Stroke History Did Not Change Safety, Effectiveness of Dabigatran

Patients with atrial fibrillation who were taking the anticoagulant dabigatran for secondary stroke prevention suffered an ischemic stroke or systemic embolism at a rate similar to patients taking warfarin in a prespecified subgroup analysis of patients from the 2-year RE-LY trial.

This analysis of 3,623 patients, published online Nov. 8 in the Lancet Neurology, was consistent with the overall results found in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial cohort of 18,113 patients. Significant differences in the rates of intracranial bleeding between patients treated with dabigatran and those taking warfarin that had been observed in the overall results of the trial also were seen among those with a history of ischemic stroke or TIA.

"Although the subgroup analyses were not powered to detect whether the effects of dabigatran compared with warfarin varied by subgroup, the overlapping 95% confidence intervals suggest that major variations in the relative effects of the drugs between the patients with or without previous stroke or transient ischemic attack are unlikely," Dr. Hans-Christoph Diener of University Hospital Essen (Germany) and his colleagues wrote (Lancet Neurol. 2010 Nov. 8 [doi:10.1016/S1474-4422(10)70274-X]).

The Food and Drug Administration approved the drug last month at doses of 150 mg and 75 mg for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The approval was based on the overall results of the open-label RE-LY trial, which randomized patients with atrial fibrillation to 110 mg or 150 mg dabigatran twice daily or warfarin adjusted to an international normalized ratio of 2.0-3.0.

The drug was approved in 2008 in the European Union, Canada, and other countries for a shorter term indication, primary prevention of venous thromboembolic events in adults after elective total hip or knee replacement surgery. Canada added the indication for stroke prevention in atrial fibrillation in October.

In the overall trial cohort, a stroke or systemic embolism occurred significantly more often among patients with a previous stroke or TIA (2.38% per year) than in those without such history (1.22% per year).

The primary outcome of stroke or systemic embolism occurred at similar rates between patients with a previous stroke or TIA who took warfarin (2.78% per year), 110 mg dabigatran (2.32% per year), and 150 mg dabigatran (2.07% per year). In the overall study population, the rate of stroke or systemic embolism did not differ among groups, occurring at 1.71% per year in patients on warfarin, 1.54% per year in patients on 110 mg dabigatran, and 1.11% per year in those on 150 mg dabigatran.

In the subgroup, intracranial bleeding occurred at a significantly lower rate in patients who took 110 mg dabigatran, compared with those who took warfarin (0.25% vs. 1.28% per year).

Patients with a history of stroke or TIA who took the 110-mg dose of dabigatran had a significantly lower rate of vascular death and all-cause mortality than did patients who received warfarin, but this effect was not seen in the 150-mg group. In this subgroup, major bleeding also occurred at a significantly lower rate among only those who received 110 mg dabigatran.

The use of antiplatelet agents or nonsteroidal anti-inflammatory drugs was balanced among the subgroups across the three treatment groups.

Based on the results in patients with a previous stroke or TIA, the investigators suggested that "150 mg dabigatran might provide better protection against stroke than warfarin, whereas 110 mg dabigatran is as efficacious as warfarin and reduces adverse events (bleeding complications and mortality)." And indeed, the FDA’s Cardiovascular and Renal Drugs Committee that evaluated dabigatran in September came to a similar conclusion, although no superiority claim over warfarin could be made. Additionally, the FDA did not include the 110-mg dosage that established noninferiority in its approved dosages, recommending the regimen of 150 mg twice daily, except in patients with impaired renal function, who would take 75 mg twice daily.

They noted that because the RE-LY trial excluded all patients with ischemic stroke or TIA within the past 2 weeks before enrollment, it "cannot provide information on the efficacy of dabigatran in the early phase after transient ischemic attack or stroke."

How dabigatran might achieve a reduction in intracranial bleeding beyond a more stable anticoagulation "is not yet known," but Dr. Diener and his associates said that it might result from an inability to cross the blood-brain barrier.

In an editorial accompanying the paper, Dr. Deidre A. Lane and Dr. Gregory Y.H. Lip wrote that this subgroup analysis of the RE-LY trial is important because it begins to fill the void of data on the benefit of oral coagulation for secondary stroke prevention and the safety of oral coagulation in patients with a previous ischemic stroke or TIA (Lancet Neurol. 2010 Nov. 8 [doi:10.1016/S1474-4422(10)70275-1]).

The analysis offers some guidance to physicians when deciding which dose of dabigatran to prescribe after going through an individualized stroke and bleeding risk assessment.

"Because of the necessary trade-off between stroke prevention and bleeding with both doses of dabigatran, consultation with patients regarding their preferences for treatment dose will be even more important to ascertain their threshold for stroke prevention over increased bleeding risk or vice versa," Dr. Lane and Dr. Lip of the University of Birmingham (England) wrote.

Boehringer Ingelheim GmbH funded the study and is marketing dabigatran as Pradaxa. Dr. Diener and some of his authors disclosed financial relationships with this company and others that manufacture or market drugs for the prevention or treatment of stroke. One author is an employee of Boehringer Ingelheim.

Dr. Lane and Dr. Lip both reported having received funding for research and lecturing from different manufacturers of drugs used for the treatment of atrial fibrillation, including Boehringer Ingelheim.

Patients with atrial fibrillation who were taking the anticoagulant dabigatran for secondary stroke prevention suffered an ischemic stroke or systemic embolism at a rate similar to patients taking warfarin in a prespecified subgroup analysis of patients from the 2-year RE-LY trial.

This analysis of 3,623 patients, published online Nov. 8 in the Lancet Neurology, was consistent with the overall results found in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial cohort of 18,113 patients. Significant differences in the rates of intracranial bleeding between patients treated with dabigatran and those taking warfarin that had been observed in the overall results of the trial also were seen among those with a history of ischemic stroke or TIA.

"Although the subgroup analyses were not powered to detect whether the effects of dabigatran compared with warfarin varied by subgroup, the overlapping 95% confidence intervals suggest that major variations in the relative effects of the drugs between the patients with or without previous stroke or transient ischemic attack are unlikely," Dr. Hans-Christoph Diener of University Hospital Essen (Germany) and his colleagues wrote (Lancet Neurol. 2010 Nov. 8 [doi:10.1016/S1474-4422(10)70274-X]).

The Food and Drug Administration approved the drug last month at doses of 150 mg and 75 mg for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The approval was based on the overall results of the open-label RE-LY trial, which randomized patients with atrial fibrillation to 110 mg or 150 mg dabigatran twice daily or warfarin adjusted to an international normalized ratio of 2.0-3.0.

The drug was approved in 2008 in the European Union, Canada, and other countries for a shorter term indication, primary prevention of venous thromboembolic events in adults after elective total hip or knee replacement surgery. Canada added the indication for stroke prevention in atrial fibrillation in October.

In the overall trial cohort, a stroke or systemic embolism occurred significantly more often among patients with a previous stroke or TIA (2.38% per year) than in those without such history (1.22% per year).

The primary outcome of stroke or systemic embolism occurred at similar rates between patients with a previous stroke or TIA who took warfarin (2.78% per year), 110 mg dabigatran (2.32% per year), and 150 mg dabigatran (2.07% per year). In the overall study population, the rate of stroke or systemic embolism did not differ among groups, occurring at 1.71% per year in patients on warfarin, 1.54% per year in patients on 110 mg dabigatran, and 1.11% per year in those on 150 mg dabigatran.

In the subgroup, intracranial bleeding occurred at a significantly lower rate in patients who took 110 mg dabigatran, compared with those who took warfarin (0.25% vs. 1.28% per year).

Patients with a history of stroke or TIA who took the 110-mg dose of dabigatran had a significantly lower rate of vascular death and all-cause mortality than did patients who received warfarin, but this effect was not seen in the 150-mg group. In this subgroup, major bleeding also occurred at a significantly lower rate among only those who received 110 mg dabigatran.

The use of antiplatelet agents or nonsteroidal anti-inflammatory drugs was balanced among the subgroups across the three treatment groups.

Based on the results in patients with a previous stroke or TIA, the investigators suggested that "150 mg dabigatran might provide better protection against stroke than warfarin, whereas 110 mg dabigatran is as efficacious as warfarin and reduces adverse events (bleeding complications and mortality)." And indeed, the FDA’s Cardiovascular and Renal Drugs Committee that evaluated dabigatran in September came to a similar conclusion, although no superiority claim over warfarin could be made. Additionally, the FDA did not include the 110-mg dosage that established noninferiority in its approved dosages, recommending the regimen of 150 mg twice daily, except in patients with impaired renal function, who would take 75 mg twice daily.

They noted that because the RE-LY trial excluded all patients with ischemic stroke or TIA within the past 2 weeks before enrollment, it "cannot provide information on the efficacy of dabigatran in the early phase after transient ischemic attack or stroke."

How dabigatran might achieve a reduction in intracranial bleeding beyond a more stable anticoagulation "is not yet known," but Dr. Diener and his associates said that it might result from an inability to cross the blood-brain barrier.

In an editorial accompanying the paper, Dr. Deidre A. Lane and Dr. Gregory Y.H. Lip wrote that this subgroup analysis of the RE-LY trial is important because it begins to fill the void of data on the benefit of oral coagulation for secondary stroke prevention and the safety of oral coagulation in patients with a previous ischemic stroke or TIA (Lancet Neurol. 2010 Nov. 8 [doi:10.1016/S1474-4422(10)70275-1]).

The analysis offers some guidance to physicians when deciding which dose of dabigatran to prescribe after going through an individualized stroke and bleeding risk assessment.

"Because of the necessary trade-off between stroke prevention and bleeding with both doses of dabigatran, consultation with patients regarding their preferences for treatment dose will be even more important to ascertain their threshold for stroke prevention over increased bleeding risk or vice versa," Dr. Lane and Dr. Lip of the University of Birmingham (England) wrote.

Boehringer Ingelheim GmbH funded the study and is marketing dabigatran as Pradaxa. Dr. Diener and some of his authors disclosed financial relationships with this company and others that manufacture or market drugs for the prevention or treatment of stroke. One author is an employee of Boehringer Ingelheim.

Dr. Lane and Dr. Lip both reported having received funding for research and lecturing from different manufacturers of drugs used for the treatment of atrial fibrillation, including Boehringer Ingelheim.

Patients with atrial fibrillation who were taking the anticoagulant dabigatran for secondary stroke prevention suffered an ischemic stroke or systemic embolism at a rate similar to patients taking warfarin in a prespecified subgroup analysis of patients from the 2-year RE-LY trial.

This analysis of 3,623 patients, published online Nov. 8 in the Lancet Neurology, was consistent with the overall results found in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial cohort of 18,113 patients. Significant differences in the rates of intracranial bleeding between patients treated with dabigatran and those taking warfarin that had been observed in the overall results of the trial also were seen among those with a history of ischemic stroke or TIA.

"Although the subgroup analyses were not powered to detect whether the effects of dabigatran compared with warfarin varied by subgroup, the overlapping 95% confidence intervals suggest that major variations in the relative effects of the drugs between the patients with or without previous stroke or transient ischemic attack are unlikely," Dr. Hans-Christoph Diener of University Hospital Essen (Germany) and his colleagues wrote (Lancet Neurol. 2010 Nov. 8 [doi:10.1016/S1474-4422(10)70274-X]).

The Food and Drug Administration approved the drug last month at doses of 150 mg and 75 mg for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The approval was based on the overall results of the open-label RE-LY trial, which randomized patients with atrial fibrillation to 110 mg or 150 mg dabigatran twice daily or warfarin adjusted to an international normalized ratio of 2.0-3.0.

The drug was approved in 2008 in the European Union, Canada, and other countries for a shorter term indication, primary prevention of venous thromboembolic events in adults after elective total hip or knee replacement surgery. Canada added the indication for stroke prevention in atrial fibrillation in October.

In the overall trial cohort, a stroke or systemic embolism occurred significantly more often among patients with a previous stroke or TIA (2.38% per year) than in those without such history (1.22% per year).

The primary outcome of stroke or systemic embolism occurred at similar rates between patients with a previous stroke or TIA who took warfarin (2.78% per year), 110 mg dabigatran (2.32% per year), and 150 mg dabigatran (2.07% per year). In the overall study population, the rate of stroke or systemic embolism did not differ among groups, occurring at 1.71% per year in patients on warfarin, 1.54% per year in patients on 110 mg dabigatran, and 1.11% per year in those on 150 mg dabigatran.

In the subgroup, intracranial bleeding occurred at a significantly lower rate in patients who took 110 mg dabigatran, compared with those who took warfarin (0.25% vs. 1.28% per year).

Patients with a history of stroke or TIA who took the 110-mg dose of dabigatran had a significantly lower rate of vascular death and all-cause mortality than did patients who received warfarin, but this effect was not seen in the 150-mg group. In this subgroup, major bleeding also occurred at a significantly lower rate among only those who received 110 mg dabigatran.

The use of antiplatelet agents or nonsteroidal anti-inflammatory drugs was balanced among the subgroups across the three treatment groups.

Based on the results in patients with a previous stroke or TIA, the investigators suggested that "150 mg dabigatran might provide better protection against stroke than warfarin, whereas 110 mg dabigatran is as efficacious as warfarin and reduces adverse events (bleeding complications and mortality)." And indeed, the FDA’s Cardiovascular and Renal Drugs Committee that evaluated dabigatran in September came to a similar conclusion, although no superiority claim over warfarin could be made. Additionally, the FDA did not include the 110-mg dosage that established noninferiority in its approved dosages, recommending the regimen of 150 mg twice daily, except in patients with impaired renal function, who would take 75 mg twice daily.

They noted that because the RE-LY trial excluded all patients with ischemic stroke or TIA within the past 2 weeks before enrollment, it "cannot provide information on the efficacy of dabigatran in the early phase after transient ischemic attack or stroke."

How dabigatran might achieve a reduction in intracranial bleeding beyond a more stable anticoagulation "is not yet known," but Dr. Diener and his associates said that it might result from an inability to cross the blood-brain barrier.

In an editorial accompanying the paper, Dr. Deidre A. Lane and Dr. Gregory Y.H. Lip wrote that this subgroup analysis of the RE-LY trial is important because it begins to fill the void of data on the benefit of oral coagulation for secondary stroke prevention and the safety of oral coagulation in patients with a previous ischemic stroke or TIA (Lancet Neurol. 2010 Nov. 8 [doi:10.1016/S1474-4422(10)70275-1]).

The analysis offers some guidance to physicians when deciding which dose of dabigatran to prescribe after going through an individualized stroke and bleeding risk assessment.

"Because of the necessary trade-off between stroke prevention and bleeding with both doses of dabigatran, consultation with patients regarding their preferences for treatment dose will be even more important to ascertain their threshold for stroke prevention over increased bleeding risk or vice versa," Dr. Lane and Dr. Lip of the University of Birmingham (England) wrote.

Boehringer Ingelheim GmbH funded the study and is marketing dabigatran as Pradaxa. Dr. Diener and some of his authors disclosed financial relationships with this company and others that manufacture or market drugs for the prevention or treatment of stroke. One author is an employee of Boehringer Ingelheim.

Dr. Lane and Dr. Lip both reported having received funding for research and lecturing from different manufacturers of drugs used for the treatment of atrial fibrillation, including Boehringer Ingelheim.