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A once-daily, oral, fixed dose of the Factor Xa inhibitor rivaroxaban was noninferior to warfarin for the prevention of stroke in patients with atrial fibrillation in a randomized, double-blind trial.
Moreover, although rates of bleeding were similar between the two groups of patients, "bleeding that proved fatal or involved a critical anatomical site occurred less frequently in the rivaroxaban group," Dr. Manesh R. Patel of Duke University, Durham, N.C., and his coauthors wrote online Aug. 10 in the New England Journal of Medicine.
"In contrast, bleeding from gastrointestinal sites, including upper, lower, and rectal sites, occurred more frequently in the rivaroxaban group."
In July, the U.S. Food and Drug Administration approved rivaroxaban (Xarelto) for the prevention of deep vein thrombosis.
The investigators enrolled 14,264 patients with elevated stroke risk from 1,178 sites in 45 countries with nonvalvular atrial fibrillation (AF). An "elevated risk" was indicated by a previous stroke history, transient ischemic attack, or systemic embolism. Johnson & Johnson and Bayer Healthcare, the U.S. and European marketers of the drug, respectively, sponsored the study, called ROCKET AF (Rivaroxaban One Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
Patients also were included if they had at least two of several risk factors, including heart failure, an ejection fraction of less than 35%, hypertension, age older than 75 years, or diabetes mellitus.
The median age of participants was 73 years, of whom nearly 40% were women. Both groups were statistically similar or identical in terms of body mass index, median systolic and diastolic blood pressure, type of AF (persistent, paroxysmal, or new-onset), and other related factors.
Patients were randomly assigned to receive either a once-daily, 20-mg dose of rivaroxaban or a standard, adjusted dose of warfarin, with a target international normalized ratio (INR) of 2-3. Patients in the rivaroxaban group who had a creatinine clearance of 30-49 mL/min received a 15-mg dose. All patients also received a placebo tablet (N. Engl. J. Med. 2011 Aug. 10 [doi:10.1056/NEJMoa1009638]).
The patients underwent treatment for a median of 590 days and had a median follow-up period of 707 days. Among the patients who received at least one dose of a study drug and had no major protocol violation, the rate of stroke or embolism was 1.7% per year for rivaroxaban, compared with 2.2% per year for warfarin. Overall, stroke or embolism occurred in 188 rivaroxaban patients and 241 warfarin patients, for a hazard ratio of 0.79 among rivaroxaban recipients (95% confidence interval, 0.66-0.96, P < .001 for noninferiority).
The rate of "major" bleeding was similar between the rivaroxaban and warfarin groups (3.6% vs. 3.4%, respectively). Major bleeding was defined as "clinically overt" bleeding associated with fatal outcome; involvement with a "critical" site including intracranial, spinal, ocular, pericardial, articular, retroperitoneal, or intramuscular areas; a drop in hemoglobin of 2 g/dL or greater; transfusion of multiple units of blood; or permanent disability.
Rates of "clinically relevant non-major bleeding" also were similar, occurring in 1,475 rivaroxaban patients and 1,449 warfarin patients (14.9% vs. 14.5%, respectively; rivaroxaban hazard ratio of 1.03; P = .44). Non-major events included overt bleeds not meeting major criteria, but requiring physician intervention.
However, rivaroxaban users were more likely to experience drops in hemoglobin of 2 g/dL or more, compared with warfarin users (2.8% vs. 2.3%, respectively; P = .02), as well as gastrointestinal bleeding (3.2% vs. 2.2%, respectively; P less than .001).
On the other hand, warfarin-treated patients more frequently experienced fatal bleeding (0.2% for rivaroxaban versus 0.5% for warfarin, P = .003) and intracranial bleeding (0.5% for rivaroxaban, versus 0.7% for warfarin, P =0.02). The target INR was maintained only 55% of the time in patients who received warfarin, the authors noted.
In addition to the study funding, Dr. Patel and several other authors of the study disclosed numerous financial relationships to pharmaceutical companies, including the makers of rivaroxaban; several authors were also employees of Johnson & Johnson as well as Bayer Healthcare.
"For the management of atrial fibrillation, oral alternatives to warfarin have arrived," wrote Dr. Gregory J. del Zoppo and Misha Eliasziw, Ph.D., in an editorial accompanying the study.
In addition to the current study of rivaroxaban, they also cited the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) study, which showed that "dabigatran, a direct thrombin inhibitor, was not inferior to warfarin."
"Both studies provide some points to ponder for a condition in which placebo controlled trials are no longer possible," they wrote (N. Engl. J. Med. 2011 Aug. 10 [doi:10.1056/NEJMe11o7516]).
Not the least of these is the "interesting" finding of a reduced rate of intracranial hemorrhage among both new agents, compared with warfarin.
"The reasons for the potential reduction ... are not clear, but one possibility is the effect on a single target in the hemostatic system by the new antithrombolytic agents versus the multiple targets by warfarin," they wrote.
"More intriguing is the possibility that cerebral vascular beds have protective features that are more apparent at the doses of either of the new agents tested."
"Fundamental studies of cerebral vascular responses to these agents ... would be instructive."
Although the new agents’ "simplicity of use" remains attractive, they noted that is important to know that these clinical trials do not address the "absence of antidotes to rapidly reverse the anticoagulation effects of either rivaroxaban or dabigatran in the case of life-threatening hemorrhage or surgery," they wrote.
Dr. del Zoppo is with the division of hematology at the University of Washington, Seattle, and disclosed no conflicts of interest. Dr. Eliasziw is with the department of community health sciences at the University of Calgary (Alta.), and disclosed previous grant support from the National Institutes of Health.
"For the management of atrial fibrillation, oral alternatives to warfarin have arrived," wrote Dr. Gregory J. del Zoppo and Misha Eliasziw, Ph.D., in an editorial accompanying the study.
In addition to the current study of rivaroxaban, they also cited the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) study, which showed that "dabigatran, a direct thrombin inhibitor, was not inferior to warfarin."
"Both studies provide some points to ponder for a condition in which placebo controlled trials are no longer possible," they wrote (N. Engl. J. Med. 2011 Aug. 10 [doi:10.1056/NEJMe11o7516]).
Not the least of these is the "interesting" finding of a reduced rate of intracranial hemorrhage among both new agents, compared with warfarin.
"The reasons for the potential reduction ... are not clear, but one possibility is the effect on a single target in the hemostatic system by the new antithrombolytic agents versus the multiple targets by warfarin," they wrote.
"More intriguing is the possibility that cerebral vascular beds have protective features that are more apparent at the doses of either of the new agents tested."
"Fundamental studies of cerebral vascular responses to these agents ... would be instructive."
Although the new agents’ "simplicity of use" remains attractive, they noted that is important to know that these clinical trials do not address the "absence of antidotes to rapidly reverse the anticoagulation effects of either rivaroxaban or dabigatran in the case of life-threatening hemorrhage or surgery," they wrote.
Dr. del Zoppo is with the division of hematology at the University of Washington, Seattle, and disclosed no conflicts of interest. Dr. Eliasziw is with the department of community health sciences at the University of Calgary (Alta.), and disclosed previous grant support from the National Institutes of Health.
"For the management of atrial fibrillation, oral alternatives to warfarin have arrived," wrote Dr. Gregory J. del Zoppo and Misha Eliasziw, Ph.D., in an editorial accompanying the study.
In addition to the current study of rivaroxaban, they also cited the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) study, which showed that "dabigatran, a direct thrombin inhibitor, was not inferior to warfarin."
"Both studies provide some points to ponder for a condition in which placebo controlled trials are no longer possible," they wrote (N. Engl. J. Med. 2011 Aug. 10 [doi:10.1056/NEJMe11o7516]).
Not the least of these is the "interesting" finding of a reduced rate of intracranial hemorrhage among both new agents, compared with warfarin.
"The reasons for the potential reduction ... are not clear, but one possibility is the effect on a single target in the hemostatic system by the new antithrombolytic agents versus the multiple targets by warfarin," they wrote.
"More intriguing is the possibility that cerebral vascular beds have protective features that are more apparent at the doses of either of the new agents tested."
"Fundamental studies of cerebral vascular responses to these agents ... would be instructive."
Although the new agents’ "simplicity of use" remains attractive, they noted that is important to know that these clinical trials do not address the "absence of antidotes to rapidly reverse the anticoagulation effects of either rivaroxaban or dabigatran in the case of life-threatening hemorrhage or surgery," they wrote.
Dr. del Zoppo is with the division of hematology at the University of Washington, Seattle, and disclosed no conflicts of interest. Dr. Eliasziw is with the department of community health sciences at the University of Calgary (Alta.), and disclosed previous grant support from the National Institutes of Health.
A once-daily, oral, fixed dose of the Factor Xa inhibitor rivaroxaban was noninferior to warfarin for the prevention of stroke in patients with atrial fibrillation in a randomized, double-blind trial.
Moreover, although rates of bleeding were similar between the two groups of patients, "bleeding that proved fatal or involved a critical anatomical site occurred less frequently in the rivaroxaban group," Dr. Manesh R. Patel of Duke University, Durham, N.C., and his coauthors wrote online Aug. 10 in the New England Journal of Medicine.
"In contrast, bleeding from gastrointestinal sites, including upper, lower, and rectal sites, occurred more frequently in the rivaroxaban group."
In July, the U.S. Food and Drug Administration approved rivaroxaban (Xarelto) for the prevention of deep vein thrombosis.
The investigators enrolled 14,264 patients with elevated stroke risk from 1,178 sites in 45 countries with nonvalvular atrial fibrillation (AF). An "elevated risk" was indicated by a previous stroke history, transient ischemic attack, or systemic embolism. Johnson & Johnson and Bayer Healthcare, the U.S. and European marketers of the drug, respectively, sponsored the study, called ROCKET AF (Rivaroxaban One Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
Patients also were included if they had at least two of several risk factors, including heart failure, an ejection fraction of less than 35%, hypertension, age older than 75 years, or diabetes mellitus.
The median age of participants was 73 years, of whom nearly 40% were women. Both groups were statistically similar or identical in terms of body mass index, median systolic and diastolic blood pressure, type of AF (persistent, paroxysmal, or new-onset), and other related factors.
Patients were randomly assigned to receive either a once-daily, 20-mg dose of rivaroxaban or a standard, adjusted dose of warfarin, with a target international normalized ratio (INR) of 2-3. Patients in the rivaroxaban group who had a creatinine clearance of 30-49 mL/min received a 15-mg dose. All patients also received a placebo tablet (N. Engl. J. Med. 2011 Aug. 10 [doi:10.1056/NEJMoa1009638]).
The patients underwent treatment for a median of 590 days and had a median follow-up period of 707 days. Among the patients who received at least one dose of a study drug and had no major protocol violation, the rate of stroke or embolism was 1.7% per year for rivaroxaban, compared with 2.2% per year for warfarin. Overall, stroke or embolism occurred in 188 rivaroxaban patients and 241 warfarin patients, for a hazard ratio of 0.79 among rivaroxaban recipients (95% confidence interval, 0.66-0.96, P < .001 for noninferiority).
The rate of "major" bleeding was similar between the rivaroxaban and warfarin groups (3.6% vs. 3.4%, respectively). Major bleeding was defined as "clinically overt" bleeding associated with fatal outcome; involvement with a "critical" site including intracranial, spinal, ocular, pericardial, articular, retroperitoneal, or intramuscular areas; a drop in hemoglobin of 2 g/dL or greater; transfusion of multiple units of blood; or permanent disability.
Rates of "clinically relevant non-major bleeding" also were similar, occurring in 1,475 rivaroxaban patients and 1,449 warfarin patients (14.9% vs. 14.5%, respectively; rivaroxaban hazard ratio of 1.03; P = .44). Non-major events included overt bleeds not meeting major criteria, but requiring physician intervention.
However, rivaroxaban users were more likely to experience drops in hemoglobin of 2 g/dL or more, compared with warfarin users (2.8% vs. 2.3%, respectively; P = .02), as well as gastrointestinal bleeding (3.2% vs. 2.2%, respectively; P less than .001).
On the other hand, warfarin-treated patients more frequently experienced fatal bleeding (0.2% for rivaroxaban versus 0.5% for warfarin, P = .003) and intracranial bleeding (0.5% for rivaroxaban, versus 0.7% for warfarin, P =0.02). The target INR was maintained only 55% of the time in patients who received warfarin, the authors noted.
In addition to the study funding, Dr. Patel and several other authors of the study disclosed numerous financial relationships to pharmaceutical companies, including the makers of rivaroxaban; several authors were also employees of Johnson & Johnson as well as Bayer Healthcare.
A once-daily, oral, fixed dose of the Factor Xa inhibitor rivaroxaban was noninferior to warfarin for the prevention of stroke in patients with atrial fibrillation in a randomized, double-blind trial.
Moreover, although rates of bleeding were similar between the two groups of patients, "bleeding that proved fatal or involved a critical anatomical site occurred less frequently in the rivaroxaban group," Dr. Manesh R. Patel of Duke University, Durham, N.C., and his coauthors wrote online Aug. 10 in the New England Journal of Medicine.
"In contrast, bleeding from gastrointestinal sites, including upper, lower, and rectal sites, occurred more frequently in the rivaroxaban group."
In July, the U.S. Food and Drug Administration approved rivaroxaban (Xarelto) for the prevention of deep vein thrombosis.
The investigators enrolled 14,264 patients with elevated stroke risk from 1,178 sites in 45 countries with nonvalvular atrial fibrillation (AF). An "elevated risk" was indicated by a previous stroke history, transient ischemic attack, or systemic embolism. Johnson & Johnson and Bayer Healthcare, the U.S. and European marketers of the drug, respectively, sponsored the study, called ROCKET AF (Rivaroxaban One Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
Patients also were included if they had at least two of several risk factors, including heart failure, an ejection fraction of less than 35%, hypertension, age older than 75 years, or diabetes mellitus.
The median age of participants was 73 years, of whom nearly 40% were women. Both groups were statistically similar or identical in terms of body mass index, median systolic and diastolic blood pressure, type of AF (persistent, paroxysmal, or new-onset), and other related factors.
Patients were randomly assigned to receive either a once-daily, 20-mg dose of rivaroxaban or a standard, adjusted dose of warfarin, with a target international normalized ratio (INR) of 2-3. Patients in the rivaroxaban group who had a creatinine clearance of 30-49 mL/min received a 15-mg dose. All patients also received a placebo tablet (N. Engl. J. Med. 2011 Aug. 10 [doi:10.1056/NEJMoa1009638]).
The patients underwent treatment for a median of 590 days and had a median follow-up period of 707 days. Among the patients who received at least one dose of a study drug and had no major protocol violation, the rate of stroke or embolism was 1.7% per year for rivaroxaban, compared with 2.2% per year for warfarin. Overall, stroke or embolism occurred in 188 rivaroxaban patients and 241 warfarin patients, for a hazard ratio of 0.79 among rivaroxaban recipients (95% confidence interval, 0.66-0.96, P < .001 for noninferiority).
The rate of "major" bleeding was similar between the rivaroxaban and warfarin groups (3.6% vs. 3.4%, respectively). Major bleeding was defined as "clinically overt" bleeding associated with fatal outcome; involvement with a "critical" site including intracranial, spinal, ocular, pericardial, articular, retroperitoneal, or intramuscular areas; a drop in hemoglobin of 2 g/dL or greater; transfusion of multiple units of blood; or permanent disability.
Rates of "clinically relevant non-major bleeding" also were similar, occurring in 1,475 rivaroxaban patients and 1,449 warfarin patients (14.9% vs. 14.5%, respectively; rivaroxaban hazard ratio of 1.03; P = .44). Non-major events included overt bleeds not meeting major criteria, but requiring physician intervention.
However, rivaroxaban users were more likely to experience drops in hemoglobin of 2 g/dL or more, compared with warfarin users (2.8% vs. 2.3%, respectively; P = .02), as well as gastrointestinal bleeding (3.2% vs. 2.2%, respectively; P less than .001).
On the other hand, warfarin-treated patients more frequently experienced fatal bleeding (0.2% for rivaroxaban versus 0.5% for warfarin, P = .003) and intracranial bleeding (0.5% for rivaroxaban, versus 0.7% for warfarin, P =0.02). The target INR was maintained only 55% of the time in patients who received warfarin, the authors noted.
In addition to the study funding, Dr. Patel and several other authors of the study disclosed numerous financial relationships to pharmaceutical companies, including the makers of rivaroxaban; several authors were also employees of Johnson & Johnson as well as Bayer Healthcare.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Major Finding: The rate of stroke or embolism was 1.7% per year for rivaroxaban, compared with 2.2% per year for warfarin, for a hazard ratio of 0.79 among rivaroxaban recipients (95% confidence interval, 0.66-0.96, P < .001 for noninferiority).
Data Source: ROCKET AF, a randomized, double-blind trial of 14,264 patients with nonvalvular AF who were at high risk for stroke.
Disclosures: The study was sponsored by Johnson & Johnson and Bayer Healthcare, the U.S. and European marketers of rivaroxaban, respectively. Dr. Patel and several other authors on this study disclosed numerous financial relationships to pharmaceutical companies, including the makers of rivaroxaban; several authors were also employees of Johnson & Johnson and Bayer Healthcare.