UPDATED: FDA-released safety data on dabigatran vs. warfarin reassuring

[UPDATED] Current recommendations and labeling regarding the use of dabigatran will not change, based on the results of a large observational cohort study comparing the risks of the direct thrombin inhibitor and warfarin in Medicare recipients, the Food and Drug Administration announced on May 13.

The study, which was completed recently and has not been published, found that dabigatran, compared with warfarin, was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, according to the FDA’s statement on the findings. The risk of major gastrointestinal bleeding, however, was higher with dabigatran, and the risk of myocardial infarction was similar in both groups.

The statement points out that other than the MI finding, the results are consistent with the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which found the MI risk was higher among those on dabigatran than with warfarin. Approval of dabigatran in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF was based on the results of the RE-LY study. Dabigatran is marketed as Pradaxa by Boehringer Ingelheim.

"As a result of our latest findings, we still consider Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use," the FDA statement said. "Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of postmarket data, and employed a more sophisticated analytical method to capture and analyze the events of concern."

The study, part of an ongoing review of dabigatran, evaluated the risks of more than 134,000 new users of dabigatran and warfarin, who were over age 65 years and had been diagnosed with atrial fibrillation during the 6 months before the medication was dispensed. The data were from 2010-2012. Patient outcomes were identified in administrative and insurance claims, and the study represented more than 37,500 person-years of follow-up.

The results were as follows, with warfarin as the reference group, and dabigatran results based on the analysis of both approved doses (75 mg and 150 mg) combined:

• For ischemic stroke, the incidence rates (IR) per 1,000 person-years were 11.3 for dabigatran, vs. 13.9 for warfarin (hazard ratio, 0.80).

• For intracranial hemorrhage, the incidence rates were 3.3 for dabigatran, vs. 9.6 for warfarin (HR, 0.34).

• For major GI bleeding, the incidence rates were 34.2 for dabigatran, vs. 26.5 for warfarin (HR, 1.28).

• For acute MI, the incidence rates were 15.7 for dabigatran, vs. 16.9 for warfarin (HR, 0.92).

• For mortality, the incidence rates were 32.6 for dabigatran vs. 37.8 for warfarin (HR, 0.86).

The FDA statement points out that the results for major GI bleeding in this study are different from a previous FDA analysis of about 10,600 new users of dabigatran and warfarin, reported in 2012, which found that GI and intracranial hemorrhage rates were lower among patients treated with dabigatran, compared with those on warfarin. However, that study included patients under age 65 years (64% were older than age 65 years), and this disparity "may reflect the age differences in the two patient populations," the FDA statement said.

In an interview, Dr. Sanjay Kaul, professor of medicine at University of California Los Angeles, said the data in the Medicare study were reassuring, “and indicate that the favorable benefit-risk balance observed in the pre-approval randomized controlled trial, RE-LY, are generalizable in real world clinical practice.”

Without a placebo control, he added, “it is unclear what to make of the MI signal observed in RE-LY, but not in this study.” And while the exact cause of increased GI bleeding remains unclear, Dr. Kaul pointed out that this risk cannot be mitigated by gastroprotective medications such as H2 blockers or proton pump inhibitors, and that “it is best to avoid this medication in patients with history of lower-GI bleeding.”

Dr. Deepak Bhatt, professor of medicine at Harvard University in Boston, also described the results of the FDA study as reassuring. The study provides real world data in a large number of patients that complement and largely mirror the results in RE-LY, he said in an interview.

“I think that all those findings regarding death, stroke, and GI bleeding are all true because they were true in the randomized clinical trial dataset, and it is good to see they also appear to be true in real life clinical practice,” he commented. 

In addition, the data “further support the idea that the novel oral anticoagulants in patients who don’t have contraindications for them, and can afford them, [are] a better option than warfarin,” said Dr. Bhatt, the executive director of Interventional Cardiovascular Programs, at Brigham and Women’s Hospital Heart and Vascular Center, Boston.

He pointed out that overall, the three novel oral anticoagulants – dabigatran and the factor Xa inhibitors, apixaban and rivaroxaban – approved for the nonvalvular AF indication, appear to reduce the risk of stroke and death, “and across the board, they all show significantly less intracranial hemorrhage.”

“The availability of agents that have a lower intracranial hemorrhage risk, such as dabigatran, really is an advantage and will hopefully lead to more patients with atrial fibrillation being appropriately treated, instead of being undertreated  because of fear of bleeding into the brain,” he said. 

The FDA plans to publish the Medicare study and will continue to review the risks of bleeding with anticoagulants.

Dabigatran is now also approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

The FDA has issued two previous safety alerts regarding the bleeding risks associated with dabigatran, in 2011 and 2012.

Dr. Kaul is a consultant to Boehringer Ingelheim and has equity interest in Johnson and Johnson. Dr. Bhatt said he has research grants with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi Aventis, and the Medicines Company. He is also on the executive committee for the RE-DUAL PCI trial, a large study comparing dabigatran to warfarin in stented patients with AF, which will be starting soon.

The FDA notice is available here. Serious adverse events associated with dabigatran and warfarin should be reported to the FDA at 800-332-1088 or at MedWatch.

[email protected]

[UPDATED] Current recommendations and labeling regarding the use of dabigatran will not change, based on the results of a large observational cohort study comparing the risks of the direct thrombin inhibitor and warfarin in Medicare recipients, the Food and Drug Administration announced on May 13.

The study, which was completed recently and has not been published, found that dabigatran, compared with warfarin, was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, according to the FDA’s statement on the findings. The risk of major gastrointestinal bleeding, however, was higher with dabigatran, and the risk of myocardial infarction was similar in both groups.

The statement points out that other than the MI finding, the results are consistent with the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which found the MI risk was higher among those on dabigatran than with warfarin. Approval of dabigatran in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF was based on the results of the RE-LY study. Dabigatran is marketed as Pradaxa by Boehringer Ingelheim.

"As a result of our latest findings, we still consider Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use," the FDA statement said. "Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of postmarket data, and employed a more sophisticated analytical method to capture and analyze the events of concern."

The study, part of an ongoing review of dabigatran, evaluated the risks of more than 134,000 new users of dabigatran and warfarin, who were over age 65 years and had been diagnosed with atrial fibrillation during the 6 months before the medication was dispensed. The data were from 2010-2012. Patient outcomes were identified in administrative and insurance claims, and the study represented more than 37,500 person-years of follow-up.

The results were as follows, with warfarin as the reference group, and dabigatran results based on the analysis of both approved doses (75 mg and 150 mg) combined:

• For ischemic stroke, the incidence rates (IR) per 1,000 person-years were 11.3 for dabigatran, vs. 13.9 for warfarin (hazard ratio, 0.80).

• For intracranial hemorrhage, the incidence rates were 3.3 for dabigatran, vs. 9.6 for warfarin (HR, 0.34).

• For major GI bleeding, the incidence rates were 34.2 for dabigatran, vs. 26.5 for warfarin (HR, 1.28).

• For acute MI, the incidence rates were 15.7 for dabigatran, vs. 16.9 for warfarin (HR, 0.92).

• For mortality, the incidence rates were 32.6 for dabigatran vs. 37.8 for warfarin (HR, 0.86).

The FDA statement points out that the results for major GI bleeding in this study are different from a previous FDA analysis of about 10,600 new users of dabigatran and warfarin, reported in 2012, which found that GI and intracranial hemorrhage rates were lower among patients treated with dabigatran, compared with those on warfarin. However, that study included patients under age 65 years (64% were older than age 65 years), and this disparity "may reflect the age differences in the two patient populations," the FDA statement said.

In an interview, Dr. Sanjay Kaul, professor of medicine at University of California Los Angeles, said the data in the Medicare study were reassuring, “and indicate that the favorable benefit-risk balance observed in the pre-approval randomized controlled trial, RE-LY, are generalizable in real world clinical practice.”

Without a placebo control, he added, “it is unclear what to make of the MI signal observed in RE-LY, but not in this study.” And while the exact cause of increased GI bleeding remains unclear, Dr. Kaul pointed out that this risk cannot be mitigated by gastroprotective medications such as H2 blockers or proton pump inhibitors, and that “it is best to avoid this medication in patients with history of lower-GI bleeding.”

Dr. Deepak Bhatt, professor of medicine at Harvard University in Boston, also described the results of the FDA study as reassuring. The study provides real world data in a large number of patients that complement and largely mirror the results in RE-LY, he said in an interview.

“I think that all those findings regarding death, stroke, and GI bleeding are all true because they were true in the randomized clinical trial dataset, and it is good to see they also appear to be true in real life clinical practice,” he commented. 

In addition, the data “further support the idea that the novel oral anticoagulants in patients who don’t have contraindications for them, and can afford them, [are] a better option than warfarin,” said Dr. Bhatt, the executive director of Interventional Cardiovascular Programs, at Brigham and Women’s Hospital Heart and Vascular Center, Boston.

He pointed out that overall, the three novel oral anticoagulants – dabigatran and the factor Xa inhibitors, apixaban and rivaroxaban – approved for the nonvalvular AF indication, appear to reduce the risk of stroke and death, “and across the board, they all show significantly less intracranial hemorrhage.”

“The availability of agents that have a lower intracranial hemorrhage risk, such as dabigatran, really is an advantage and will hopefully lead to more patients with atrial fibrillation being appropriately treated, instead of being undertreated  because of fear of bleeding into the brain,” he said. 

The FDA plans to publish the Medicare study and will continue to review the risks of bleeding with anticoagulants.

Dabigatran is now also approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

The FDA has issued two previous safety alerts regarding the bleeding risks associated with dabigatran, in 2011 and 2012.

Dr. Kaul is a consultant to Boehringer Ingelheim and has equity interest in Johnson and Johnson. Dr. Bhatt said he has research grants with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi Aventis, and the Medicines Company. He is also on the executive committee for the RE-DUAL PCI trial, a large study comparing dabigatran to warfarin in stented patients with AF, which will be starting soon.

The FDA notice is available here. Serious adverse events associated with dabigatran and warfarin should be reported to the FDA at 800-332-1088 or at MedWatch.

[email protected]

[UPDATED] Current recommendations and labeling regarding the use of dabigatran will not change, based on the results of a large observational cohort study comparing the risks of the direct thrombin inhibitor and warfarin in Medicare recipients, the Food and Drug Administration announced on May 13.

The study, which was completed recently and has not been published, found that dabigatran, compared with warfarin, was associated with a lower risk of ischemic stroke, intracranial hemorrhage, and death, according to the FDA’s statement on the findings. The risk of major gastrointestinal bleeding, however, was higher with dabigatran, and the risk of myocardial infarction was similar in both groups.

The statement points out that other than the MI finding, the results are consistent with the results of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, which found the MI risk was higher among those on dabigatran than with warfarin. Approval of dabigatran in 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF was based on the results of the RE-LY study. Dabigatran is marketed as Pradaxa by Boehringer Ingelheim.

"As a result of our latest findings, we still consider Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use," the FDA statement said. "Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of postmarket data, and employed a more sophisticated analytical method to capture and analyze the events of concern."

The study, part of an ongoing review of dabigatran, evaluated the risks of more than 134,000 new users of dabigatran and warfarin, who were over age 65 years and had been diagnosed with atrial fibrillation during the 6 months before the medication was dispensed. The data were from 2010-2012. Patient outcomes were identified in administrative and insurance claims, and the study represented more than 37,500 person-years of follow-up.

The results were as follows, with warfarin as the reference group, and dabigatran results based on the analysis of both approved doses (75 mg and 150 mg) combined:

• For ischemic stroke, the incidence rates (IR) per 1,000 person-years were 11.3 for dabigatran, vs. 13.9 for warfarin (hazard ratio, 0.80).

• For intracranial hemorrhage, the incidence rates were 3.3 for dabigatran, vs. 9.6 for warfarin (HR, 0.34).

• For major GI bleeding, the incidence rates were 34.2 for dabigatran, vs. 26.5 for warfarin (HR, 1.28).

• For acute MI, the incidence rates were 15.7 for dabigatran, vs. 16.9 for warfarin (HR, 0.92).

• For mortality, the incidence rates were 32.6 for dabigatran vs. 37.8 for warfarin (HR, 0.86).

The FDA statement points out that the results for major GI bleeding in this study are different from a previous FDA analysis of about 10,600 new users of dabigatran and warfarin, reported in 2012, which found that GI and intracranial hemorrhage rates were lower among patients treated with dabigatran, compared with those on warfarin. However, that study included patients under age 65 years (64% were older than age 65 years), and this disparity "may reflect the age differences in the two patient populations," the FDA statement said.

In an interview, Dr. Sanjay Kaul, professor of medicine at University of California Los Angeles, said the data in the Medicare study were reassuring, “and indicate that the favorable benefit-risk balance observed in the pre-approval randomized controlled trial, RE-LY, are generalizable in real world clinical practice.”

Without a placebo control, he added, “it is unclear what to make of the MI signal observed in RE-LY, but not in this study.” And while the exact cause of increased GI bleeding remains unclear, Dr. Kaul pointed out that this risk cannot be mitigated by gastroprotective medications such as H2 blockers or proton pump inhibitors, and that “it is best to avoid this medication in patients with history of lower-GI bleeding.”

Dr. Deepak Bhatt, professor of medicine at Harvard University in Boston, also described the results of the FDA study as reassuring. The study provides real world data in a large number of patients that complement and largely mirror the results in RE-LY, he said in an interview.

“I think that all those findings regarding death, stroke, and GI bleeding are all true because they were true in the randomized clinical trial dataset, and it is good to see they also appear to be true in real life clinical practice,” he commented. 

In addition, the data “further support the idea that the novel oral anticoagulants in patients who don’t have contraindications for them, and can afford them, [are] a better option than warfarin,” said Dr. Bhatt, the executive director of Interventional Cardiovascular Programs, at Brigham and Women’s Hospital Heart and Vascular Center, Boston.

He pointed out that overall, the three novel oral anticoagulants – dabigatran and the factor Xa inhibitors, apixaban and rivaroxaban – approved for the nonvalvular AF indication, appear to reduce the risk of stroke and death, “and across the board, they all show significantly less intracranial hemorrhage.”

“The availability of agents that have a lower intracranial hemorrhage risk, such as dabigatran, really is an advantage and will hopefully lead to more patients with atrial fibrillation being appropriately treated, instead of being undertreated  because of fear of bleeding into the brain,” he said. 

The FDA plans to publish the Medicare study and will continue to review the risks of bleeding with anticoagulants.

Dabigatran is now also approved for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

The FDA has issued two previous safety alerts regarding the bleeding risks associated with dabigatran, in 2011 and 2012.

Dr. Kaul is a consultant to Boehringer Ingelheim and has equity interest in Johnson and Johnson. Dr. Bhatt said he has research grants with Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi Aventis, and the Medicines Company. He is also on the executive committee for the RE-DUAL PCI trial, a large study comparing dabigatran to warfarin in stented patients with AF, which will be starting soon.

The FDA notice is available here. Serious adverse events associated with dabigatran and warfarin should be reported to the FDA at 800-332-1088 or at MedWatch.

[email protected]