OBJECTIVE: In patients with chronic coronary or peripheral artery disease enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, randomised antithrombotic treatments were stopped after a median follow-up of 23 months because of benefits of the combination of rivaroxaban 2.5 mg two times per day and aspirin 100 mg once daily compared with aspirin 100 mg once daily. We assessed the effect of switching to non-study aspirin at the time of early stopping. METHODS: Incident composite of myocardial infarction, stroke or cardiovascular death was estimated per 100 person-years (py) during randomised treatment (n=18 278) and after study treatment discontinuation to non-study aspirin (n=14 068). RESULTS: During randomised treatment, the combination compared with aspirin reduced the composite (2.2 vs 2.9/100 py, HR: 0.76, 95% CI 0.66 to 0.86), stroke (0.5 vs 0.8/100 py, HR: 0.58, 95% CI 0.44 to 0.76) and cardiovascular death (0.9 vs 1.2/100 py, HR: 0.78, 95% CI 0.64 to 0.96). During 1.02 years after early stopping, participants originally randomised to the combination compared with those randomised to aspirin had similar rates of the composite (2.1 vs 2.0/100 py, HR: 1.08, 95% CI 0.84 to 1.39) and cardiovascular death (1.0 vs 0.8/100 py, HR: 1.26, 95% CI 0.85 to 1.86) but higher stroke rate (0.7 vs 0.4/100 py, HR: 1.74, 95% CI 1.05 to 2.87) including a significant increase in ischaemic stroke during the first 6 months after switching to non-study aspirin. CONCLUSION: Discontinuing study rivaroxaban and aspirin to non-study aspirin was associated with the loss of cardiovascular benefits and a stroke excess. TRIAL REGISTRATION NUMBER: NCT01776424.

Bayer HealthCare Pharmaceuticals Whippany New Jersey USA

Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School Boston Massachusetts USA

Cardiocenter University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Cardiology Dupuytren University Hospital Limoges France

Department of Cardiology INSERM U1094 Tropical Neuroepidemiology Limoges France

Department of Cardiology Laval University Heart and Lung Institute Quebec Québec Canada

Department of Medicine University of Edinburgh Edinburgh UK

Department of Medicine University of Washington Medical Centre Seattle Washington USA

Kardiologische Studienpraxis und ClinPhenomics GmbH and Co Studienzentrum Schaumainkai Frankfurt Frankfurt Germany

Population Health Research Institute Hamilton Health Sciences McMaster University Hamilton Ontario Canada

doi: 10.1136/heartjnl-2021-318941 PubMed

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Sundström J, Hedberg J, Thuresson M, et al. . Low-dose aspirin discontinuation and risk of cardiovascular events: a Swedish nationwide, population-based cohort study. Circulation 2017;136:1183–92. 10.1161/CIRCULATIONAHA.117.028321 PubMed DOI

Rivera-Caravaca JM, Roldán V, Esteve-Pastor MA, et al. . Cessation of oral anticoagulation is an important risk factor for stroke and mortality in atrial fibrillation patients. Thromb Haemost 2017;117:1448–54. 10.1160/TH16-12-0961 PubMed DOI

Eikelboom JW, Connolly SJ, Bosch J, et al. . Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319–30. 10.1056/NEJMoa1709118 PubMed DOI

Eikelboom JW, Bosch JJ, Connolly SJ, et al. . Major Bleeding in Patients With Coronary or Peripheral Artery Disease Treated With Rivaroxaban Plus Aspirin. J Am Coll Cardiol 2019;74:1519–28. 10.1016/j.jacc.2019.07.065 PubMed DOI

Anand SS, Bosch J, Eikelboom JW, et al. . Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:219–29. 10.1016/S0140-6736(17)32409-1 PubMed DOI

Bosch J, Eikelboom JW, Connolly SJ, et al. . Rationale, design and baseline characteristics of participants in the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial. Can J Cardiol 2017;33:1027–35. 10.1016/j.cjca.2017.06.001 PubMed DOI

Connolly SJ, Eikelboom JW, Bosch J, et al. . Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018;391:205–18. 10.1016/S0140-6736(17)32458-3 PubMed DOI

Cairns JA, Eikelboom JW, Shestakovska O, et al. . Monitoring emerging data from theCOMPASS trial of an antithrombotic agent. J Am Coll Cardiol 2019;73:2769–72. 10.1016/j.jacc.2019.03.479 PubMed DOI

Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 1999;94:496–509. 10.1080/01621459.1999.10474144 DOI

Patel MR, Hellkamp AS, Lokhnygina Y, et al. . Outcomes of discontinuing rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: analysis from the ROCKET AF trial (rivaroxaban once-daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol 2013;61:651–8. 10.1016/j.jacc.2012.09.057 PubMed DOI

Ruff CT, Giugliano RP, Braunwald E, et al. . Transition of patients from blinded study drug to open-label anticoagulation: the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol 2014;64:576–84. 10.1016/j.jacc.2014.05.028 PubMed DOI

Eikelboom JW, Vanassche T, Connolly SJ. Switching patients from blinded study drug to warfarin at the end of the ENGAGE AF-TIMI 48 trial: setting a new standard. J Am Coll Cardiol 2014;64:585–7. 10.1016/j.jacc.2014.06.008 PubMed DOI

Groot AE, Vermeij J-DM, Westendorp WF, et al. . Continuation or discontinuation of anticoagulation in the early phase after acute ischemic stroke. Stroke 2018;49:1762–5. 10.1161/STROKEAHA.118.021514 PubMed DOI

Devereaux PJ, Mrkobrada M, Sessler DI, et al. . Aspirin in patients undergoing noncardiac surgery. N Engl J Med 2014;370:1494–503. 10.1056/NEJMoa1401105 PubMed DOI

Connolly SJ, Ezekowitz MD, Yusuf S, et al. . Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51. 10.1056/NEJMoa0905561 PubMed DOI

Patel MR, Mahaffey KW, Garg J, et al. . Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 10.1056/NEJMoa1009638 PubMed DOI

Spronk HMH, de Jong AM, Crijns HJ, et al. . Pleiotropic effects of factor Xa and thrombin: what to expect from novel anticoagulants. Cardiovasc Res 2014;101:344–51. 10.1093/cvr/cvt343 PubMed DOI

Sharma M, Hart RG, Connolly SJ, et al. . Stroke outcomes in the COMPASS trial. Circulation 2019;139:1134–45. 10.1161/CIRCULATIONAHA.118.035864 PubMed DOI

da Silva RE, Amato AA, Sousa TdoR, et al. . The patient's safety and access to experimental drugs after the termination of clinical trials: regulations and trends. Eur J Clin Pharmacol 2018;74:1001–10. 10.1007/s00228-018-2474-9 PubMed DOI

Dainesi SM, Goldbaum M. Provision of investigational drug after clinical research: review of literature, national and international guidelines. Rev Assoc Med Bras 2011;57:696–702. 10.1016/S0104-4230(11)70139-7 PubMed DOI

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NCT01776424