Post-authorization safety study (PASS) investigating the bleeding risk in patients treated with rivaroxaban


Rivaroxaban (Xarelto®) is a direct oral anticoagulant (DOAC) promising better control of therapy in comparison to vitamin K antagonists such as phenprocoumon. It was approved across Europe in 2008 by the European Medicines Agency (EMA) for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery. In December 2011, the approval was extended to the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, to the treatment of deep vein thrombosis and pulmonary embolism, and the prevention of recurrent deep vein thrombosis and pulmonary embolism in adults. Since May 2013, rivaroxaban has also been approved for the prevention of atherothrombotic events in adult patients following acute coronary syndrome with elevated cardiac biomarkers to be administered with acetylsalicylic acid alone or with acetylsalicylic acid plus clopidogrel or ticlopidine.

Because of their anticoagulant properties, rivaroxaban as well as other anticoagulants such as vita-min K antagonists (VKA) are associated with an increased risk of bleeding. For instance, compared to the internationally common VKA warfarin, rivaroxaban showed a similar frequency of clinically relevant bleedings with significantly less intracranial and fatal bleedings, whereas gastrointestinal bleedings were more frequent.

Especially the prophylactic indications include a patient population with potentially numerous comorbidities and comedications. They also require long-term therapy in which a risk-benefit-assessment is particularly important. EMA therefore requires the manufacturer Bayer AG in a risk-management plan to conduct post-authorization safety studies (PASS) in different European coun-tries by 2021. The aim of this safety study is to examine severe adverse side effects under rivaroxa-ban treatment in routine clinical practice compared to phenprocoumon, the VKA most often used in Germany, and in the indication of acute coronary syndrome compared to therapy with antiplatelet agents.

Based on data from the German Pharmacoepidemiological Research database (GePaRD), a cohort study will compare different endpoints between new users of rivaroxaban and the respective standard therapy. The primary safety outcome is the occurrence of bleeding events such as intracranial hemorrhage, gastrointestinal, and urogenital bleeding. Another safety outcome will be the occurrence of non- infectious liver disease. Further, to enable a risk-benefit- assessment, outcomes related to effectiveness such as deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, and mortality will be investigated. Similar studies which are part of this PASS program will be conducted in Great Britain, Sweden, and the Netherlands by 2021.

Funding period

Begin:   November 2010
End:   December 2022


  • Pharmaceutical industry


 Annemarie Voß

Selected project-related publications

    Presentations at scientific meetings/conferences

  • Fassmer A, Jobski K, Haug U, Schink T. Rivaroxaban vs. phenprocoumon use in Germany and risk of bleeding: A claims data analysis based on 80,000 patients. Congress "Health - Exploring Complexity: An Interdisciplinary Systems Approach (HEC2016)." Joint Annual Meeting of the German Society for Medical Informatics, Biometry and Epidemiology (GMDS), the German Society for Epidemiology (DGEpi), the International Epidemiological Association - European Region (IEA-EEF) and the European Federation for Medical Informatics Association (EFMI), 28 August-2 September 2016, Munich. (Abstract published in: European Journal of Epidemiology. 2016;31(Suppl.1):S51)
  • Posters at scientific meetings/conferences

  • Fassmer A, Jobski K, Haug U, Schink T. Rivaroxaban vs. phenprocoumon use in Germany and risk of bleeding: A claims data analysis based on 80,000 patients. 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), 25-28 August 2016, Dublin, Ireland.