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., Competing Interests: Competing interests: GRD reports speaking honoraria from Bayer and Eli-Lilly. JB serves on the Advisory Board of and has received honoraria from Bayer AG. DL has received speaking honoraria from Bayer AG. VA received honoraria from Bayer, Amgen, NovoNordisk, Novartis, BMS/Pfizer alliance and Sanofi. SDB is employed by Bayer U.S., LLC, as a clinical research physician. DLB reports the following relationships advisory board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, PLX Pharma and Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care and TobeSoft; chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Medtelligence/ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), VA CART Research and Publications Committee (chair); research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic and The Medicines Company; royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site coinvestigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott) and Svelte; trustee: American College of Cardiology; unfunded research: Flow Co, Merck, Novo Nordisk and Takeda. SJC has received major research grants, consulting fees and speaker fees from Sanofi-Aventis, Janssen, Pfizer, Bristol-Myers Squibb, Boehringer-Ingelheim, Boston Scientific, Abbott, Bayer Pharmaceuticals Inc, Portola Pharmaceutical, Medtronic, Daiichi Sankyo and Servier. KAAF has received grants from Bayer/Janssen and AstraZeneca and has received consultancy fees from Bayer/Janssen, Sanofi/Regeneron and Verseon. EM is employed by Bayer AG, as a global clinical leader. PW has received grants and honoraria from Bayer AG, Boehringer Ingelheim, AstraZeneca and Servier. BRW has received speaking honoraria from Bayer AG. SY has received grants and honoraria from Bayer AG, Boehringer-Ingelheim, AstraZeneca, Bristol-Myers Squibb and Cadila Pharmaceuticals. JWE has received consulting fees and grant support from AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, Sanofi and Servier., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)