FDA approves apixaban for nonvalvular atrial fibrillation population

The approval of the factor Xa inhibitor apixaban provides another oral anticoagulant that is available to treat patients with atrial fibrillation.

Apixaban was approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in people with nonvalvular atrial fibrillation. It will be marketed as Eliquis, by Bristol-Myers Squibb and Pfizer.

The recommended dose is 5 mg twice daily; a lower dose, 2.5 mg twice daily, is recommended for people with at least two of the following features: age 80 years or older, body weight of 60 kg or less, or a serum creatinine of at least 1.5 mg/dL, according to the prescribing information. The lower dose is also recommended when administered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole and clarithromycin.

Rivaroxaban (Xarelto), a factor Xa inhibitor first approved in 2011, and dabigatran (Pradaxa), a direct thrombin inhibitor approved in 2010, are also indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reducing the risk of recurrence of DVT and of PE; and for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

The FDA statement announcing the approval on Dec. 28 said that the safety and efficacy of apixaban was studied in a trial of more than 18,000 patients with nonvalvular atrial fibrillation, which determined that the rate of strokes among those treated with apixaban was lower than among those on warfarin.

In that study, the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 18,201 patients were treated with 5 mg or 2.5 mg of apixaban twice a day, or warfarin, targeted to an INR range of 2.0-3.0, for a median of 89 weeks. Apixaban was superior to warfarin in reducing the risk of ischemic or hemorrhagic stroke, and systemic embolism: 1.27%/year for those on apixaban vs. 1.60%/year among those on warfarin, a 21% reduced risk that was statistically significant.

Superiority over warfarin in ARISTOTLE was "primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin," and the rates of "purely ischemic strokes" were similar in patients on warfarin and those on apixaban, according to the prescribing information.

The rate of major bleeds was also significantly lower among those on apixaban (2.13% per year) than in those on warfarin (3.09% per year).

The FDA statement points out that apixaban should not be used to treat patients with prosthetic heart valves or with atrial fibrillation that is caused by a heart valve problem, who were not studied. In addition, "there is no agent that can reverse the anticoagulant effect" of apixaban, according to the FDA.

"The randomized clinical trial data for apixaban are quite strong and as doctors gain more familiarity with this medication, it will be a valuable alternative to warfarin for many patients with atrial fibrillation," Dr. Deepak Bhatt, professor of medicine, Harvard Medical School, Boston, and chief of cardiology at the Veterans Affairs Boston Healthcare System, said in an interview.

"Overall, it is good to have therapeutic choices but it is up to the physician community to optimize the use of these agents," said Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Medical Center, Los Angeles.

"With the approval of apixaban, the anticoagulant space has become somewhat crowded," he said in an interview, noting that in the absence of studies directly comparing these drugs, "physicians will have to figure out which patients are best treated with which agent." For now, he cautioned about manufacturers marketing the advantages of their individual agents. For example, rivaroxaban, approved for nonvalvular atrial fibrillation and for prevention and treatment of venous thromboembolism, has the broadest indication and with the once-daily recommended dosing, has a potential dose advantage, he noted. And while all agents reduce hemorrhagic stroke, "dabigatran at the 150-mg dose is the only agent that significantly reduces the risk of ischemic stroke compared with warfarin."

With the reduced stroke and bleeding risk, apixaban has "the most desirable benefit-risk balance ... and might be preferable in patients with mild to moderate renal impairment given its least dependence on renal clearance," he noted.

He said that all three agents have been shown to have a modest benefit on mortality, and that the mortality benefit was statistically significant only with apixaban because of the size of the ARISTOTLE study. Although an increased risk of MI was a signal reported with dabigatran, but not with Rivaroxaban and apixaban, "the clinical relevance of this observation is not clear," he said.

The approval comes with a Risk Evaluation and Mitigation Strategy (REMS), required by the FDA to ensure that the drug’s benefits drug outweigh its risks, which includes a patient medication guide describing the risks of the drug to be distributed to patients with each filled prescription.

Apixaban should be "widely available" in the United States by the end of January 2013, according to a statement issued by BMS on Jan. 2.

The wholesale acquisition cost for apixaban is $8.35 per day, for both doses, according to a spokesperson for Pfizer.

Dr. Kaul said he had no disclosures relevant to apixaban. He is a stockholder in Johnson & Johnson, a cosponsor for rivaroxaban, and sat on the FDA advisory committees that reviewed dabigatran and rivaroxaban. There was no advisory panel meeting on apixaban.

Dr. Bhatt said that he has received research grants from BMS, and has served on the steering committee of APPRAISE-2 (apixaban studied in acute coronary syndromes). His other disclosures include being a member of the clinical trial steering committees of the Duke Clinical Research Institute.

The prescribing information is available here. The patient medication guide is available at the FDA.

Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program or at 800-332-1088.

The approval of the factor Xa inhibitor apixaban provides another oral anticoagulant that is available to treat patients with atrial fibrillation.

Apixaban was approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in people with nonvalvular atrial fibrillation. It will be marketed as Eliquis, by Bristol-Myers Squibb and Pfizer.

The recommended dose is 5 mg twice daily; a lower dose, 2.5 mg twice daily, is recommended for people with at least two of the following features: age 80 years or older, body weight of 60 kg or less, or a serum creatinine of at least 1.5 mg/dL, according to the prescribing information. The lower dose is also recommended when administered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole and clarithromycin.

Rivaroxaban (Xarelto), a factor Xa inhibitor first approved in 2011, and dabigatran (Pradaxa), a direct thrombin inhibitor approved in 2010, are also indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reducing the risk of recurrence of DVT and of PE; and for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

The FDA statement announcing the approval on Dec. 28 said that the safety and efficacy of apixaban was studied in a trial of more than 18,000 patients with nonvalvular atrial fibrillation, which determined that the rate of strokes among those treated with apixaban was lower than among those on warfarin.

In that study, the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 18,201 patients were treated with 5 mg or 2.5 mg of apixaban twice a day, or warfarin, targeted to an INR range of 2.0-3.0, for a median of 89 weeks. Apixaban was superior to warfarin in reducing the risk of ischemic or hemorrhagic stroke, and systemic embolism: 1.27%/year for those on apixaban vs. 1.60%/year among those on warfarin, a 21% reduced risk that was statistically significant.

Superiority over warfarin in ARISTOTLE was "primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin," and the rates of "purely ischemic strokes" were similar in patients on warfarin and those on apixaban, according to the prescribing information.

The rate of major bleeds was also significantly lower among those on apixaban (2.13% per year) than in those on warfarin (3.09% per year).

The FDA statement points out that apixaban should not be used to treat patients with prosthetic heart valves or with atrial fibrillation that is caused by a heart valve problem, who were not studied. In addition, "there is no agent that can reverse the anticoagulant effect" of apixaban, according to the FDA.

"The randomized clinical trial data for apixaban are quite strong and as doctors gain more familiarity with this medication, it will be a valuable alternative to warfarin for many patients with atrial fibrillation," Dr. Deepak Bhatt, professor of medicine, Harvard Medical School, Boston, and chief of cardiology at the Veterans Affairs Boston Healthcare System, said in an interview.

"Overall, it is good to have therapeutic choices but it is up to the physician community to optimize the use of these agents," said Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Medical Center, Los Angeles.

"With the approval of apixaban, the anticoagulant space has become somewhat crowded," he said in an interview, noting that in the absence of studies directly comparing these drugs, "physicians will have to figure out which patients are best treated with which agent." For now, he cautioned about manufacturers marketing the advantages of their individual agents. For example, rivaroxaban, approved for nonvalvular atrial fibrillation and for prevention and treatment of venous thromboembolism, has the broadest indication and with the once-daily recommended dosing, has a potential dose advantage, he noted. And while all agents reduce hemorrhagic stroke, "dabigatran at the 150-mg dose is the only agent that significantly reduces the risk of ischemic stroke compared with warfarin."

With the reduced stroke and bleeding risk, apixaban has "the most desirable benefit-risk balance ... and might be preferable in patients with mild to moderate renal impairment given its least dependence on renal clearance," he noted.

He said that all three agents have been shown to have a modest benefit on mortality, and that the mortality benefit was statistically significant only with apixaban because of the size of the ARISTOTLE study. Although an increased risk of MI was a signal reported with dabigatran, but not with Rivaroxaban and apixaban, "the clinical relevance of this observation is not clear," he said.

The approval comes with a Risk Evaluation and Mitigation Strategy (REMS), required by the FDA to ensure that the drug’s benefits drug outweigh its risks, which includes a patient medication guide describing the risks of the drug to be distributed to patients with each filled prescription.

Apixaban should be "widely available" in the United States by the end of January 2013, according to a statement issued by BMS on Jan. 2.

The wholesale acquisition cost for apixaban is $8.35 per day, for both doses, according to a spokesperson for Pfizer.

Dr. Kaul said he had no disclosures relevant to apixaban. He is a stockholder in Johnson & Johnson, a cosponsor for rivaroxaban, and sat on the FDA advisory committees that reviewed dabigatran and rivaroxaban. There was no advisory panel meeting on apixaban.

Dr. Bhatt said that he has received research grants from BMS, and has served on the steering committee of APPRAISE-2 (apixaban studied in acute coronary syndromes). His other disclosures include being a member of the clinical trial steering committees of the Duke Clinical Research Institute.

The prescribing information is available here. The patient medication guide is available at the FDA.

Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program or at 800-332-1088.

The approval of the factor Xa inhibitor apixaban provides another oral anticoagulant that is available to treat patients with atrial fibrillation.

Apixaban was approved by the Food and Drug Administration for reducing the risk of stroke and systemic embolism in people with nonvalvular atrial fibrillation. It will be marketed as Eliquis, by Bristol-Myers Squibb and Pfizer.

The recommended dose is 5 mg twice daily; a lower dose, 2.5 mg twice daily, is recommended for people with at least two of the following features: age 80 years or older, body weight of 60 kg or less, or a serum creatinine of at least 1.5 mg/dL, according to the prescribing information. The lower dose is also recommended when administered with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as ketoconazole and clarithromycin.

Rivaroxaban (Xarelto), a factor Xa inhibitor first approved in 2011, and dabigatran (Pradaxa), a direct thrombin inhibitor approved in 2010, are also indicated for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Rivaroxaban is also approved for the treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and for the reducing the risk of recurrence of DVT and of PE; and for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery.

The FDA statement announcing the approval on Dec. 28 said that the safety and efficacy of apixaban was studied in a trial of more than 18,000 patients with nonvalvular atrial fibrillation, which determined that the rate of strokes among those treated with apixaban was lower than among those on warfarin.

In that study, the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, 18,201 patients were treated with 5 mg or 2.5 mg of apixaban twice a day, or warfarin, targeted to an INR range of 2.0-3.0, for a median of 89 weeks. Apixaban was superior to warfarin in reducing the risk of ischemic or hemorrhagic stroke, and systemic embolism: 1.27%/year for those on apixaban vs. 1.60%/year among those on warfarin, a 21% reduced risk that was statistically significant.

Superiority over warfarin in ARISTOTLE was "primarily attributable to a reduction in hemorrhagic stroke and ischemic strokes with hemorrhagic conversion compared to warfarin," and the rates of "purely ischemic strokes" were similar in patients on warfarin and those on apixaban, according to the prescribing information.

The rate of major bleeds was also significantly lower among those on apixaban (2.13% per year) than in those on warfarin (3.09% per year).

The FDA statement points out that apixaban should not be used to treat patients with prosthetic heart valves or with atrial fibrillation that is caused by a heart valve problem, who were not studied. In addition, "there is no agent that can reverse the anticoagulant effect" of apixaban, according to the FDA.

"The randomized clinical trial data for apixaban are quite strong and as doctors gain more familiarity with this medication, it will be a valuable alternative to warfarin for many patients with atrial fibrillation," Dr. Deepak Bhatt, professor of medicine, Harvard Medical School, Boston, and chief of cardiology at the Veterans Affairs Boston Healthcare System, said in an interview.

"Overall, it is good to have therapeutic choices but it is up to the physician community to optimize the use of these agents," said Dr. Sanjay Kaul, director of the vascular physiology and thrombosis research laboratory at Cedars-Sinai Medical Center, Los Angeles.

"With the approval of apixaban, the anticoagulant space has become somewhat crowded," he said in an interview, noting that in the absence of studies directly comparing these drugs, "physicians will have to figure out which patients are best treated with which agent." For now, he cautioned about manufacturers marketing the advantages of their individual agents. For example, rivaroxaban, approved for nonvalvular atrial fibrillation and for prevention and treatment of venous thromboembolism, has the broadest indication and with the once-daily recommended dosing, has a potential dose advantage, he noted. And while all agents reduce hemorrhagic stroke, "dabigatran at the 150-mg dose is the only agent that significantly reduces the risk of ischemic stroke compared with warfarin."

With the reduced stroke and bleeding risk, apixaban has "the most desirable benefit-risk balance ... and might be preferable in patients with mild to moderate renal impairment given its least dependence on renal clearance," he noted.

He said that all three agents have been shown to have a modest benefit on mortality, and that the mortality benefit was statistically significant only with apixaban because of the size of the ARISTOTLE study. Although an increased risk of MI was a signal reported with dabigatran, but not with Rivaroxaban and apixaban, "the clinical relevance of this observation is not clear," he said.

The approval comes with a Risk Evaluation and Mitigation Strategy (REMS), required by the FDA to ensure that the drug’s benefits drug outweigh its risks, which includes a patient medication guide describing the risks of the drug to be distributed to patients with each filled prescription.

Apixaban should be "widely available" in the United States by the end of January 2013, according to a statement issued by BMS on Jan. 2.

The wholesale acquisition cost for apixaban is $8.35 per day, for both doses, according to a spokesperson for Pfizer.

Dr. Kaul said he had no disclosures relevant to apixaban. He is a stockholder in Johnson & Johnson, a cosponsor for rivaroxaban, and sat on the FDA advisory committees that reviewed dabigatran and rivaroxaban. There was no advisory panel meeting on apixaban.

Dr. Bhatt said that he has received research grants from BMS, and has served on the steering committee of APPRAISE-2 (apixaban studied in acute coronary syndromes). His other disclosures include being a member of the clinical trial steering committees of the Duke Clinical Research Institute.

The prescribing information is available here. The patient medication guide is available at the FDA.

Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program or at 800-332-1088.