A new post-marketing study evaluating the safety of once-daily XARELTO (rivaroxaban) shows, in patients with non-valvular atrial fibrillation (NVAF), rates and patterns of major bleeding in routine clinical practice are generally consistent with those observed in Phase 3 clinical trials used to approve the medicine for this indication. These fifteen-month results, published in Clinical Cardiology, represent initial findings from an ongoing, five-year, observational study of patients using XARELTO daily over the course of their lives.
“These findings reaffirm the safety profile of XARELTO,” said W. Frank Peacock (co-author of the manuscript), M.D., FACEP, Associate Chair and Research Director, Emergency Medicine, Baylor College of Medicine. “We anticipate future findings from this five-year observational study will continue to provide real-world information about the use of XARELTO in routine clinical practice.”
Researchers analyzed data from January 1, 2013 to March 31, 2014 using U.S. Department of Defense (DoD) integrated electronic healthcare records, via a collaboration with Health ResearchTx LLC (HRTX), to evaluate major bleeding rates in NVAF patients treated with XARELTO in the real-world clinical setting. Of the 27,467 patients receiving XARELTO, an incidence of major bleeding was observed at 2.86 per 100 person-years, which was generally consistent with rates reported in the ROCKET-AF clinical trial. Additionally, patients who experienced major bleeding were older (with a mean age of 78) and fatal outcomes were rare.
Janssen Pharmaceuticals, Inc. (Janssen) designed the study, in conjunction with DoD and HRTX, and in agreement with the U.S. Food and Drug Administration (FDA), to proactively ascertain, analyze and report potential side effects with XARELTO use, including major bleeding events, associated risk factors and bleeding-related clinical outcomes in NVAF patients receiving XARELTO. Major bleeding cases for this study were ascertained using a validated Cunningham (2011) algorithm, which was generally consistent with, but not identical to the definition of major bleeding used in clinical studies, because it relied on retrospectively identified electronic medical records. While the results are not intended for any direct comparison, these data show rates and patterns of major bleeding were generally consistent with those reported in the previous large randomized FDA registration trial of XARELTO.
“After more than three years on the market and more than 10 million patients prescribed we continue to monitor the safety performance of our medicine. We are pleased with these findings, which demonstrate XARELTO is performing as expected in the real-world setting,” said Paul Burton, M.D., Ph.D., Vice President, Medical Affairs, Janssen. “With studies completed in over 85,000 patients and ongoing post-marketing studies that will include more than 74,000 patients, we continue to advance our real world data to ensure doctors and patients are equipped with the latest information about XARELTO to optimize patient care.”
By the time of its completion, more than 275,000 patients will have participated in the XARELTO clinical development program, other completed and ongoing clinical trials, investigative registries and non-interventional studies. As a part of this program, Janssen is conducting a number of post-marketing surveillance studies, through its ongoing development partnership with Bayer HealthCare, to further assess the benefit-risk profile of XARELTO in real-world settings. Results to date have shown the safety and efficacy observed since the medicine was approved are generally consistent with completed Phase 3 clinical trials. It is anticipated that by July 2015, this robust program of Phase 4, observational studies will include more than 74,000 patients across six approved indications, including the following studies:
- XAMOSXAMOS is a non-interventional Phase 4 study, which showed in routine clinical practice, patients treated with XARELTO were observed to have a numerically lower rate of venous thromboembolism (VTE) in patients after major orthopedic surgery, and were not observed to have a higher rate of major bleeding, compared to standard of care. The study was not randomized, so the comparison needs to be interpreted with caution. The study included over 17,700 patients from 37 countries.
- XALIA is a multi-center, prospective, non-interventional, observational study currently investigating the safety and efficacy of a single-drug approach with XARELTO® compared with standard therapy for the treatment of acute VTE. The study cohort will include more than 4,800 patients in over 20 European countries. The first patient was enrolled in June 2012, with results expected in 2015.
- XANTUS is a prospective, international, observational, post-authorization, non-interventional study designed to collect safety and efficacy data on the use of XARELTO® for stroke prevention in routine clinical practice. This ongoing study will enroll approximately 6,000 patients with NVAF prescribed XARELTO, irrespective of their level of stroke risk. While this study is focused in Europe, similar studies (XANTUS-EL and XANAP) are ongoing in Latin America and Asia-Pacific.
Additionally, data published in Current Medical Research and Opinion found XARELTO and warfarin did not differ significantly in real-world effectiveness and safety for the prevention of stroke and systemic embolism in patients with NVAF. Findings from this U.S. healthcare claims database evaluating more than 18,270 patients also showed XARELTO was associated with fewer cases of VTE and significantly better treatment persistence compared to warfarin.
 Goodman SG, et al. Factors Associated with Major Bleeding Events: Insights from the Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation 23(ROCKET AF), Journal of the American College of Cardiology (2013), doi:0.1016/j.jacc.2013.11.013. In press.
Characterizing Major Bleeding in Patients With Nonvalvular Atrial Fibrillation: A Pharmacovigilance Study of 27 467 Patients Taking Rivaroxaban, Sally Tamayo MD, W. Frank Peacock MD, Manesh Patel MD, Nicholas Sicignano MPH, Kathleen P. Hopf MPH, Larry E. Fields MD, MBA, Troy Sarich PhD, Shujian Wu MD, PhD, Daniel Yannicelli MD and Zhong Yuan MD, PhD, Clinical Cardiology, DOI: 10.1002/clc.22373, published online 14 January 2015.