Reassuring Worldwide Safety Data on Rivaroxaban in AF

July 02, 2018

The largest dataset yet reported on use of the new novel oral anticoagulant (NOAC) rivaroxaban (Xarelto, Bayer) in patients with atrial fibrillation (AF) has shown reassuringly low rates of bleeding, stroke, and treatment discontinuation, with broadly consistent results across regions.

The real-world analysis of rivaroxaban use in 11,121 patients from 47 countries is published online July 2 in the Journal of the American College of Cardiology.

This observational dataset is the largest prospective safety study of a single NOAC published so far. A prior paper reported on the use of rivaroxaban in around 6700 patients in Europe, which was mandated by the European Medicines Agency as part of the approval of the drug in Europe.

"This paper has now added in an extra approximately 4500 patients from Asia, Africa, and South America and gives more reassurance on the safety of rivaroxaban and particularly important data on its use in patients from different parts of the world," study author Paulus Kirchhof, MD, University of Birmingham, United Kingdom, told Medscape Medical News.

"Our results show a very reassuring safety profile of the drug with a 0.2% rate of fatal bleeding, and an ICH rate of 0.2%.  It also suggests impressive efficacy with an annualized rate of stroke of just 1.0%. This compares well to the randomized trials, which showed an ICH [intracerebral hemorrhage] rate of 0.4% to 0.5% and an annualized stroke rate of 1.5%. So we can say that in everyday practice it looks very similar if not a little bit better than the results of the randomized trials," he added.

Kirchhof noted that NOACs are increasingly being used to replace warfarin because they do not require monitoring and clinical trials of the new drugs have shown efficacy similar to that of warfarin but better safety.

"However, there are always concerns when new drugs are used in clinical practice in different populations that they may show different outcomes than in the strictly controlled environments of a randomized controlled trial, so these large observational datasets of use in the real world are very much needed."

He pointed out that in the case of rivaroxaban it was particularly important to obtain data from different populations, especially in Asia, where a lower dose of the drug is used. 

Pooled Analysis

"A dose of 15 mg/day was approved in several Asian countries, which is the same as the dose recommended for patients with reduced kidney function in Europe and North America. There was a study done in Japan on the 15-mg dose, but there hasn't been much postapproval data available from countries using this dose, so it's good to have that in this paper," he said.

The United States is not included in this study. Separate papers published on the use of the drug in the United States have shown similar results, he added.

The current study was a preplanned pooled analysis of XANTUS (Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation) worldwide registries, in which patients with AF newly starting rivaroxaban for stroke prevention were followed for 1 year.

Primary outcomes were treatment-emergent major bleeding, adverse events, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and nonmajor bleeding.

Patients in the dataset had a mean age of 70.5 years, and 43% were female. Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%).

Results showed 1.7 major bleeding events/100 patient-years, varying from 0.7 in Latin America to 2.3 in Western Europe, Canada, and Israel.

The rate of all-cause death was 1.9/100 patient-years, ranging from 1.5 in Eastern Europe to 2.7 in Latin America, the Middle East, and Africa.

The rate of stroke or systemic embolism was 1.0 per 100 patient-years, varying from  0 in Latin America to 1.8 in East Asia.

One-year treatment persistence was 77.4%, ranging from 66.4% in East Asia 66.4% to 84.4% in Eastern Europe.

The authors note that in this dataset rivaroxaban was rarely used in patients who would not have been eligible for clinical trials, with 97.3% of patients having a CHA2DS2-VASc score of at least 1, only 1.9% of patients having a creatinine clearance of less than 30 mL/min, and approximately three quarters of patients receiving the indicated dose of rivaroxaban.

"Unique and Valuable" Research

In an accompanying editorial, Jeff S. Healey, MD, Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, said that "understanding regional variation in the use of a new medication and the associated clinical outcomes is a unique and valuable facet of this analysis, which will help local physicians to better understand and improve the use of NOAC therapy in their region."

"This important paper demonstrates that the use of rivaroxaban is largely in accordance with published guidelines, and the rates of stroke and major bleeding were the same or better compared with the seminal NOAC trials in AF," he writes.

Healey says these data represent what typical clinicians might expect if they use a NOAC in accordance with local product labeling and practice guidelines "and are a testament to the successful introduction of NOACs into the clinical practice."  

"The clinical trials of anticoagulation for stroke prevention in AF are among the most successful in all of medicine. Now, it appears that the translation of their results into clinical practice has achieved a similar status," he concludes.

On how rivaroxaban compares with other NOACs, Kirchhof said it wasn't possible to compare between trials but all the clinical trial and observational data looked similar in terms of safety and stroke prevention.

He said he uses all four NOACs — rivaroxaban, dabigatran, apixaban, and edoxaban — regularly, and he does not believe there is any reason to favor any one particular agent over the others in general terms. However, he added, in some specific circumstances there are reasons to choose one over another.

"For example dabigatran comes in quite large capsules, which some patients find difficult to swallow, but it is the only NOAC approved at two different doses so may be a good choice for patients in whom a slow start to anticoagulation is thought appropriate — ie, if there is a concern about bleeding risk.

"Apixaban is the least reliant on kidney function for clearance so may be the best for patients with renal disease. Then they all have slightly different side effect profiles — and for some reason patients may have nuisance bleeding on one but this often stops when switched to a different one. So it's great to have four different options."

The XANTUS research program was funded by Bayer. Kirchhof has received research support from 3M Medica, MEDA Pharma, AstraZeneca, Bayer HealthCare, Biosense Webster, Boehringer Ingelheim, Daiichi-Sankyo, German Cardiac Society, Medtronic, Merck Sharp & Dohme, Otsuka Pharma, Pfizer/ Bristol-Myers Squibb, Sanofi, Servier, Siemens, and Takeda; has received honoraria from several such companies; and is listed as an inventor on two pending patents held by the University of Birmingham on therapy and markers for AF. Some coauthors are employees of Bayer. Healey has received research grants from Bristol-Myers Squibb, Pfizer, and Boehringer Ingelheim and speaking fees from Bristol-Myers Squibb, Pfizer, Servier, and Bayer.

J Am Coll Cardiol. Published online July 2, 2018. Abstract, Editorial

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