Rivaroxaban real-world evidence: Validating safety and effectiveness in clinical practice

Summary

Randomised controlled trials (RCTs) are considered the gold standard of clinical research as they use rigorous methodologies, detailed protocols, pre-specified statistical analyses and well-defined patient cohorts. However, RCTs do not take into account the complexity of real-world clinical decision-making. To tackle this, real-world data are being increasingly used to evaluate the long-term safety and effectiveness of a given therapy in routine clinical practice and in patients who may not be represented in RCTs, addressing key clinical questions that may remain. Real-world evidence plays a substantial role in supporting the use of non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) in clinical practice. By providing data on patient profiles and the use of anticoagulation therapies in routine clinical practice, real-world evidence expands the current awareness of NOACs, helping to ensure that clinicians are well-informed on their use to implement patient-tailored clinical decisions. There are various issues with current anticoagulation strategies, including under- or overtreatment and frequent monitoring with VKAs. Real-world studies have demonstrated that NOAC use is increasing (Dresden NOAC registry and Global Anticoagulant Registry in the FIELD-AF [GARFIELD-AF]), as well as reaffirming the safety and effectiveness of rivaroxaban previously observed in RCTs (XArelto on preveNtion of sTroke and non-central nervoUS system systemic embolism in patients with non-valvular atrial fibrillation [XANTUS] and IMS Disease Analyzer). This article will describe the latest updates in real-world evidence across a variety of methodologies, such as non-interventional studies (NIS), registries and database analyses studies. It is anticipated that these studies will provide valuable clinical insights into the management of thromboembolism, and enhance the current knowledge on anticoagulant use and outcomes for patients.

• References

• 1 Revicki DA, Frank L. Pharmacoeconomic evaluation in the real world. Effectiveness versus efficacy studies. Pharmacoeconomics 1999; 15: 423-434.
• 2 Cohen AT. et al. Why do we need observational studies of everyday patients in the real-life setting?. Eur Heart J Suppl 2015; 17 (Suppl D) D2-D8.
• 3 Garrison Jr LP. et al. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health 2007; 10: 326-335.
• 4 Annemans L. et al. Real-Life Data: A Growing Need. ISPOR. Available at: http://www.ispor.org/news/articles/oct07/rld.asp Accessed June 22, 2016.
• 5 Beyer-Westendorf J. et al. Venous thromboembolism prevention and treatment: expanding the rivaroxaban knowledge base with real-life data. Eur Heart J Suppl 2015; 17 (Suppl D) D32-D41.
• 6 Cox JL, de Pouvourville G. Achieving access: addressing the needs of payors and health technology assessment agencies. Eur Heart J Suppl 2015; 17 (Suppl D) D15-D20.
• 7 Theobald K. et al. Quality assurance in non-interventional studies. Ger Med Sci 2009; 07 Doc 29.
• 8 Camm AJ. et al. XANTUS: rationale and design of a noninterventional study of rivaroxaban for the prevention of stroke in patients with atrial fibrillation. Vasc Health Risk Manag 2014; 10: 425-434.
• 9 Camm AJ. et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J 2016; 37: 1145-1153.
• 10 Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia (XANAP). https://clinicaltrials.gov/ct2/show/NCT01750788
• 11 Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region (XANTUS-EL). https://clinicaltrials.gov/ct2/show/ NCT01800006
• 12 Nessel C. et al. Incidence and outcomes of gastrointestinal hemorrhage in patients with atrial fibrillation treated with rivaroxaban or warfarin: Results from the ROCKET AF trial. Chest 2012; 142 (4_MeetingAbstracts): 84A.
• 13 Patel MR. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
• 14 Tamayo S. et al. Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban. Clin Cardiol 2015; 38: 63-68.
• 15 Beyer-Westendorf J. et al. Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 2014; 124: 955-962.
• 16 Amarenco P. et al. Outcomes associated with off-label dosing of rivaroxaban in the XANTUS study. Oral presentation at European Stroke Organisation Conference 2016. Eur Stroke J 2016; 01 (1 Suppl.) 3-612.
• 17 Ageno W. et al. Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 2016; 03: e12-e21.
• 18 Ageno W. et al. XALIA: rationale and design of a non-interventional study of rivaroxaban compared with standard therapy for initial and long-term anticoagulation in deep vein thrombosis. Thromb J 2014; 12: 16.
• 19 van Bellen B. et al. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin 2014; 30: 829-837.
• 20 EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
• 21 An Observational Post-Authorization Safety Specialist Cohort Event Monitoring Study (SCEM) to Monitor the Safety and Utilization of Rivaroxaban (Xarel-to®) (ROSE). https://clinicaltrials gov/ct2/show/NCT01871194
• 22 The Drug Safety Research Unit (DSRU) – The Rivaroxaban Observational Safety Evaluation (ROSE) Study. The Drug Safety Research Unit. Available at http://www.dsru.org/study-recruitment/rose/ Accessed June 22, 2016.
• 23 Trotter JP. Patient registries: a new gold standard for “real world” research. Ochsner J 2002; 04: 211-214.
• 24 Kakkar AK. et al. International longitudinal registry of patients with atrial fibrillation at risk of stroke: Global Anticoagulant Registry in the FIELD (GAR-FIELD). Am Heart J 2012; 163: 13-19.
• 25 Kakkar AK. et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS One 2013; 08: e63479.
• 26 Bassand JP. Truly low-risk patients with newly diagnosed non-valvular atrial fibrillation at risk of stroke: 1-year outcomes from the GARFIELD Registry. Eur Heart J 2014; 35 (Suppl): 1108.
• 27 Haas S. et al. International normalized ratio control and 1-year outcomes in patients with newly diagnosed atrial fibrillation: the GARFIELD Registry. Eur Heart J 2014; 35 (Suppl) 1110.
• 28 Cate H. et al. Quality of vitamin k antagonist control and 1-year outcomes: a global perspective from the GARFIELD-AF registry. J Thromb Haemost 2015; 13: 1-997.
• 29 Camm AJ. Patterns of uptake of non-vitamin K antagonist oral anticoagulants in Europe: an analysis from the GARFIELD-AF registry. Eur Heart J 2015; 36 (Suppl) 242.
• 30 Camm AJ. Evolving antithrombotic treatment patterns in patients with newly diagnosed atrial fibrillation in GARFIELD-AF. Eur Heart J 2015; 36 (Suppl) 745-746.
• 31 Kakkar AK. GARFIELD-AF – Global status of GARFIELD-AF. Oral symposium presentation at European Society of Cardiology (ESC) Congress. 2015
• 32 Goldhaber SZ. GARFIELD-AF – Impact of comorbidities on outcomes in cohorts 1–3. Oral symposium presentation at European Society of Cardiology (ESC) Congress. 2015
• 33 Global Anticoagulant Registry in the FIELD- Venous Thromboembolic Events (GARFIELD-VTE). https://clinicaltrials gov/ct2/show/NCT02155491
• 34 GARFIELD-VTE Information. Thrombosis Research Institute. Available at http://www.tri-london.ac.uk/garfield-vte/information Accessed June 22, 2016.
• 35 Akao M. et al. Stroke prevention in atrial fibrillation: evidence from real-life studies. Eur Heart J Suppl 2015; 17 (Suppl D) D42-D52.
• 36 Freeman JV. et al. Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circ Cardiovasc Qual Outcomes 2015; 08: 393-402.
• 37 Pokorney S. et al. The myth of the stable INR patient: Results from ORBIT-AF. J Am Coll Cardiol 2015; 65: 10_S.
• 38 Lip GY. et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score. J Am Coll Cardiol 2011; 57: 173-180.
• 39 O’Brien EC. et al. The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J 2015; 36: 3258-3264.
• 40 Steinberg BA. et al. Increased Heart Rate Is Associated With Higher Mortality in Patients With Atrial Fibrillation (AF): Results From the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF). J Am Heart Assoc 2015; 04: e002031.
• 41 Steinberg BA. et al. Real-world experiences with novel anticoagulants for AF: Initial insights from ORBIT-AF Phase II. Circ Cardiovasc Qual Outcomes 2014; 07 (Suppl) A336.
• 42 Beyer-Westendorf J. Dresden NOAC registry: Data on File..
• 43 Beyer-Westendorf J. et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014; 35: 1888-1896.
• 44 Beyer-Westendorf J. et al. Safety of switching from vitamin K antagonists to dabigatran or rivaroxaban in daily care – results from the Dresden NOAC registry. Br J Clin Pharmacol 2014; 78: 908-917.
• 45 Hecker J. et al. Effectiveness and safety of rivaroxaban therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2016; 115: 939-949.
• 46 Marten S. et al. Pattern and Management of ISTH Major Bleeding Complications with Direct Oral Anticoagulants – Results of the Prospective Dresden NOAC Registry (NCT01588119). Blood 2015; 126: 892.
• 47 Beyer-Westendorf J. et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost 2015; 113: 1247-1257.
• 48 Beyer-Westendorf J. et al. Drug persistence with rivaroxaban therapy in atrial fibrillation patients-results from the Dresden non-interventional oral anticoagulation registry. Europace 2015; 17: 530-538.
• 49 Beyer-Westendorf J. et al. Real-world persistence and adherence to oral antico agulation for stroke risk reduction in patients with atrial fibrillation. Europace 2016; 18: 1150-1157.
• 50 Coleman CI. et al. REal-LIfe Evidence of stroke prevention in patients with atrial Fibrillation – The RELIEF study. Int J Cardiol 2016; 203: 882-884.
• 51 Martinez C. et al. Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer. Thromb Haemost 2014; 112: 255-263.
• 52 Cunningham A. et al. An automated database case definition for serious bleeding related to oral anticoagulant use. Pharmacoepidemiol Drug Saf 2011; 20: 560-566.
• 53 Bayer AGPharma. Xarelto Summary of Product Characteristics. European Medicines Agency. Available at: http://www.ema.europa.eu/docs/en_GB/docu ment_library/EPAR_-_Product_Information/human/ 000944/WC500057108.pdf
• 54 Tamayo S. et al. Abstract 17246: Risk Factors for Major Bleeding Events in Riva roxaban Users With Atrial Fibrillation: A Nested Case-control Study. Circulation 2015; 132 (Suppl. 03) A17246.
• 55 New Data from U.S. Post-Approval Study Assess Ischemic Stroke and Intracranial Hemorrhage Rates in People with Non-Valvular Atrial Fibrillation Comparing Both Rivaroxaban with Warfarin and Apixaban with Warfarin. PR News-wire. Available at: http://www.prnewswire.com/news-releases/new-data-from-us-post-approval-study-assess-ischemic-stroke-and-intracranial-hemorrhage-rates-in-people-with-non-valvular-atrial-fibrillation-comparing-both-rivaroxaban-with-warfarin-and-apixaban-with-warfarin-300252765.html Accessed June 22, 2016.
• 56 Becher H. et al. Validity and representativeness of the “Disease Analyzer” patient database for use in pharmacoepidemiological and pharmacoeconomic studies. Int J Clin Pharmacol Ther 2009; 47: 617-626.
• 57 Turpie AG. et al. A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thromb Haemost 2014; 111: 94-102.
• 58 Turpie AG. et al. Rationale and design of XAMOS: noninterventional study of rivaroxaban for prophylaxis of venous thromboembolism after major hip and knee surgery. Vasc Health Risk Manag 2012; 08: 363-370.
• 59 Observational Studies: Regulatory Considerations. Samedan Ltd. Available at http://www.samedanltd.com/magazine/11/issue/175/article/3276 Accessed June 22, 2016.
• 60 Benefits of a national patient registry. World Hemophilia Federation. Available at http://www1.wfh.org/publication/files/pdf-1381.pdf Accessed June 22, 2016.
• 61 Levine MN, Julian JA. Registries that show efficacy: good, but not good enough. J Clin Oncol 2008; 26: 5316-5319.
• 62 Riley GF. Administrative and claims records as sources of health care cost data. Med Care 2009; 47 (7 Suppl 1) S51-S55.
• 63 Bowman S. Impact of Electronic Health Record Systems on Information Integrity: Quality and Safety Implications. Perspect Health Inf Manag. 2013 10. 1c: eCollection 2013
• 64 Global Anticoagulant Registry in the Field – Atrial Fibrillation (GARFIELD-AF). https://clinicaltrials gov/ct2/show/NCT01090362
• 65 GARFIELD-AF Information. Thrombosis Research Institute. Available at: http://www.tri-london.ac.uk/garfield/information Accessed June 22, 2016.
• 66 Piccini JP. et al. Outcomes registry for better informed treatment of atrial fibrillation: rationale and design of ORBIT-AF. Am Heart J 2011; 162: 606-612.
• 67 Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). https://clinicaltrials gov/ct2/show/NCT01165710
• 68 Steinberg BA. et al. Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II: rationale and design of the ORBIT-AF II registry. Am Heart J 2014; 168: 160-167.
• 69 Köhler C. et al. Acute Treatment Of Pulmonary Embolism With Rivaroxaban – Real Life Data From The Prospective Dresden Noac Registry (NCT01588119). Blood 2013; 122: 2380.