ROCKET AF hit the AHA on Monday morning. Results of ROCKET AF (Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared With Warfarin in Patients with Nonvalvular Atrial Fibrillation) had been the topic of intense speculation and interest.
The trial showed that the experimental factor Xa inhibitor rivaroxaban was as effective as warfarin in preventing stroke in 14,264 AF patients and did not increase their risk of bleeding. In the per protocol analysis, the rate of stroke and embolism was lower in the rivaroxaban group than in the warfarin group (p<0.001 for non-inferiority, p=0.018 for superiority). Major bleeding complications occurred at a similar rate (p=0.576).
Rate of stroke and embolism:
- Rivaroxaban: 1.71 events per 100 patient-years
- Warfarin: 2.16 events per 100 patient-years
Major bleeding complications:
- Rivaroxaban: 3.60 events per 100 patient-years
- Warfarin: 3.45 events per 100 patient-years
However, in the full intention-to-treat analysis, the superiority of rivaroxaban over warfarin did not achieve statistical significance (p=0.177). Intracerebral hemorrhage occurred in 55 patients on riveroxaban and 84 on warfarin (p=0.019).
“The main implication is that we have an alternative to warfarin,” said Robert Califf, M.D., co-principal investigator of the study, in an AHA press release. “Equally important, there was no increase in bleeding, so we have a drug you can take once a day, without monitoring, that is at least as good as warfarin and carries no additional risk.”
Here is the AHA press release:
- The new anti-clotting drug rivaroxaban was comparable to warfarin in preventing stroke and non-CNS embolic events in a study of patients with atrial fibrillation that was unrelated to heart valve dysfunction.
- The drug did not increase the incidence of bleeding in the population studied.
CHICAGO, Nov. 15, 2010 – A new anti-clotting drug is as effective as the standard medication in preventing stroke and blood clots, and does not increase bleeding risk among patients with the most common form of irregular heartbeat, atrial fibrillation, according to late-breaking randomized, double-blind clinical trial results presented at the American Heart Association’s Scientific Sessions 2010.
In Stroke Prevention Using the Oral Direct Factor Xa Inhibitor Rivaroxaban Compared With Warfarin in Patients with Nonvalvular Atrial Fibrillation (ROCKET AF), investigators compared the new drug rivaroxaban with the traditional medicine warfarin in 14,264 patients with atrial fibrillation that was not related to heart valve disease. The median time that patients spent in the therapeutic range with warfarin during the course of the trial was 57.8 percent. Patients spent on average 11.9 percent of time above the therapeutic range, while they were below this range 19.7 percent of the time. In the primary analysis, measuring what happened to research participants while they were actually taking the study drug, those taking rivaroxaban compared with warfarin had fewer strokes and blood clots (emboli) to other parts of the body. With rivaroxaban there were 1.71 events per 100 patient-years (188 patients) and with warfarin 2.16 (241patients), p<0.001 for non-inferiority, p=0.018 for superiority. Major bleeding complications were comparable in both treatment groups, occurring at a rate of 3.60 per 100 patient-years (395 patients) with rivaroxaban and 3.45 per 100 patient-years (386 patients) with warfarin (p=0.576).The full intention-to-treat analysis, which counts all events from the time of randomization until study completion, regardless of whether participants were taking medication, found fewer strokes and blood clots occurred in participants assigned to rivaroxaban (269 patients) versus warfarin (306 patients). However, this difference fell short of statistical significance for declaring rivaroxaban superior to warfarin (p=0.177).Bleeding inside the skull cavity and/or brain tissue occurred in 55 patients on rivaroxaban and 84 on warfarin (p=0.019). “The main implication is that we have an alternative to warfarin,” said Robert M. Califf, M.D., co-principal investigator of the study and vice chancellor for clinical research at Duke University School of Medicine in Durham, N.C. “Equally important, there was no increase in bleeding, so we have a drug you can take once a day, without monitoring, that is at least as good as warfarin and carries no additional risk.”Rivaroxaban is one of several new drugs now in clinical trials that seek to replace warfarin, which for 50-plus years has been the primary anti-clotting medication on the market. Researchers have long sought a substitute for warfarin which requires frequent monitoring because it can interact with other medications and even certain foods to cause potentially excessive bleeding or lack of adequate blood thinning.This study, which comprised one of the largest patient populations of its kind, included 14,264 patients with irregular heartbeat (atrial fibrillation) unrelated to heart valve dysfunction at more than 1,100 hospitals in 45 countries. The median age was 73 and 43.5 percent were 75 years or older.
Forty percent of participants were women and 83 percent were white. More than half (55 percent) had suffered a prior stroke or a brief period of decreased blood flow to the brain (transient ischemic attack, or TIA).Researchers randomized participants to receive either 20 milligrams of rivaroxaban daily or an appropriately adjusted dose of warfarin. The study was conducted from December 2006 to May 2010, and average treatment lasted 19 months.Both rivaroxaban and warfarin prevent dangerous blood clots by blocking the action of vitamin-K-dependent proteins called clotting factors; rivaroxaban targets a specific clotting factor called Xa (i.e., 10a). While some blood clotting is necessary to prevent bleeding complications, too much can cause formation of life-threatening clots in patients with atrial fibrillation. “Warfarin is an effective drug to prevent stroke and emboli in the condition of atrial fibrillation, but it has to be monitored and many people are unhappy taking it,” said Keith A.A. Fox, M.B. Ch.B., study co-chair, president of the British Cardiovascular Society and professor of cardiology at the University of Edinburgh. “Patients and clinicians have been looking for an alternative for a long time, and the investigation of oral factor Xa inhibitors provided a good opportunity to see if a different class of drugs could be effective.”More than 2.5 million Americans live with irregular heartbeat, which increases the risk of stroke by four to five times and causes 15-20 percent of all blood-clot-related strokes. The disorder causes more than 11,000 deaths in the U.S. annually.The trial was coordinated by the Duke Clinical Research Institute and led by an international executive committee. Additional committee members are Guenter Breithardt, M.D.; Jonathan Halperin, M.D.; Graeme Hankey, M.D.; Kenneth Mahaffey, M.D.; Manesh Patel, M.D.; Daniel Singer, M.D.; Richard Becker, M.D.; Scott Berkowitz, M.D.; Werner Hacke, M.D.; Christopher Nessel, M.D.; and John Paolini, M.D. Investigator disclosures are on the abstract. Johnson & Johnson and Bayer HealthCare funded the study.
Here is the J&J press release:
Rivaroxaban Significantly Reduces Risk of Stroke in Patients with Atrial Fibrillation with Comparable Safety vs. Warfarin in Pivotal Phase 3 Study
Results Presented as a Late-Breaker at the Scientific Sessions of the American Heart Association
CHICAGO, NOVEMBER 15, 2010 /PRNewswire/ — Johnson & Johnson Pharmaceutical Research & Development, L.L.C. announced today that results from the pivotal Phase 3 double-blind ROCKET AF trial showed rivaroxaban given once daily was superior in reducing the risk of stroke and non-CNS systemic embolism in patients with atrial fibrillation (AF) with comparable safety versus warfarin, the most commonly used medicine for the prevention of stroke in AF patients.1
In the study, rivaroxaban was superior to warfarin for the primary efficacy endpoint, showing a 21% relative risk reduction (RRR) for stroke and non-CNS systemic embolism in the pre-specified on-treatment population2 (1.7%3 vs. 2.2%, respectively, p=0.015). Additionally, in the intent to treat population (ITT),4 which followed all patients randomized in the trial until its completion, whether or not they completed the full course of therapy or switched to other options, rivaroxaban showed comparable benefits to warfarin (2.1% vs. 2.4%, p<0.001 for non-inferiority). This result indicates that the treatment benefits compared to warfarin were sustained as long as the patients received rivaroxaban.
Rivaroxaban-treated patients also had numerically fewer myocardial infarctions (0.9% vs. 1.1%, p=0.121), and an observed reduction in rates of all-cause mortality compared to warfarin (1.9% vs. 2.2%, p=0.073), though these results were not statistically significantly different.
For the principal safety measure, rivaroxaban showed similar rates of major5 and non-major clinically relevant bleeding events,6 compared to warfarin (14.9% vs. 14.5%, p=0.442). Rates of major bleeding were also comparable between rivaroxaban and warfarin (3.6% vs. 3.5%, p=0.576). Patients treated with rivaroxaban had fewer intracranial hemorrhages (0.5% vs. 0.7%, p=0.019), critical organ bleeds (0.8% vs. 1.2%, p=0.007) and bleeding-related deaths (0.2% vs. 0.5%, p=0.003) compared to those treated with warfarin, but showed increased rates of hemoglobin/hematocrit drop (2.8% vs. 2.3%, p=0.019) and transfusions (1.7% vs. 1.3%, p=0.044), compared to warfarin. The frequency of abnormal laboratory values of liver function was balanced between the treatment groups. Rivaroxaban had similar rates of discontinuation due to adverse events compared to warfarin, and did not require routine laboratory coagulation monitoring.
“Given the prevalence and morbidity associated with atrial fibrillation, and the well-known difficulties with warfarin use, it is exciting to have an alternative which was documented in this study to be effective with no increase in significant bleeding,” said Robert M. Califf, M.D., study co-chairman and Vice Chancellor for Clinical Research from Duke University.
With 14,264 randomized patients, ROCKET AF is the largest double-blind study completed to date for the prevention of stroke in patients with AF. The study compared oral, once-daily rivaroxaban (20 mg, or 15 mg in patients with moderate renal insufficiency) to dose-adjusted warfarin.
“Results from the ROCKET AF study suggest that rivaroxaban has the potential to offer protection for the millions of Americans living with atrial fibrillation who carry the risk of suffering a stroke, which is often devastating and disabling,” said Peter M. DiBattiste, M.D., Vice President of Cardiovascular Development at Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
This is the seventh consecutive Phase 3 trial in the ongoing rivaroxaban global development program that has demonstrated either non-inferiority or superiority to standard of care.7-13
About Atrial Fibrillation
AF is the most common sustained cardiac rhythm disorder and affects more than 2.3 million people in the U.S.14 In patients with AF, the heart’s irregular heartbeat makes them vulnerable to the formation of a blood clot in the atria, which can travel to the brain, potentially resulting in a stroke. Strokes can lead to physical and behavioral impairments, or even death. People living with AF are at a five-fold increased risk for stroke compared with the general population, and almost one third will suffer from a stroke in their lifetime.15,16
About ROCKET AF
ROCKET AF (Rivaroxaban Once daily oral direct Factor Xa inhibition Compared with vitamin Kantagonism for prevention of stroke and Embolism Trial in AtrialFibrillation) was a prospective, randomized, double-blind, double-dummy parallel group outcomes study comparing once-daily rivaroxaban (20 mg, or 15 mg for patients with moderate renal impairment) with dose-adjusted warfarin in 14,264 patients with non-valvular atrial fibrillation who are at risk for stroke and non-CNS systemic embolism.
This was an event-driven trial, which ended when the pre-specified number of efficacy events was accumulated. The primary objective of ROCKET AF was to demonstrate the efficacy of once-daily rivaroxaban as non-inferior to dose-adjusted warfarin in the prevention of stroke and non-CNS systemic embolism in patients with non-valvular AF. The patients with AF evaluated in ROCKET AF typify those who are treated today by physicians with an anticoagulant to help reduce the risk of stroke.
Rivaroxaban is a novel oral anticoagulant being evaluated for the prevention and treatment of a broad range of disorders in which blood clotting plays a major role. In clinical studies, the compound has shown no requirement for routine laboratory coagulation monitoring, and limited risk for food and drug interactions. The extensive program of clinical trials evaluating rivaroxaban makes rivaroxaban the most studied oral, direct Factor Xa inhibitor in the world today. By the time of its completion, more than 65,000 patients will have participated in the rivaroxaban clinical development program. Rivaroxaban is being developed jointly by Johnson & Johnson Pharmaceutical Research & Development, L.L.C., which is part of the Johnson & Johnson family of companies, and Bayer HealthCare AG.
(This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from J&JPRD and/or Johnson & Johnson’s expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended January 3, 2010. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. Neither J&JPRD nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)