGULANTS

Although effective, warfarin requires frequent monitoring and dosage adjustment, has a delayed onset and protracted offset, and interacts with commonly consumed vitamin K–containing foods and frequently used drugs. These drawbacks prompted evaluation of existing antiplatelet agents, in combination or in conjunction with lower adjusted or fixed-dose warfarin. These regimens proved inferior,^39–42 spurring interest in developing alternative oral anticoagulants.

TSOACs act by directly inhibiting thrombin (factor IIa) or by reducing thrombin production indirectly by inhibiting factor Xa. Three TSOACs are approved. Each was compared with adjusted-dose warfarin in randomized controlled trials.

Dabigatran

Dabigatran etexilate was the first TSOAC approved in the United States.

Pharmacokinetics. Dabigatran etexilate has a bioavailability of 3% to 7% after oral administration. Its absorption is enhanced in an acidic gastric environment and is limited by P-glycoprotein-facilitated transport out of enterocytes. Dabigatran etexilate is hydrolyzed to its active metabolite dabigatran, which directly inhibits thrombin. Maximal plasma drug concentration and peak anticoagulant effect are achieved within 0.5 to 2 hours after administration.

Dabigatran is predominantly excreted by the kidneys, and has a half-life of 12 to 17 hours in patients with normal renal function. The half-life extends to 27 hours in those with moderately severe renal impairment (creatinine clearance 15–30 mL/min). The recommended dose of 150 mg twice daily should be reduced to 75 mg twice daily in patients with a creatinine clearance of 15 to 30 mL/min. This drug is contraindicated in patients with a creatinine clearance less than 15 mL/min.^43,44

Efficacy. The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial⁴⁵ randomly assigned 18,113 patients with nonvalvular atrial fibrillation at risk of thromboembolism (mean CHADS₂ score 2.1) to receive either dabigatran (either 150 mg twice daily or 110 mg twice daily) or warfarin (adjusted to an INR of 2.0 to 3.0). Of note, the lower approved dose of dabigatran (75 mg twice daily) was not tested in RE-LY.

At 2 years, higher-dose dabigatran was significantly more effective than both warfarin (RR 0.65, 95% CI 0.52–0.81, P < .05) and lower-dose dabigatran (RR 0.73, 95% CI 0.58–0.91, P < .05) in reducing the rate of systemic embolic events.

The risk of combined major bleeding events was no different with higher-dose dabigatran than with warfarin (RR 0.93, 95% CI 0.81–1.07, P < .05), but the rate of hemorrhagic stroke was significantly less with dabigatran than with warfarin (RR 0.26, 95% CI 0.14–0.49, P < .05). Higher rates of major gastrointestinal bleeding and dyspepsia occurred with dabigatran.

Post hoc analysis found more myocardial infarctions with dabigatran than with warfarin

Concern about the safety of dabigatran was raised when post hoc evaluation of RE-LY found a higher incidence of myocardial infarction with dabigatran than with warfarin (RR 1.38, 95% CI 1–1.91, P = .048).⁴⁶ Corroborating data were reported by Uchino and Hernandez,⁴⁷ comparing dabigatran with either warfarin or low-molecular-weight heparin. However, without directly comparing dabigatran and placebo, it is unclear whether the small increase in myocardial infarction reflects a direct effect of dabigatran or absence of a protective effect of warfarin or low-molecular-weight heparin.

Rivaroxaban

Rivaroxaban is a direct factor Xa inhibitor that blocks the amplified burst of thrombin production and in turn inhibits platelet aggregation and thrombus formation.

Pharmacokinetics. Rivaroxaban’s oral bioavailability is 80% to 100% after a single 15- or 20-mg dose taken with food. Its maximal anticoagulant effect is achieved within 2 hours. Two-thirds of the active drug is metabolized by either CYP450-dependent (CYP3A4, 2J2) or CYP-independent mechanisms; the inactive drug is then excreted in the urine and feces. The remaining, active drug is removed by the kidneys using the P-glycoprotein transporter.

The half-life of rivaroxaban is 5 to 9 hours. The recommended dosage of 20 mg daily should be reduced to 15 mg daily if the creatinine clearance rate is 30 to 50 mL/min, or to 10 mg if the creatinine clearance rate is 15 to 30 mL/min. Rivaroxaban is contraindicated in patients whose creatinine clearance rate is less than 15 mL/min.^48–52

Efficacy and safety. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF),⁵³ 14,264 at-risk patients with nonvalvular atrial fibrillation (mean CHADS₂ score 3.5) were randomly assigned to receive either rivaroxaban 20 mg daily (or 15 mg daily if their creatinine clearance was 30–49 mL/min; the lowest dose of rivaroxaban, 10 mg, was not studied in this trial) or warfarin (target INR 2.0–3.0). Outcomes with rivaroxaban compared with warfarin:

• Systemic embolism:
  HR 0.79, 95% CI 0.66–0.96, P < .01, noninferiority
• Total bleeding: no difference
• Intracranial bleeding:
  HR 0.67, 95% CI 0.47–0.93, P = .02
• Fatal bleeding:
  HR 0.50, 95% CI 0.31–0.79, P = .003
• Major gastrointestinal bleeding:
  3.2% vs 2.2%, P < .001.

Apixaban

Apixaban is also a direct factor Xa inhibitor.

Pharmacokinetics. Apixaban’s oral bioavailability is 50%, with maximal blood concentration achieved at 3 to 4 hours. One-quarter of the drug is metabolized via CYP3A4. The remaining active drug is excreted by the kidneys and biliary/intestinal system via the P-glycoprotein transporter. Apixaban’s half-life is 9 to 14 hours.

Target-specific oral anticoagulants have no approved antidotes, but several have been suggested

The recommended dosage is 5 mg twice daily, but it should be reduced to 2.5 mg twice daily if at least two of the following characteristics are present: age 80 or older, weight 60 kg or less, and serum creatinine 1.5 mg/dL or more.^54,55

Efficacy and safety. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial⁵⁶ enrolled 18,201 patients with nonvalvular atrial fibrillation (mean CHADS₂ score 2.1) randomly assigned to receive either apixaban (5 mg twice daily with dosage reduction to 2.5 mg twice daily as noted above) or warfarin (target INR 2.0–3.0).

Compared with warfarin, apixaban was associated with lower risk of:

• Systemic embolism
  (HR 0.79, 95% CI 0.66–0.95, P = .01)
• Major bleeding
  (HR 0.69, 95% CI 0.60–0.80, P < .001)
• Intracranial hemorrhage
  (HR 0.42, 95% CI 0.30–0.58, P < .001)
• All-cause mortality
  (HR 0.89 95% CI 0.80–0.99, P = .047).

Drug interactions with the novel oral anticoagulants

TSOACs were developed with the intent to avoid many of the shortcomings of warfarin. Each has a broader therapeutic window and a rapid onset of action, enabling fixed dosing without need for serial monitoring. Compared with warfarin, they have significantly fewer dietary and drug interactions.

Nonetheless, drug interactions do exist and are important to recognize (Tables 1–3). These primarily result from inhibition or induction of cytochrome P450 enzyme activity or P-glycoprotein transporter action, involved in metabolism and elimination of active drug.

Reversibility of the target-specific oral anticoagulants

While the anticoagulant effects of warfarin can be reversed by vitamin K, fresh-frozen plasma, and prothrombin complex concentrate, TSOACs have no currently approved antidotes. Management of bleeding due to these agents was recently reviewed in this journal by Fawole et al.⁵⁷

Several nonspecific hemostatic agents have been suggested, including recombinant factor VIIa or prothrombin complex concentrates. The anticoagulant effect of rivaroxaban has been shown to be reversed by prothrombin complex concentrate in vitro; clinical effect has not been demonstrated.⁵⁸ PRT06445 (andexanet alfa), a recombinant protein antidote specific for factor Xa inhibitors, has entered clinical studies, with a phase 2 trial reporting high reversing capability for apixaban.⁵⁹

Unlike rivaroxaban and apixaban, which are highly bound to plasma protein, dabigatran can be effectively removed with hemodialysis. Liesenfeld et al⁶⁰ showed that longer dialysis duration was the most relevant variable for reducing dabigatran plasma levels. Current clinical experience is limited, and standard recommendations and formal guidance are lacking.

Switching oral anticoagulants

Suggested approaches for switching between anticoagulants are listed in Table 4.⁶¹

CHOOSING ANTITHROMBOTIC THERAPY

In valvular atrial fibrillation: warfarin

Anticoagulation with warfarin is advised for valvular atrial fibrillation. Patients with bioprosthetic heart valves or rheumatic valvular disease were not evaluated in randomized controlled trials of TSOACs. Dabigatran in particular is contraindicated in patients with mechanical heart valves, as the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement (RE-ALIGN)⁶² found higher rates of stroke, valve-related thrombosis, and myocardial infarction in patients receiving dabigatran.

In nonvalvular atrial fibrillation

According to the 2014 guidelines,¹ oral anticoagulation is preferred in all patients with nonvalvular atrial fibrillation but those at lowest risk (CHA₂DS₂-VASc = 0).

Experience with TSOACs is lacking in patients with end-stage kidney disease (creatinine clearance < 15 mL/min), and warfarin is advised in this group.

TSOACs are recommended in patients with nonvalvular atrial fibrillation in whom therapeutic INR levels cannot be maintained with warfarin. For most patients with nonvalvular atrial fibrillation, TSOACs are an option equivalent to warfarin. Anticoagulant choice is largely driven by dosing convenience, out-of-pocket cost for treatment with a TSOAC, and ready availability of antidotes for warfarin in case of bleeding (Tables 5 and 6).

In patients with nonvalvular atrial fibrillation, TSOACs are as effective as warfarin in preventing systemic thromboembolism, and some of them have been shown to be superior in terms of lower rates of ischemic stroke (dabigatran), systemic embolism (apixaban), and mortality (apixaban; trend for dabigatran). All TSOACs demonstrate modestly favorable bleeding risk profiles compared with warfarin, with lower risk of intracranial hemorrhage. Potential differences in efficacy and safety among TSOACs are unknown since there have been no randomized direct comparisons between them. A summary of landmark trial results and assessment of the advantages and disadvantages of each are listed in Table 7.

Two groups of patients with nonvalvular atrial fibrillation warrant special consideration: 

Patients with hypertrophic cardiomyopathy. There are no randomized controlled trials of anticoagulation therapy in patients with hypertrophic cardiomyopathy; however, because of their high risk of thromboembolism, anticoagulation is indicated irrespective of the  CHA₂DS₂-VASc score. TSOACs are an option as an alternative to warfarin.

Patients with coronary artery disease and an indication for antiplatelet therapy. In this group the decision for concurrent anticoagulation is guided by the CHA₂DS₂-VASc score. For patients who have intracoronary stents, dual antiplatelet therapy is the standard of care for reducing risk of cardiovascular events after stent implantation.⁶³ When triple therapy (ie, two antiplatelet drugs and an anticoagulant) is indicated, such as after intracoronary stent placement, the guidelines suggest trying to minimize the duration of triple therapy. For instance, a bare-metal stent may be preferred. Alternatively, after coronary revascularization, it may be reasonable to use clopidogrel 75 mg daily with an oral anticoagulant and to omit aspirin.

Interrupting and bridging anticoagulation

Patients with atrial fibrillation often require suspension of anticoagulation, most commonly before an elective invasive procedure. The duration of interruption, timing of resumption, and need for bridging anticoagulation are guided by clinical judgment, which considers risk of thromboembolism and severity of procedure-related bleeding risk.

In general, if therapy needs to be interrupted, it should be restarted as soon as possible

In general, if therapy needs to be interrupted, it should be restarted as soon as possible. Short-term interruption does not seem to be associated with clinically significant risk of thromboembolic events, whereas postoperative heparin bridging therapy increases the risk of hematoma with implantation of a cardiac electronic device.^64,65

To date, evidence is lacking to advise upon periprocedure bridging anticoagulation. The Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) study (NCT00786474)— enrolling chronically anticoagulated patients undergoing an invasive procedure to randomly receive placebo or bridging low-molecular-weight heparin—may provide guidance.

Currently, it is common practice in low-risk patients undergoing an invasive procedure with significant bleeding risk to interrupt anticoagulation for up to 1 week without bridging. Warfarin is typically held 3 to 5 days, while TSOACs are held for 24 hours if renal function is preserved or up to 2 to 3 days if renal function is severely impaired (creatinine clearance 15–30 mL/min). If complete hemostasis is necessary, it could be confirmed by a normalized INR (for warfarin), activated partial thromboplastin time (dabigatran), or prothrombin time (apixaban or rivaroxaban).

For patients at high risk (valvular atrial fibrillation or CHA₂DS₂-VASc ≥ 2), bridging with unfractionated heparin or low-molecular-weight heparin during periods of subtherapeutic anticoagulation is common. Alternatively, it is becoming increasingly common to perform cardiac electronic device implantation, catheter ablation, and coronary angiography and intervention without interrupting anticoagulation.^66–72

Recently, concern has been raised over a possible increase in thromboembolism upon discontinuation of rivaroxaban and apixaban. ROCKET-AF reported a spike in thrombotic events in the rivaroxaban-treated group at the end of the trial (HR 1.50, 95% CI 1.05–2.15, P = .026). This raised concern for a possible “rebound” effect upon drug cessation. Yet a post hoc analysis of ROCKET-AF demonstrated that events clustered in the rivaroxaban-treated cohort who completed the study and were transitioning to open-label warfarin, and this alone accounted for the rise in stroke occurrence. In contrast, there was no increase in the cohort of patients treated with rivaroxaban who either temporarily interrupted or permanently discontinued the drug.⁷³ The authors concluded that increased stroke was the consequence of transiently interrupted anticoagulation, rather than a rebound prothrombotic effect. Similar results were reported in ARISTOTLE.

Another possibility is that, during the transition to warfarin therapy, transient hypercoagulability could be a function of warfarin. Azoulay et al⁷⁴ observed in a large cohort that warfarin was associated with a 71% increased risk of stroke in the first 30 days after initiation, compared with decreased risk thereafter. Nevertheless, there is now a black- box warning recommendation for all three TSOACs that if discontinuation is required for a reason other than pathological bleeding, bridging with another anticoagulant should  at least be considered.

The perioperative management of the TSOACs was recently reviewed in this journal by Anderson et al.⁷⁵

WEIGHING THE RISKS OF STROKE AND BLEEDING

Stroke is the most feared complication in patients with atrial fibrillation. Risk reduction is an important goal in management, yet decisions for individuals must take into account both stroke and bleeding risks related to antithrombotic therapy.

In deciding whether to start anticoagulation, weigh the risk of both stroke and bleeding

The 2014 guidelines¹ differ from past versions. First, they endorse the use of CHA₂DS₂-VASc for categorizing stroke risk in patients with nonvalvular atrial fibrillation. This in turn guides antithrombotic therapy. This scheme effectively identifies patients at very low risk of stroke (men with a score of 0, women with a score of 0 or 1), in whom it is reasonable to omit antithrombotic therapy. For all patients with valvular heart disease or hypertrophic cardiomyopathy, unless bleeding risk is prohibitive, anticoagulation is recommended irrespective of the CHA₂DS₂-VASc score. Second, they incorporate the TSOACs, which offer convenience and improved safety in select patients.

While the guidelines mention the potential relevance of subclinical atrial tachyarrhythmias as they pertain to stroke risk, there is no specific recommendation as to their management. We do take into consideration the finding of atrial high-rate events (≥ 180 bpm, ≥ 6 minutes in duration) diagnostically confirmed by cardiac implantable electronic devices or telemetric monitoring, particularly in patients with a clinical profile of high stroke risk. In addition, atriopathy with increased left atrial size and renal insufficiency, as discussed in this review, appear to correlate with greater risk of thromboembolism, yet neither is a component of the stroke risk scheme endorsed by the guidelines.

Other risk factors, some unknown to us, undoubtedly exist. Again, our empiric judgment is to at least consider these nontraditional risk factors while guided primarily by the CHA₂DS₂-VASc score when assessing stroke risk in patients with atrial fibrillation.

The goal in managing patients with atrial fibrillation is to balance thromboembolic risk reduction with the risk of bleeding associated with antithrombotic therapy.  

Antithrombotic therapy reduces the risk of systemic embolism in patients with atrial fibrillation, but one approach does not suit all patients. The decision whether to start this therapy—and which agent to use—must take into account the patient’s risk of thromboembolism as well as bleeding.

Antithrombotic therapy encompasses antiplatelet drugs such as aspirin and clopidogrel and anticoagulants such as warfarin and the target-specific oral anticoagulants (TSOACs). Oral anticoagulation is more effective than antiplatelet therapy and is preferred in all but those at lowest risk, in whom either antiplatelet therapy or no therapy is deemed adequate.

Patients with valvular atrial fibrillation, specifically those who have rheumatic mitral stenosis or a prosthetic heart valve, are at significantly higher risk of systemic embolization. Their overall risk-benefit profile is nearly always in favor of anticoagulation. But the same is not necessarily true for patients with nonvalvular atrial fibrillation.

The following discussion sets forth our rationale for clinical decision-making, based on recommendations in the 2014 guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society.¹ The second half of this review outlines the oral anticoagulants currently available.

ONE IN FOUR PEOPLE

Atrial fibrillation is common, with an incidence that increases with age. It affects more than 10% of people over age 80 and is often  associated with cardiovascular disease.² Based on Framingham Heart Study data, a person’s lifetime risk of developing it is about 25%.³

FIVEFOLD RISK OF STROKE

The most serious complication of atrial fibrillation is arterial thromboembolism, of which ischemic stroke is the most common and most feared manifestation. The risk of stroke is five times higher than normal in patients with atrial fibrillation.³ More than 15% of strokes may be attributable to atrial fibrillation, and the proportion increases with age.⁴

The risk of thromboembolism appears to be similar in patients with clinically manifest atrial fibrillation irrespective of the type (paroxysmal, persistent, or permanent). The Stroke Prevention in Atrial Fibrillation (SPAF) study⁵ and the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W)⁶ showed that patients who had paroxysmal atrial fibrillation and at least one risk factor for thromboembolism had stroke rates comparable to those of their counterparts who had persistent and permanent atrial fibrillation.

Subclinical atrial fibrillation may be an important cause of stroke. Clinically silent episodes can be detected by implantable electronic devices, which record episodes of atrial tachyarrhythmia (atrial high-rate events).  Subclinical episodes have been detected in 10% to 28% of monitored patients who did not have a history of atrial fibrillation.^7,8 Patients who have atrial high-rate events detected by implantable devices have a higher risk of future clinically manifest atrial fibrillation, thromboembolic events, or both.^7–9 Yet characteristics of atrial high-rate episodes that predict risk are not well defined and warrant further investigation.

CLINICAL RISK FACTORS FOR STROKE

To date, thousands of patients with nonvalvular atrial fibrillation have participated in randomized clinical trials of stroke prevention. The placebo groups from these trials provide a sizable database for retrospectively identifying clinical characteristics associated with thromboembolism. The Atrial Fibrillation Investigators¹⁰ pooled data from five large trials and found that risk factors consistently associated with stroke in multivariate analysis included diabetes mellitus, hypertension, prior systemic embolism, and advanced age.

Though the risk of stroke increases with age with no lower limit, most studies identify age 65 as a threshold, with further escalating risk after age 75. Moreover, women were observed to be at higher risk in some but not all studies. These risk factors have become components of commonly used risk-stratification schemes.

Hypertrophic cardiomyopathy. Maron et al¹¹ reported that atrial fibrillation in patients with hypertrophic cardiomyopathy was independently associated with thromboembolism. In 900 patients with hypertrophic cardiomyopathy, the prevalence of systemic embolism was 6%. Patients with hypertrophic cardiomyopathy and a thromboembolic complication were seven times more likely to have atrial fibrillation than matched counterparts free of thromboembolism. A notable subset of patients experienced a stroke or embolic event before age 50, and the authors advised that the risk of thromboembolism should be considered in patients of any age with hypertrophic cardiomyopathy and atrial fibrillation.

Olivotto et al¹² similarly found patients with hypertrophic cardiomyopathy and atrial fibrillation to be at significantly greater risk of stroke (odds ratio [OR] 17.7, 95% confidence interval [CI] 4.1–75.9, P < .001).

Chronic kidney disease is also associated with a higher risk of thromboembolism in patients with atrial fibrillation. A glomerular filtration rate of 60 mL/min or less is independently and inversely predictive of risk.^13,14

While patients with end-stage renal disease have been largely excluded from stroke prevention trials, Vázquez et al¹⁵ prospectively followed 190 dialysis patients for 12 months. In multivariate analysis, compared with matched controls without documented atrial fibrillation, patients receiving renal replacement therapy and having any form of atrial fibrillation were eight times more likely to have systemic embolization.

IMAGING-BASED RISK FACTORS

In addition to clinical factors, several imaging-based factors have been associated with stroke risk in patients with atrial fibrillation.

Complex aortic atheroma or markers of blood stasis within the left atrium, such as reduced left atrial appendage emptying flow (< 20 cm/second), dense spontaneous echo contrast, or left atrial appendage thrombus, seen on transesophageal echocardiography, were independently associated with increased systemic embolic risk in the third SPAF substudy.¹⁶ Moreover, multivariate analysis of SPAF data found both left ventricular dysfunction of any severity and increased left atrial size (diameter corrected for body surface area by M-mode > 2.5 cm/m2) to be independent predictors of thromboembolism.¹⁷

Although enlargement of the left atrium has not been incorporated into traditional risk stratification schemes, data from Osranek et al¹⁸ further implicate it as a marker of risk. The cohort was small (N = 46), but consisted of patients with lone atrial fibrillation followed for nearly 30 years. Patients with normal left atrial size enjoyed a benign course, while those with left atrial enlargement (> 32 mL/m²) at diagnosis or later during follow-up had significantly worse event-free survival (hazard ratio [HR] 4.46, 95% CI 1.56–12.74, P < .01). All embolic strokes occurred in the group with left atrial enlargement.

RISK STRATIFICATION SCHEMES

Several models for predicting systemic embolism risk in patients with nonvalvular atrial fibrillation have been proposed and validated.

The CHADS₂ score has been the most widely applied, being simple to use.^19,20 It assigns 1 point each for Congestive heart failure, Hypertension, Age 75 or older, and Diabetes, and 2 points for prior Stroke or systemic thromboembolism.

In patients with chronic nonvalvular atrial fibrillation, Gage et al¹⁹ reported that the stroke rate was lowest in those with a score of 0, with an annual adjusted stroke rate of 1.9% per year, and highest in those with the maximal possible score (ie, 6), with a rate of 18.2%. The rate increased by a factor of 1.5 with each point in the CHADS₂ score.

CHA₂DS₂-VASc. Endorsed for use in both the American and European guidelines,^1,21 CHA₂DS₂-VASc is an extension of CHADS₂. Points are assigned as follows:

• Congestive heart failure or left ventricular dysfunction (moderate to severe left ventricular dysfunction or recent heart failure exacerbation requiring hospitalization irrespective of ejection fraction): 1 point
• Hypertension: 1 point
• Age ≥ 75: 2 points; age 65–74: 1 point
• Diabetes mellitus: 1 point
• Stroke, transient ischemic attack, or thromboembolism: 2 points
• Vascular disease (prior myocardial infarction, peripheral arterial disease, or aortic plaque): 1 point
• Sex, female: 1 point
• Maximum score: 9 points.

Low risk is defined as a score of 0 for a man or, for a woman with no other risk factors, 1. A score of 1 for a man indicates moderate risk, and a score of 2 or more is high risk. Lip et al²² found that, in untreated patients with nonvalvular atrial fibrillation, rates of stroke ranged from 0 with a score of 0 to 15.2% per year with a score of 9 points.

In a large cohort with over 11,000 patient-years of follow-up, 98% of the thromboembolic events occurred in people with a CHA₂DS₂-VASc score of 2 or more. Moreover, more than 99% of patients with a score of less than 2 were free of stroke and thromboembolism.²³

Compared with CHADS₂, CHA₂DS₂-VASc has superior negative predictive power

Compared with the CHADS₂ score, CHA₂DS₂-VASc has superior negative predictive power. Of 1,084 patients from the European Heart Survey for Atrial Fibrillation, the newer scheme classified significantly fewer patients as being at either low risk (score of 0; 9% vs 20%) or intermediate risk (score of 1; 15% vs 35%).²³ Though the overall rate of stroke was low, those categorized as being at low or intermediate risk by CHA₂DS₂-VASc had significantly fewer thromboembolic events than their counterparts according to CHADS₂ (0.6% vs 3.3%).

Olesen et al²⁴ similarly showed that in patients with a CHADS₂ score of 0, reclassification by CHA₂DS₂-VASc yielded a range of annual stroke rates from 0.84% with a score of 0 up to 3.2% with a score of 3.

RISK-BASED ANTITHROMBOTIC THERAPY IN NONVALVULAR ATRIAL FIBRILLATION

The 2014 atrial fibrillation guidelines¹ state that the decision to give antithrombotic therapy for atrial fibrillation should be individualized, based on the absolute and relative risks of stroke and bleeding, and ought to take into consideration the patient’s preferences. For patients with nonvalvular atrial fibrillation, selection of antithrombotic therapy should take into account the risk of thromboembolism determined by the CHA₂DS₂-VASc score and be irrespective of the pattern of atrial fibrillation (paroxysmal, persistent, or permanent). Antithrombotic therapy is similarly recommended for patients with atrial flutter, according to the same risk profile used for atrial fibrillation.

Studies have consistently shown^24–27 that the risk of ischemic stroke without anticoagulation exceeds the risk of intracranial bleeding with anticoagulation in nearly all patients except those at lowest risk of thromboembolism. The CHA₂DS₂-VASc score better identified those at truly low risk, in whom treatment may offer more risk than benefit.^24–27

The HAS-BLED score²⁸ assigns points as follows:

• Hypertension (systolic blood pressure > 160 mm Hg): 1 point
• Abnormal renal function (dialysis, renal transplantation, or serum creatinine > 2.6 mg/mL) or liver function (cirrhosis, bilirubin more than two times the upper limit, or aminotransferase levels more than three times the upper limit): 1 or 2 points
• Stroke: 1 point
• Bleeding (prior major bleeding event or predisposition to bleeding): 1 point
• Labile international normalized ratio (INR) (supratherapeutic or time in therapeutic range < 60%): 1 point
• Elderly (age > 65): 1 point
• Drugs (antiplatelet, nonsteroidal anti-inflammatory) or alcohol (more than eight drinks per week): 1 or 2 points
• Maximum total: 9 points.

HAS-BLED is a practical and validated approach for estimating bleeding risk and is mentioned in the guidelines, but it is not recommended for use in guiding decisions about antithrombotic therapy. Specifically, it should not be used to exclude patients, but rather to identify those at high risk (score ≥ 3) who may require closer observation and more attentive monitoring of the INR.

ANTITHROMBOTIC THERAPY

Antithrombotic agents available for use in the United States include antiplatelet drugs (eg, aspirin and clopidogrel) and anticoagulants (unfractionated heparin and low-molecular-weight heparin, vitamin K antagonists such as warfarin, and direct thrombin and factor Xa inhibitors). Anticoagulation has been shown in randomized controlled trials to be superior to both placebo and antiplatelet agents used either alone or in combination.²⁹

Aspirin has been downgraded

Aspirin has been compared with placebo in seven randomized controlled trials. Only the original SPAF study, in which aspirin 325 mg/day was used, found that it was beneficial. This result alone accounted for the 19% reduction in relative risk (95% CI 1%–35%, P < .05) in a meta-analysis performed by Hart et al.²⁹ Even when combined with clopidogrel 75 mg/day, aspirin 75 to 100 mg/day is still inferior to warfarin.⁵ While dual antiplatelet therapy resulted in a 28% relative reduction in thromboembolism (95% CI 17%–38%, P < .01) compared with aspirin alone, major bleeding significantly increased by 57% (95% CI 29%–92%, P < .01).

Although aspirin may be beneficial, differences among patients may influence its efficacy. It may be more effective in preventing noncardioembolic stroke, particularly in diabetic and hypertensive patients.^30,31 To date, aspirin has not been shown to be beneficial in low-risk populations.

The 2014 guidelines downgraded the recommendation for aspirin therapy. For patients at low risk and for some at intermediate risk, it is permissible to forgo therapy altogether, including aspirin.¹

ORAL ANTICOAGULANTS

The rest of this paper reviews the oral anticoagulants that are approved for reducing the risk of thromboembolism in atrial fibrillation, focusing on each agent’s mechanism of action, pharmacokinetics, clinical efficacy, and safety.

WARFARIN, A VITAMIN K ANTAGONIST

Warfarin inhibits synthesis of vitamin K-dependent clotting factors (ie, factors II, VII, IX, and X) and proteins C and S by inhibiting the C1 subunit of vitamin K epoxide reductase, thereby interfering with production of vitamin K₁ epoxide and consequent regeneration of vitamin K.

Pharmacokinetics. Warfarin is nearly completely absorbed after oral administration. Its anticoagulant effect can be seen within 24 hours of administration, but its peak effect is typically apparent only after 72 hours. Elimination occurs predominantly through metabolism by cytochrome P450 enzymes, principally CYP2C9. Its effective half-life ranges from 20 to 60 hours, with a mean of 40 hours.³²

Warfarin’s effect, dosage, and bleeding risk are influenced by multiple factors, including vitamin K-containing foods such as green leafy vegetables, medications that either inhibit or induce hepatic cytochrome P450 enzymes, and polymorphisms in the VKORC1 and CYP2C9 genes.³²

Reversal. Warfarin’s anticoagulant effect is reversed with vitamin K, but this reversal may not become apparent for 6 to 24 hours. In contrast, fresh-frozen plasma and prothrombin protein concentrate, which contain clotting factors, reverse warfarin immediately. Currently, a three-factor prothrombin protein concentrate (factors II, IX, and X) and a four-factor concentrate (factors II, VII, IX, and X plus proteins C and S) are available in the United States. Although prothrombin protein concentrate works rapidly and has a lower volume of administration, available data do not indicate it is clinically superior to fresh-frozen plasma.^33,34 The ongoing randomized PROTECT trial (NCT00618098), comparing fresh-frozen plasma and four-factor prothrombin protein concentrate for reversal of vitamin K antagonist therapy, may provide further insight.

Efficacy and safety. Randomized controlled trials in patients with nonvalvular atrial fibrillation have shown that warfarin (in doses adjusted to maintain an INR greater than 2) is highly efficacious in preventing systemic embolism, with a relative risk reduction of 61% (95% CI 47%–71%, P < .05) compared with placebo.^29,35 An INR of 2 to 3 is recommended for patients with nonvalvular atrial fibrillation, and those with atrial fibrillation and either a bioprosthetic valve or rheumatic heart disease. In contrast, an INR of 2.5 to 3.5 is recommended for patients with atrial fibrillation and mechanical valves in the aortic or mitral positions.^1,36

An INR of 2 to 3 offers maximum protection with minimal risk of bleeding

Stroke prevention with warfarin is most effective when the achieved mean time in the therapeutic range is at least 70%. The risk of intracranial hemorrhage increases significantly at INRs higher than 3. An INR of 2 to 3 offers maximum protection with minimal risk of bleeding.^37,38 Systematic follow-up of patients through anticoagulation clinics produces better compliance and control and is encouraged.

TARGET-SPECIFIC ORAL ANTICOAGULANTS

Although effective, warfarin requires frequent monitoring and dosage adjustment, has a delayed onset and protracted offset, and interacts with commonly consumed vitamin K–containing foods and frequently used drugs. These drawbacks prompted evaluation of existing antiplatelet agents, in combination or in conjunction with lower adjusted or fixed-dose warfarin. These regimens proved inferior,^39–42 spurring interest in developing alternative oral anticoagulants.

TSOACs act by directly inhibiting thrombin (factor IIa) or by reducing thrombin production indirectly by inhibiting factor Xa. Three TSOACs are approved. Each was compared with adjusted-dose warfarin in randomized controlled trials.

Dabigatran

Dabigatran etexilate was the first TSOAC approved in the United States.

Pharmacokinetics. Dabigatran etexilate has a bioavailability of 3% to 7% after oral administration. Its absorption is enhanced in an acidic gastric environment and is limited by P-glycoprotein-facilitated transport out of enterocytes. Dabigatran etexilate is hydrolyzed to its active metabolite dabigatran, which directly inhibits thrombin. Maximal plasma drug concentration and peak anticoagulant effect are achieved within 0.5 to 2 hours after administration.

Dabigatran is predominantly excreted by the kidneys, and has a half-life of 12 to 17 hours in patients with normal renal function. The half-life extends to 27 hours in those with moderately severe renal impairment (creatinine clearance 15–30 mL/min). The recommended dose of 150 mg twice daily should be reduced to 75 mg twice daily in patients with a creatinine clearance of 15 to 30 mL/min. This drug is contraindicated in patients with a creatinine clearance less than 15 mL/min.^43,44

Efficacy. The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial⁴⁵ randomly assigned 18,113 patients with nonvalvular atrial fibrillation at risk of thromboembolism (mean CHADS₂ score 2.1) to receive either dabigatran (either 150 mg twice daily or 110 mg twice daily) or warfarin (adjusted to an INR of 2.0 to 3.0). Of note, the lower approved dose of dabigatran (75 mg twice daily) was not tested in RE-LY.

At 2 years, higher-dose dabigatran was significantly more effective than both warfarin (RR 0.65, 95% CI 0.52–0.81, P < .05) and lower-dose dabigatran (RR 0.73, 95% CI 0.58–0.91, P < .05) in reducing the rate of systemic embolic events.

The risk of combined major bleeding events was no different with higher-dose dabigatran than with warfarin (RR 0.93, 95% CI 0.81–1.07, P < .05), but the rate of hemorrhagic stroke was significantly less with dabigatran than with warfarin (RR 0.26, 95% CI 0.14–0.49, P < .05). Higher rates of major gastrointestinal bleeding and dyspepsia occurred with dabigatran.

Post hoc analysis found more myocardial infarctions with dabigatran than with warfarin

Concern about the safety of dabigatran was raised when post hoc evaluation of RE-LY found a higher incidence of myocardial infarction with dabigatran than with warfarin (RR 1.38, 95% CI 1–1.91, P = .048).⁴⁶ Corroborating data were reported by Uchino and Hernandez,⁴⁷ comparing dabigatran with either warfarin or low-molecular-weight heparin. However, without directly comparing dabigatran and placebo, it is unclear whether the small increase in myocardial infarction reflects a direct effect of dabigatran or absence of a protective effect of warfarin or low-molecular-weight heparin.

Rivaroxaban

Rivaroxaban is a direct factor Xa inhibitor that blocks the amplified burst of thrombin production and in turn inhibits platelet aggregation and thrombus formation.

Pharmacokinetics. Rivaroxaban’s oral bioavailability is 80% to 100% after a single 15- or 20-mg dose taken with food. Its maximal anticoagulant effect is achieved within 2 hours. Two-thirds of the active drug is metabolized by either CYP450-dependent (CYP3A4, 2J2) or CYP-independent mechanisms; the inactive drug is then excreted in the urine and feces. The remaining, active drug is removed by the kidneys using the P-glycoprotein transporter.

The half-life of rivaroxaban is 5 to 9 hours. The recommended dosage of 20 mg daily should be reduced to 15 mg daily if the creatinine clearance rate is 30 to 50 mL/min, or to 10 mg if the creatinine clearance rate is 15 to 30 mL/min. Rivaroxaban is contraindicated in patients whose creatinine clearance rate is less than 15 mL/min.^48–52

Efficacy and safety. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF),⁵³ 14,264 at-risk patients with nonvalvular atrial fibrillation (mean CHADS₂ score 3.5) were randomly assigned to receive either rivaroxaban 20 mg daily (or 15 mg daily if their creatinine clearance was 30–49 mL/min; the lowest dose of rivaroxaban, 10 mg, was not studied in this trial) or warfarin (target INR 2.0–3.0). Outcomes with rivaroxaban compared with warfarin:

• Systemic embolism:
  HR 0.79, 95% CI 0.66–0.96, P < .01, noninferiority
• Total bleeding: no difference
• Intracranial bleeding:
  HR 0.67, 95% CI 0.47–0.93, P = .02
• Fatal bleeding:
  HR 0.50, 95% CI 0.31–0.79, P = .003
• Major gastrointestinal bleeding:
  3.2% vs 2.2%, P < .001.

Apixaban

Apixaban is also a direct factor Xa inhibitor.

Pharmacokinetics. Apixaban’s oral bioavailability is 50%, with maximal blood concentration achieved at 3 to 4 hours. One-quarter of the drug is metabolized via CYP3A4. The remaining active drug is excreted by the kidneys and biliary/intestinal system via the P-glycoprotein transporter. Apixaban’s half-life is 9 to 14 hours.

Target-specific oral anticoagulants have no approved antidotes, but several have been suggested

The recommended dosage is 5 mg twice daily, but it should be reduced to 2.5 mg twice daily if at least two of the following characteristics are present: age 80 or older, weight 60 kg or less, and serum creatinine 1.5 mg/dL or more.^54,55

Efficacy and safety. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial⁵⁶ enrolled 18,201 patients with nonvalvular atrial fibrillation (mean CHADS₂ score 2.1) randomly assigned to receive either apixaban (5 mg twice daily with dosage reduction to 2.5 mg twice daily as noted above) or warfarin (target INR 2.0–3.0).

Compared with warfarin, apixaban was associated with lower risk of:

• Systemic embolism
  (HR 0.79, 95% CI 0.66–0.95, P = .01)
• Major bleeding
  (HR 0.69, 95% CI 0.60–0.80, P < .001)
• Intracranial hemorrhage
  (HR 0.42, 95% CI 0.30–0.58, P < .001)
• All-cause mortality
  (HR 0.89 95% CI 0.80–0.99, P = .047).

Drug interactions with the novel oral anticoagulants

TSOACs were developed with the intent to avoid many of the shortcomings of warfarin. Each has a broader therapeutic window and a rapid onset of action, enabling fixed dosing without need for serial monitoring. Compared with warfarin, they have significantly fewer dietary and drug interactions.

Nonetheless, drug interactions do exist and are important to recognize (Tables 1–3). These primarily result from inhibition or induction of cytochrome P450 enzyme activity or P-glycoprotein transporter action, involved in metabolism and elimination of active drug.

Reversibility of the target-specific oral anticoagulants

While the anticoagulant effects of warfarin can be reversed by vitamin K, fresh-frozen plasma, and prothrombin complex concentrate, TSOACs have no currently approved antidotes. Management of bleeding due to these agents was recently reviewed in this journal by Fawole et al.⁵⁷

Several nonspecific hemostatic agents have been suggested, including recombinant factor VIIa or prothrombin complex concentrates. The anticoagulant effect of rivaroxaban has been shown to be reversed by prothrombin complex concentrate in vitro; clinical effect has not been demonstrated.⁵⁸ PRT06445 (andexanet alfa), a recombinant protein antidote specific for factor Xa inhibitors, has entered clinical studies, with a phase 2 trial reporting high reversing capability for apixaban.⁵⁹

Unlike rivaroxaban and apixaban, which are highly bound to plasma protein, dabigatran can be effectively removed with hemodialysis. Liesenfeld et al⁶⁰ showed that longer dialysis duration was the most relevant variable for reducing dabigatran plasma levels. Current clinical experience is limited, and standard recommendations and formal guidance are lacking.

Switching oral anticoagulants

Suggested approaches for switching between anticoagulants are listed in Table 4.⁶¹

CHOOSING ANTITHROMBOTIC THERAPY

In valvular atrial fibrillation: warfarin

Anticoagulation with warfarin is advised for valvular atrial fibrillation. Patients with bioprosthetic heart valves or rheumatic valvular disease were not evaluated in randomized controlled trials of TSOACs. Dabigatran in particular is contraindicated in patients with mechanical heart valves, as the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement (RE-ALIGN)⁶² found higher rates of stroke, valve-related thrombosis, and myocardial infarction in patients receiving dabigatran.

In nonvalvular atrial fibrillation

According to the 2014 guidelines,¹ oral anticoagulation is preferred in all patients with nonvalvular atrial fibrillation but those at lowest risk (CHA₂DS₂-VASc = 0).

Experience with TSOACs is lacking in patients with end-stage kidney disease (creatinine clearance < 15 mL/min), and warfarin is advised in this group.

TSOACs are recommended in patients with nonvalvular atrial fibrillation in whom therapeutic INR levels cannot be maintained with warfarin. For most patients with nonvalvular atrial fibrillation, TSOACs are an option equivalent to warfarin. Anticoagulant choice is largely driven by dosing convenience, out-of-pocket cost for treatment with a TSOAC, and ready availability of antidotes for warfarin in case of bleeding (Tables 5 and 6).

In patients with nonvalvular atrial fibrillation, TSOACs are as effective as warfarin in preventing systemic thromboembolism, and some of them have been shown to be superior in terms of lower rates of ischemic stroke (dabigatran), systemic embolism (apixaban), and mortality (apixaban; trend for dabigatran). All TSOACs demonstrate modestly favorable bleeding risk profiles compared with warfarin, with lower risk of intracranial hemorrhage. Potential differences in efficacy and safety among TSOACs are unknown since there have been no randomized direct comparisons between them. A summary of landmark trial results and assessment of the advantages and disadvantages of each are listed in Table 7.

Two groups of patients with nonvalvular atrial fibrillation warrant special consideration: 

Patients with hypertrophic cardiomyopathy. There are no randomized controlled trials of anticoagulation therapy in patients with hypertrophic cardiomyopathy; however, because of their high risk of thromboembolism, anticoagulation is indicated irrespective of the  CHA₂DS₂-VASc score. TSOACs are an option as an alternative to warfarin.

Patients with coronary artery disease and an indication for antiplatelet therapy. In this group the decision for concurrent anticoagulation is guided by the CHA₂DS₂-VASc score. For patients who have intracoronary stents, dual antiplatelet therapy is the standard of care for reducing risk of cardiovascular events after stent implantation.⁶³ When triple therapy (ie, two antiplatelet drugs and an anticoagulant) is indicated, such as after intracoronary stent placement, the guidelines suggest trying to minimize the duration of triple therapy. For instance, a bare-metal stent may be preferred. Alternatively, after coronary revascularization, it may be reasonable to use clopidogrel 75 mg daily with an oral anticoagulant and to omit aspirin.

Interrupting and bridging anticoagulation

Patients with atrial fibrillation often require suspension of anticoagulation, most commonly before an elective invasive procedure. The duration of interruption, timing of resumption, and need for bridging anticoagulation are guided by clinical judgment, which considers risk of thromboembolism and severity of procedure-related bleeding risk.

In general, if therapy needs to be interrupted, it should be restarted as soon as possible

In general, if therapy needs to be interrupted, it should be restarted as soon as possible. Short-term interruption does not seem to be associated with clinically significant risk of thromboembolic events, whereas postoperative heparin bridging therapy increases the risk of hematoma with implantation of a cardiac electronic device.^64,65

To date, evidence is lacking to advise upon periprocedure bridging anticoagulation. The Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) study (NCT00786474)— enrolling chronically anticoagulated patients undergoing an invasive procedure to randomly receive placebo or bridging low-molecular-weight heparin—may provide guidance.

Currently, it is common practice in low-risk patients undergoing an invasive procedure with significant bleeding risk to interrupt anticoagulation for up to 1 week without bridging. Warfarin is typically held 3 to 5 days, while TSOACs are held for 24 hours if renal function is preserved or up to 2 to 3 days if renal function is severely impaired (creatinine clearance 15–30 mL/min). If complete hemostasis is necessary, it could be confirmed by a normalized INR (for warfarin), activated partial thromboplastin time (dabigatran), or prothrombin time (apixaban or rivaroxaban).

For patients at high risk (valvular atrial fibrillation or CHA₂DS₂-VASc ≥ 2), bridging with unfractionated heparin or low-molecular-weight heparin during periods of subtherapeutic anticoagulation is common. Alternatively, it is becoming increasingly common to perform cardiac electronic device implantation, catheter ablation, and coronary angiography and intervention without interrupting anticoagulation.^66–72

Recently, concern has been raised over a possible increase in thromboembolism upon discontinuation of rivaroxaban and apixaban. ROCKET-AF reported a spike in thrombotic events in the rivaroxaban-treated group at the end of the trial (HR 1.50, 95% CI 1.05–2.15, P = .026). This raised concern for a possible “rebound” effect upon drug cessation. Yet a post hoc analysis of ROCKET-AF demonstrated that events clustered in the rivaroxaban-treated cohort who completed the study and were transitioning to open-label warfarin, and this alone accounted for the rise in stroke occurrence. In contrast, there was no increase in the cohort of patients treated with rivaroxaban who either temporarily interrupted or permanently discontinued the drug.⁷³ The authors concluded that increased stroke was the consequence of transiently interrupted anticoagulation, rather than a rebound prothrombotic effect. Similar results were reported in ARISTOTLE.

Another possibility is that, during the transition to warfarin therapy, transient hypercoagulability could be a function of warfarin. Azoulay et al⁷⁴ observed in a large cohort that warfarin was associated with a 71% increased risk of stroke in the first 30 days after initiation, compared with decreased risk thereafter. Nevertheless, there is now a black- box warning recommendation for all three TSOACs that if discontinuation is required for a reason other than pathological bleeding, bridging with another anticoagulant should  at least be considered.

The perioperative management of the TSOACs was recently reviewed in this journal by Anderson et al.⁷⁵

WEIGHING THE RISKS OF STROKE AND BLEEDING

Stroke is the most feared complication in patients with atrial fibrillation. Risk reduction is an important goal in management, yet decisions for individuals must take into account both stroke and bleeding risks related to antithrombotic therapy.

In deciding whether to start anticoagulation, weigh the risk of both stroke and bleeding

The 2014 guidelines¹ differ from past versions. First, they endorse the use of CHA₂DS₂-VASc for categorizing stroke risk in patients with nonvalvular atrial fibrillation. This in turn guides antithrombotic therapy. This scheme effectively identifies patients at very low risk of stroke (men with a score of 0, women with a score of 0 or 1), in whom it is reasonable to omit antithrombotic therapy. For all patients with valvular heart disease or hypertrophic cardiomyopathy, unless bleeding risk is prohibitive, anticoagulation is recommended irrespective of the CHA₂DS₂-VASc score. Second, they incorporate the TSOACs, which offer convenience and improved safety in select patients.

While the guidelines mention the potential relevance of subclinical atrial tachyarrhythmias as they pertain to stroke risk, there is no specific recommendation as to their management. We do take into consideration the finding of atrial high-rate events (≥ 180 bpm, ≥ 6 minutes in duration) diagnostically confirmed by cardiac implantable electronic devices or telemetric monitoring, particularly in patients with a clinical profile of high stroke risk. In addition, atriopathy with increased left atrial size and renal insufficiency, as discussed in this review, appear to correlate with greater risk of thromboembolism, yet neither is a component of the stroke risk scheme endorsed by the guidelines.

Other risk factors, some unknown to us, undoubtedly exist. Again, our empiric judgment is to at least consider these nontraditional risk factors while guided primarily by the CHA₂DS₂-VASc score when assessing stroke risk in patients with atrial fibrillation.

The goal in managing patients with atrial fibrillation is to balance thromboembolic risk reduction with the risk of bleeding associated with antithrombotic therapy.  

Antithrombotic therapy reduces the risk of systemic embolism in patients with atrial fibrillation, but one approach does not suit all patients. The decision whether to start this therapy—and which agent to use—must take into account the patient’s risk of thromboembolism as well as bleeding.

Antithrombotic therapy encompasses antiplatelet drugs such as aspirin and clopidogrel and anticoagulants such as warfarin and the target-specific oral anticoagulants (TSOACs). Oral anticoagulation is more effective than antiplatelet therapy and is preferred in all but those at lowest risk, in whom either antiplatelet therapy or no therapy is deemed adequate.

Patients with valvular atrial fibrillation, specifically those who have rheumatic mitral stenosis or a prosthetic heart valve, are at significantly higher risk of systemic embolization. Their overall risk-benefit profile is nearly always in favor of anticoagulation. But the same is not necessarily true for patients with nonvalvular atrial fibrillation.

The following discussion sets forth our rationale for clinical decision-making, based on recommendations in the 2014 guidelines from the American Heart Association, American College of Cardiology, and Heart Rhythm Society.¹ The second half of this review outlines the oral anticoagulants currently available.

ONE IN FOUR PEOPLE

Atrial fibrillation is common, with an incidence that increases with age. It affects more than 10% of people over age 80 and is often  associated with cardiovascular disease.² Based on Framingham Heart Study data, a person’s lifetime risk of developing it is about 25%.³

FIVEFOLD RISK OF STROKE

The most serious complication of atrial fibrillation is arterial thromboembolism, of which ischemic stroke is the most common and most feared manifestation. The risk of stroke is five times higher than normal in patients with atrial fibrillation.³ More than 15% of strokes may be attributable to atrial fibrillation, and the proportion increases with age.⁴

The risk of thromboembolism appears to be similar in patients with clinically manifest atrial fibrillation irrespective of the type (paroxysmal, persistent, or permanent). The Stroke Prevention in Atrial Fibrillation (SPAF) study⁵ and the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W)⁶ showed that patients who had paroxysmal atrial fibrillation and at least one risk factor for thromboembolism had stroke rates comparable to those of their counterparts who had persistent and permanent atrial fibrillation.

Subclinical atrial fibrillation may be an important cause of stroke. Clinically silent episodes can be detected by implantable electronic devices, which record episodes of atrial tachyarrhythmia (atrial high-rate events).  Subclinical episodes have been detected in 10% to 28% of monitored patients who did not have a history of atrial fibrillation.^7,8 Patients who have atrial high-rate events detected by implantable devices have a higher risk of future clinically manifest atrial fibrillation, thromboembolic events, or both.^7–9 Yet characteristics of atrial high-rate episodes that predict risk are not well defined and warrant further investigation.

CLINICAL RISK FACTORS FOR STROKE

To date, thousands of patients with nonvalvular atrial fibrillation have participated in randomized clinical trials of stroke prevention. The placebo groups from these trials provide a sizable database for retrospectively identifying clinical characteristics associated with thromboembolism. The Atrial Fibrillation Investigators¹⁰ pooled data from five large trials and found that risk factors consistently associated with stroke in multivariate analysis included diabetes mellitus, hypertension, prior systemic embolism, and advanced age.

Though the risk of stroke increases with age with no lower limit, most studies identify age 65 as a threshold, with further escalating risk after age 75. Moreover, women were observed to be at higher risk in some but not all studies. These risk factors have become components of commonly used risk-stratification schemes.

Hypertrophic cardiomyopathy. Maron et al¹¹ reported that atrial fibrillation in patients with hypertrophic cardiomyopathy was independently associated with thromboembolism. In 900 patients with hypertrophic cardiomyopathy, the prevalence of systemic embolism was 6%. Patients with hypertrophic cardiomyopathy and a thromboembolic complication were seven times more likely to have atrial fibrillation than matched counterparts free of thromboembolism. A notable subset of patients experienced a stroke or embolic event before age 50, and the authors advised that the risk of thromboembolism should be considered in patients of any age with hypertrophic cardiomyopathy and atrial fibrillation.

Olivotto et al¹² similarly found patients with hypertrophic cardiomyopathy and atrial fibrillation to be at significantly greater risk of stroke (odds ratio [OR] 17.7, 95% confidence interval [CI] 4.1–75.9, P < .001).

Chronic kidney disease is also associated with a higher risk of thromboembolism in patients with atrial fibrillation. A glomerular filtration rate of 60 mL/min or less is independently and inversely predictive of risk.^13,14

While patients with end-stage renal disease have been largely excluded from stroke prevention trials, Vázquez et al¹⁵ prospectively followed 190 dialysis patients for 12 months. In multivariate analysis, compared with matched controls without documented atrial fibrillation, patients receiving renal replacement therapy and having any form of atrial fibrillation were eight times more likely to have systemic embolization.

IMAGING-BASED RISK FACTORS

In addition to clinical factors, several imaging-based factors have been associated with stroke risk in patients with atrial fibrillation.

Complex aortic atheroma or markers of blood stasis within the left atrium, such as reduced left atrial appendage emptying flow (< 20 cm/second), dense spontaneous echo contrast, or left atrial appendage thrombus, seen on transesophageal echocardiography, were independently associated with increased systemic embolic risk in the third SPAF substudy.¹⁶ Moreover, multivariate analysis of SPAF data found both left ventricular dysfunction of any severity and increased left atrial size (diameter corrected for body surface area by M-mode > 2.5 cm/m2) to be independent predictors of thromboembolism.¹⁷

Although enlargement of the left atrium has not been incorporated into traditional risk stratification schemes, data from Osranek et al¹⁸ further implicate it as a marker of risk. The cohort was small (N = 46), but consisted of patients with lone atrial fibrillation followed for nearly 30 years. Patients with normal left atrial size enjoyed a benign course, while those with left atrial enlargement (> 32 mL/m²) at diagnosis or later during follow-up had significantly worse event-free survival (hazard ratio [HR] 4.46, 95% CI 1.56–12.74, P < .01). All embolic strokes occurred in the group with left atrial enlargement.

RISK STRATIFICATION SCHEMES

Several models for predicting systemic embolism risk in patients with nonvalvular atrial fibrillation have been proposed and validated.

The CHADS₂ score has been the most widely applied, being simple to use.^19,20 It assigns 1 point each for Congestive heart failure, Hypertension, Age 75 or older, and Diabetes, and 2 points for prior Stroke or systemic thromboembolism.

In patients with chronic nonvalvular atrial fibrillation, Gage et al¹⁹ reported that the stroke rate was lowest in those with a score of 0, with an annual adjusted stroke rate of 1.9% per year, and highest in those with the maximal possible score (ie, 6), with a rate of 18.2%. The rate increased by a factor of 1.5 with each point in the CHADS₂ score.

CHA₂DS₂-VASc. Endorsed for use in both the American and European guidelines,^1,21 CHA₂DS₂-VASc is an extension of CHADS₂. Points are assigned as follows:

• Congestive heart failure or left ventricular dysfunction (moderate to severe left ventricular dysfunction or recent heart failure exacerbation requiring hospitalization irrespective of ejection fraction): 1 point
• Hypertension: 1 point
• Age ≥ 75: 2 points; age 65–74: 1 point
• Diabetes mellitus: 1 point
• Stroke, transient ischemic attack, or thromboembolism: 2 points
• Vascular disease (prior myocardial infarction, peripheral arterial disease, or aortic plaque): 1 point
• Sex, female: 1 point
• Maximum score: 9 points.

Low risk is defined as a score of 0 for a man or, for a woman with no other risk factors, 1. A score of 1 for a man indicates moderate risk, and a score of 2 or more is high risk. Lip et al²² found that, in untreated patients with nonvalvular atrial fibrillation, rates of stroke ranged from 0 with a score of 0 to 15.2% per year with a score of 9 points.

In a large cohort with over 11,000 patient-years of follow-up, 98% of the thromboembolic events occurred in people with a CHA₂DS₂-VASc score of 2 or more. Moreover, more than 99% of patients with a score of less than 2 were free of stroke and thromboembolism.²³

Compared with CHADS₂, CHA₂DS₂-VASc has superior negative predictive power

Compared with the CHADS₂ score, CHA₂DS₂-VASc has superior negative predictive power. Of 1,084 patients from the European Heart Survey for Atrial Fibrillation, the newer scheme classified significantly fewer patients as being at either low risk (score of 0; 9% vs 20%) or intermediate risk (score of 1; 15% vs 35%).²³ Though the overall rate of stroke was low, those categorized as being at low or intermediate risk by CHA₂DS₂-VASc had significantly fewer thromboembolic events than their counterparts according to CHADS₂ (0.6% vs 3.3%).

Olesen et al²⁴ similarly showed that in patients with a CHADS₂ score of 0, reclassification by CHA₂DS₂-VASc yielded a range of annual stroke rates from 0.84% with a score of 0 up to 3.2% with a score of 3.

RISK-BASED ANTITHROMBOTIC THERAPY IN NONVALVULAR ATRIAL FIBRILLATION

The 2014 atrial fibrillation guidelines¹ state that the decision to give antithrombotic therapy for atrial fibrillation should be individualized, based on the absolute and relative risks of stroke and bleeding, and ought to take into consideration the patient’s preferences. For patients with nonvalvular atrial fibrillation, selection of antithrombotic therapy should take into account the risk of thromboembolism determined by the CHA₂DS₂-VASc score and be irrespective of the pattern of atrial fibrillation (paroxysmal, persistent, or permanent). Antithrombotic therapy is similarly recommended for patients with atrial flutter, according to the same risk profile used for atrial fibrillation.

Studies have consistently shown^24–27 that the risk of ischemic stroke without anticoagulation exceeds the risk of intracranial bleeding with anticoagulation in nearly all patients except those at lowest risk of thromboembolism. The CHA₂DS₂-VASc score better identified those at truly low risk, in whom treatment may offer more risk than benefit.^24–27

The HAS-BLED score²⁸ assigns points as follows:

• Hypertension (systolic blood pressure > 160 mm Hg): 1 point
• Abnormal renal function (dialysis, renal transplantation, or serum creatinine > 2.6 mg/mL) or liver function (cirrhosis, bilirubin more than two times the upper limit, or aminotransferase levels more than three times the upper limit): 1 or 2 points
• Stroke: 1 point
• Bleeding (prior major bleeding event or predisposition to bleeding): 1 point
• Labile international normalized ratio (INR) (supratherapeutic or time in therapeutic range < 60%): 1 point
• Elderly (age > 65): 1 point
• Drugs (antiplatelet, nonsteroidal anti-inflammatory) or alcohol (more than eight drinks per week): 1 or 2 points
• Maximum total: 9 points.

HAS-BLED is a practical and validated approach for estimating bleeding risk and is mentioned in the guidelines, but it is not recommended for use in guiding decisions about antithrombotic therapy. Specifically, it should not be used to exclude patients, but rather to identify those at high risk (score ≥ 3) who may require closer observation and more attentive monitoring of the INR.

ANTITHROMBOTIC THERAPY

Antithrombotic agents available for use in the United States include antiplatelet drugs (eg, aspirin and clopidogrel) and anticoagulants (unfractionated heparin and low-molecular-weight heparin, vitamin K antagonists such as warfarin, and direct thrombin and factor Xa inhibitors). Anticoagulation has been shown in randomized controlled trials to be superior to both placebo and antiplatelet agents used either alone or in combination.²⁹

Aspirin has been downgraded

Aspirin has been compared with placebo in seven randomized controlled trials. Only the original SPAF study, in which aspirin 325 mg/day was used, found that it was beneficial. This result alone accounted for the 19% reduction in relative risk (95% CI 1%–35%, P < .05) in a meta-analysis performed by Hart et al.²⁹ Even when combined with clopidogrel 75 mg/day, aspirin 75 to 100 mg/day is still inferior to warfarin.⁵ While dual antiplatelet therapy resulted in a 28% relative reduction in thromboembolism (95% CI 17%–38%, P < .01) compared with aspirin alone, major bleeding significantly increased by 57% (95% CI 29%–92%, P < .01).

Although aspirin may be beneficial, differences among patients may influence its efficacy. It may be more effective in preventing noncardioembolic stroke, particularly in diabetic and hypertensive patients.^30,31 To date, aspirin has not been shown to be beneficial in low-risk populations.

The 2014 guidelines downgraded the recommendation for aspirin therapy. For patients at low risk and for some at intermediate risk, it is permissible to forgo therapy altogether, including aspirin.¹

ORAL ANTICOAGULANTS

The rest of this paper reviews the oral anticoagulants that are approved for reducing the risk of thromboembolism in atrial fibrillation, focusing on each agent’s mechanism of action, pharmacokinetics, clinical efficacy, and safety.

WARFARIN, A VITAMIN K ANTAGONIST

Warfarin inhibits synthesis of vitamin K-dependent clotting factors (ie, factors II, VII, IX, and X) and proteins C and S by inhibiting the C1 subunit of vitamin K epoxide reductase, thereby interfering with production of vitamin K₁ epoxide and consequent regeneration of vitamin K.

Pharmacokinetics. Warfarin is nearly completely absorbed after oral administration. Its anticoagulant effect can be seen within 24 hours of administration, but its peak effect is typically apparent only after 72 hours. Elimination occurs predominantly through metabolism by cytochrome P450 enzymes, principally CYP2C9. Its effective half-life ranges from 20 to 60 hours, with a mean of 40 hours.³²

Warfarin’s effect, dosage, and bleeding risk are influenced by multiple factors, including vitamin K-containing foods such as green leafy vegetables, medications that either inhibit or induce hepatic cytochrome P450 enzymes, and polymorphisms in the VKORC1 and CYP2C9 genes.³²

Reversal. Warfarin’s anticoagulant effect is reversed with vitamin K, but this reversal may not become apparent for 6 to 24 hours. In contrast, fresh-frozen plasma and prothrombin protein concentrate, which contain clotting factors, reverse warfarin immediately. Currently, a three-factor prothrombin protein concentrate (factors II, IX, and X) and a four-factor concentrate (factors II, VII, IX, and X plus proteins C and S) are available in the United States. Although prothrombin protein concentrate works rapidly and has a lower volume of administration, available data do not indicate it is clinically superior to fresh-frozen plasma.^33,34 The ongoing randomized PROTECT trial (NCT00618098), comparing fresh-frozen plasma and four-factor prothrombin protein concentrate for reversal of vitamin K antagonist therapy, may provide further insight.

Efficacy and safety. Randomized controlled trials in patients with nonvalvular atrial fibrillation have shown that warfarin (in doses adjusted to maintain an INR greater than 2) is highly efficacious in preventing systemic embolism, with a relative risk reduction of 61% (95% CI 47%–71%, P < .05) compared with placebo.^29,35 An INR of 2 to 3 is recommended for patients with nonvalvular atrial fibrillation, and those with atrial fibrillation and either a bioprosthetic valve or rheumatic heart disease. In contrast, an INR of 2.5 to 3.5 is recommended for patients with atrial fibrillation and mechanical valves in the aortic or mitral positions.^1,36

An INR of 2 to 3 offers maximum protection with minimal risk of bleeding

Stroke prevention with warfarin is most effective when the achieved mean time in the therapeutic range is at least 70%. The risk of intracranial hemorrhage increases significantly at INRs higher than 3. An INR of 2 to 3 offers maximum protection with minimal risk of bleeding.^37,38 Systematic follow-up of patients through anticoagulation clinics produces better compliance and control and is encouraged.

TARGET-SPECIFIC ORAL ANTICOAGULANTS

Although effective, warfarin requires frequent monitoring and dosage adjustment, has a delayed onset and protracted offset, and interacts with commonly consumed vitamin K–containing foods and frequently used drugs. These drawbacks prompted evaluation of existing antiplatelet agents, in combination or in conjunction with lower adjusted or fixed-dose warfarin. These regimens proved inferior,^39–42 spurring interest in developing alternative oral anticoagulants.

TSOACs act by directly inhibiting thrombin (factor IIa) or by reducing thrombin production indirectly by inhibiting factor Xa. Three TSOACs are approved. Each was compared with adjusted-dose warfarin in randomized controlled trials.

Dabigatran

Dabigatran etexilate was the first TSOAC approved in the United States.

Pharmacokinetics. Dabigatran etexilate has a bioavailability of 3% to 7% after oral administration. Its absorption is enhanced in an acidic gastric environment and is limited by P-glycoprotein-facilitated transport out of enterocytes. Dabigatran etexilate is hydrolyzed to its active metabolite dabigatran, which directly inhibits thrombin. Maximal plasma drug concentration and peak anticoagulant effect are achieved within 0.5 to 2 hours after administration.

Dabigatran is predominantly excreted by the kidneys, and has a half-life of 12 to 17 hours in patients with normal renal function. The half-life extends to 27 hours in those with moderately severe renal impairment (creatinine clearance 15–30 mL/min). The recommended dose of 150 mg twice daily should be reduced to 75 mg twice daily in patients with a creatinine clearance of 15 to 30 mL/min. This drug is contraindicated in patients with a creatinine clearance less than 15 mL/min.^43,44

Efficacy. The Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial⁴⁵ randomly assigned 18,113 patients with nonvalvular atrial fibrillation at risk of thromboembolism (mean CHADS₂ score 2.1) to receive either dabigatran (either 150 mg twice daily or 110 mg twice daily) or warfarin (adjusted to an INR of 2.0 to 3.0). Of note, the lower approved dose of dabigatran (75 mg twice daily) was not tested in RE-LY.

At 2 years, higher-dose dabigatran was significantly more effective than both warfarin (RR 0.65, 95% CI 0.52–0.81, P < .05) and lower-dose dabigatran (RR 0.73, 95% CI 0.58–0.91, P < .05) in reducing the rate of systemic embolic events.

The risk of combined major bleeding events was no different with higher-dose dabigatran than with warfarin (RR 0.93, 95% CI 0.81–1.07, P < .05), but the rate of hemorrhagic stroke was significantly less with dabigatran than with warfarin (RR 0.26, 95% CI 0.14–0.49, P < .05). Higher rates of major gastrointestinal bleeding and dyspepsia occurred with dabigatran.

Post hoc analysis found more myocardial infarctions with dabigatran than with warfarin

Concern about the safety of dabigatran was raised when post hoc evaluation of RE-LY found a higher incidence of myocardial infarction with dabigatran than with warfarin (RR 1.38, 95% CI 1–1.91, P = .048).⁴⁶ Corroborating data were reported by Uchino and Hernandez,⁴⁷ comparing dabigatran with either warfarin or low-molecular-weight heparin. However, without directly comparing dabigatran and placebo, it is unclear whether the small increase in myocardial infarction reflects a direct effect of dabigatran or absence of a protective effect of warfarin or low-molecular-weight heparin.

Rivaroxaban

Rivaroxaban is a direct factor Xa inhibitor that blocks the amplified burst of thrombin production and in turn inhibits platelet aggregation and thrombus formation.

Pharmacokinetics. Rivaroxaban’s oral bioavailability is 80% to 100% after a single 15- or 20-mg dose taken with food. Its maximal anticoagulant effect is achieved within 2 hours. Two-thirds of the active drug is metabolized by either CYP450-dependent (CYP3A4, 2J2) or CYP-independent mechanisms; the inactive drug is then excreted in the urine and feces. The remaining, active drug is removed by the kidneys using the P-glycoprotein transporter.

The half-life of rivaroxaban is 5 to 9 hours. The recommended dosage of 20 mg daily should be reduced to 15 mg daily if the creatinine clearance rate is 30 to 50 mL/min, or to 10 mg if the creatinine clearance rate is 15 to 30 mL/min. Rivaroxaban is contraindicated in patients whose creatinine clearance rate is less than 15 mL/min.^48–52

Efficacy and safety. In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF),⁵³ 14,264 at-risk patients with nonvalvular atrial fibrillation (mean CHADS₂ score 3.5) were randomly assigned to receive either rivaroxaban 20 mg daily (or 15 mg daily if their creatinine clearance was 30–49 mL/min; the lowest dose of rivaroxaban, 10 mg, was not studied in this trial) or warfarin (target INR 2.0–3.0). Outcomes with rivaroxaban compared with warfarin:

• Systemic embolism:
  HR 0.79, 95% CI 0.66–0.96, P < .01, noninferiority
• Total bleeding: no difference
• Intracranial bleeding:
  HR 0.67, 95% CI 0.47–0.93, P = .02
• Fatal bleeding:
  HR 0.50, 95% CI 0.31–0.79, P = .003
• Major gastrointestinal bleeding:
  3.2% vs 2.2%, P < .001.

Apixaban

Apixaban is also a direct factor Xa inhibitor.

Pharmacokinetics. Apixaban’s oral bioavailability is 50%, with maximal blood concentration achieved at 3 to 4 hours. One-quarter of the drug is metabolized via CYP3A4. The remaining active drug is excreted by the kidneys and biliary/intestinal system via the P-glycoprotein transporter. Apixaban’s half-life is 9 to 14 hours.

Target-specific oral anticoagulants have no approved antidotes, but several have been suggested

The recommended dosage is 5 mg twice daily, but it should be reduced to 2.5 mg twice daily if at least two of the following characteristics are present: age 80 or older, weight 60 kg or less, and serum creatinine 1.5 mg/dL or more.^54,55

Efficacy and safety. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial⁵⁶ enrolled 18,201 patients with nonvalvular atrial fibrillation (mean CHADS₂ score 2.1) randomly assigned to receive either apixaban (5 mg twice daily with dosage reduction to 2.5 mg twice daily as noted above) or warfarin (target INR 2.0–3.0).

Compared with warfarin, apixaban was associated with lower risk of:

• Systemic embolism
  (HR 0.79, 95% CI 0.66–0.95, P = .01)
• Major bleeding
  (HR 0.69, 95% CI 0.60–0.80, P < .001)
• Intracranial hemorrhage
  (HR 0.42, 95% CI 0.30–0.58, P < .001)
• All-cause mortality
  (HR 0.89 95% CI 0.80–0.99, P = .047).

Drug interactions with the novel oral anticoagulants

TSOACs were developed with the intent to avoid many of the shortcomings of warfarin. Each has a broader therapeutic window and a rapid onset of action, enabling fixed dosing without need for serial monitoring. Compared with warfarin, they have significantly fewer dietary and drug interactions.

Nonetheless, drug interactions do exist and are important to recognize (Tables 1–3). These primarily result from inhibition or induction of cytochrome P450 enzyme activity or P-glycoprotein transporter action, involved in metabolism and elimination of active drug.

Reversibility of the target-specific oral anticoagulants

While the anticoagulant effects of warfarin can be reversed by vitamin K, fresh-frozen plasma, and prothrombin complex concentrate, TSOACs have no currently approved antidotes. Management of bleeding due to these agents was recently reviewed in this journal by Fawole et al.⁵⁷

Several nonspecific hemostatic agents have been suggested, including recombinant factor VIIa or prothrombin complex concentrates. The anticoagulant effect of rivaroxaban has been shown to be reversed by prothrombin complex concentrate in vitro; clinical effect has not been demonstrated.⁵⁸ PRT06445 (andexanet alfa), a recombinant protein antidote specific for factor Xa inhibitors, has entered clinical studies, with a phase 2 trial reporting high reversing capability for apixaban.⁵⁹

Unlike rivaroxaban and apixaban, which are highly bound to plasma protein, dabigatran can be effectively removed with hemodialysis. Liesenfeld et al⁶⁰ showed that longer dialysis duration was the most relevant variable for reducing dabigatran plasma levels. Current clinical experience is limited, and standard recommendations and formal guidance are lacking.

Switching oral anticoagulants

Suggested approaches for switching between anticoagulants are listed in Table 4.⁶¹

CHOOSING ANTITHROMBOTIC THERAPY

In valvular atrial fibrillation: warfarin

Anticoagulation with warfarin is advised for valvular atrial fibrillation. Patients with bioprosthetic heart valves or rheumatic valvular disease were not evaluated in randomized controlled trials of TSOACs. Dabigatran in particular is contraindicated in patients with mechanical heart valves, as the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients After Heart Valve Replacement (RE-ALIGN)⁶² found higher rates of stroke, valve-related thrombosis, and myocardial infarction in patients receiving dabigatran.

In nonvalvular atrial fibrillation

According to the 2014 guidelines,¹ oral anticoagulation is preferred in all patients with nonvalvular atrial fibrillation but those at lowest risk (CHA₂DS₂-VASc = 0).

Experience with TSOACs is lacking in patients with end-stage kidney disease (creatinine clearance < 15 mL/min), and warfarin is advised in this group.

TSOACs are recommended in patients with nonvalvular atrial fibrillation in whom therapeutic INR levels cannot be maintained with warfarin. For most patients with nonvalvular atrial fibrillation, TSOACs are an option equivalent to warfarin. Anticoagulant choice is largely driven by dosing convenience, out-of-pocket cost for treatment with a TSOAC, and ready availability of antidotes for warfarin in case of bleeding (Tables 5 and 6).

In patients with nonvalvular atrial fibrillation, TSOACs are as effective as warfarin in preventing systemic thromboembolism, and some of them have been shown to be superior in terms of lower rates of ischemic stroke (dabigatran), systemic embolism (apixaban), and mortality (apixaban; trend for dabigatran). All TSOACs demonstrate modestly favorable bleeding risk profiles compared with warfarin, with lower risk of intracranial hemorrhage. Potential differences in efficacy and safety among TSOACs are unknown since there have been no randomized direct comparisons between them. A summary of landmark trial results and assessment of the advantages and disadvantages of each are listed in Table 7.

Two groups of patients with nonvalvular atrial fibrillation warrant special consideration: 

Patients with hypertrophic cardiomyopathy. There are no randomized controlled trials of anticoagulation therapy in patients with hypertrophic cardiomyopathy; however, because of their high risk of thromboembolism, anticoagulation is indicated irrespective of the  CHA₂DS₂-VASc score. TSOACs are an option as an alternative to warfarin.

Patients with coronary artery disease and an indication for antiplatelet therapy. In this group the decision for concurrent anticoagulation is guided by the CHA₂DS₂-VASc score. For patients who have intracoronary stents, dual antiplatelet therapy is the standard of care for reducing risk of cardiovascular events after stent implantation.⁶³ When triple therapy (ie, two antiplatelet drugs and an anticoagulant) is indicated, such as after intracoronary stent placement, the guidelines suggest trying to minimize the duration of triple therapy. For instance, a bare-metal stent may be preferred. Alternatively, after coronary revascularization, it may be reasonable to use clopidogrel 75 mg daily with an oral anticoagulant and to omit aspirin.

Interrupting and bridging anticoagulation

Patients with atrial fibrillation often require suspension of anticoagulation, most commonly before an elective invasive procedure. The duration of interruption, timing of resumption, and need for bridging anticoagulation are guided by clinical judgment, which considers risk of thromboembolism and severity of procedure-related bleeding risk.

In general, if therapy needs to be interrupted, it should be restarted as soon as possible

In general, if therapy needs to be interrupted, it should be restarted as soon as possible. Short-term interruption does not seem to be associated with clinically significant risk of thromboembolic events, whereas postoperative heparin bridging therapy increases the risk of hematoma with implantation of a cardiac electronic device.^64,65

To date, evidence is lacking to advise upon periprocedure bridging anticoagulation. The Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery (BRIDGE) study (NCT00786474)— enrolling chronically anticoagulated patients undergoing an invasive procedure to randomly receive placebo or bridging low-molecular-weight heparin—may provide guidance.

Currently, it is common practice in low-risk patients undergoing an invasive procedure with significant bleeding risk to interrupt anticoagulation for up to 1 week without bridging. Warfarin is typically held 3 to 5 days, while TSOACs are held for 24 hours if renal function is preserved or up to 2 to 3 days if renal function is severely impaired (creatinine clearance 15–30 mL/min). If complete hemostasis is necessary, it could be confirmed by a normalized INR (for warfarin), activated partial thromboplastin time (dabigatran), or prothrombin time (apixaban or rivaroxaban).

For patients at high risk (valvular atrial fibrillation or CHA₂DS₂-VASc ≥ 2), bridging with unfractionated heparin or low-molecular-weight heparin during periods of subtherapeutic anticoagulation is common. Alternatively, it is becoming increasingly common to perform cardiac electronic device implantation, catheter ablation, and coronary angiography and intervention without interrupting anticoagulation.^66–72

Recently, concern has been raised over a possible increase in thromboembolism upon discontinuation of rivaroxaban and apixaban. ROCKET-AF reported a spike in thrombotic events in the rivaroxaban-treated group at the end of the trial (HR 1.50, 95% CI 1.05–2.15, P = .026). This raised concern for a possible “rebound” effect upon drug cessation. Yet a post hoc analysis of ROCKET-AF demonstrated that events clustered in the rivaroxaban-treated cohort who completed the study and were transitioning to open-label warfarin, and this alone accounted for the rise in stroke occurrence. In contrast, there was no increase in the cohort of patients treated with rivaroxaban who either temporarily interrupted or permanently discontinued the drug.⁷³ The authors concluded that increased stroke was the consequence of transiently interrupted anticoagulation, rather than a rebound prothrombotic effect. Similar results were reported in ARISTOTLE.

Another possibility is that, during the transition to warfarin therapy, transient hypercoagulability could be a function of warfarin. Azoulay et al⁷⁴ observed in a large cohort that warfarin was associated with a 71% increased risk of stroke in the first 30 days after initiation, compared with decreased risk thereafter. Nevertheless, there is now a black- box warning recommendation for all three TSOACs that if discontinuation is required for a reason other than pathological bleeding, bridging with another anticoagulant should  at least be considered.

The perioperative management of the TSOACs was recently reviewed in this journal by Anderson et al.⁷⁵

WEIGHING THE RISKS OF STROKE AND BLEEDING

Stroke is the most feared complication in patients with atrial fibrillation. Risk reduction is an important goal in management, yet decisions for individuals must take into account both stroke and bleeding risks related to antithrombotic therapy.

In deciding whether to start anticoagulation, weigh the risk of both stroke and bleeding

The 2014 guidelines¹ differ from past versions. First, they endorse the use of CHA₂DS₂-VASc for categorizing stroke risk in patients with nonvalvular atrial fibrillation. This in turn guides antithrombotic therapy. This scheme effectively identifies patients at very low risk of stroke (men with a score of 0, women with a score of 0 or 1), in whom it is reasonable to omit antithrombotic therapy. For all patients with valvular heart disease or hypertrophic cardiomyopathy, unless bleeding risk is prohibitive, anticoagulation is recommended irrespective of the CHA₂DS₂-VASc score. Second, they incorporate the TSOACs, which offer convenience and improved safety in select patients.

While the guidelines mention the potential relevance of subclinical atrial tachyarrhythmias as they pertain to stroke risk, there is no specific recommendation as to their management. We do take into consideration the finding of atrial high-rate events (≥ 180 bpm, ≥ 6 minutes in duration) diagnostically confirmed by cardiac implantable electronic devices or telemetric monitoring, particularly in patients with a clinical profile of high stroke risk. In addition, atriopathy with increased left atrial size and renal insufficiency, as discussed in this review, appear to correlate with greater risk of thromboembolism, yet neither is a component of the stroke risk scheme endorsed by the guidelines.

Other risk factors, some unknown to us, undoubtedly exist. Again, our empiric judgment is to at least consider these nontraditional risk factors while guided primarily by the CHA₂DS₂-VASc score when assessing stroke risk in patients with atrial fibrillation.

The goal in managing patients with atrial fibrillation is to balance thromboembolic risk reduction with the risk of bleeding associated with antithrombotic therapy.