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Early stopping of a randomised trial for efficacy: a medical, ethical and regulatory challenge
  1. Arthur Darmon1,2,
  2. Gregory Ducrocq1,2
  1. 1FACT (French Alliance for Cardiovascular Trials), DHU-FIRE, Hopital Bichat-Claude Bernard, Paris, France
  2. 2Université de Paris, Assistance Publique—Hôpitaux de Paris, Paris, France
  1. Correspondence to Dr Arthur Darmon, Department of Cardiology, Assistance Publique - Hopitaux de Paris, 75004 Paris, France; arthur.darmon{at}gmail.com

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In 2017, the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS1) trial demonstrated the efficacy of a combination of low-dose rivaroxaban 2.5 mg two times per day and aspirin 100 mg one time per day in reducing ischaemic events in a broad population of high-risk patients with chronic coronary syndromes and/or peripheral arterial disease. The European Society of Cardiology therefore recommends this combination therapy for long-term secondary prevention in high-risk patients. COMPASS was prematurely terminated after a mean follow-up of 23 months due to a clear benefit in the combination arm. This decision, although ethically justified, raises important questions both in the context of this specific study and also in the context of clinical research in general.

Dagenais et al2 led a post hoc analysis of the COMPASS trial to assess the effect of switching study treatment combination of low-dose rivaroxaban and aspirin to non-study aspirin after early stopping of the trial. Patients included in the rivaroxaban alone arm were not considered in the present analysis. Patients were followed from the time of the early stopping until last contact, which could be the final follow-up of the proton pump inhibitor randomisation, in August 2018, or the beginning of the long-term open-label extension (LTOLE) study during which patients received the combination of rivaroxaban and aspirin for 3 years or until the medication was available on the market. This LTOLE study began after regulatory and ethical approval in different countries. Median follow-up duration was 1.02 years (0.74, 1.11). The main outcomes were similar to the main COMPASS analysis: a composite of cardiovascular (CV) death, myocardial infarction (MI), stroke, its individual components and limb events. Events were verified using a computer-programmed algorithm or were adjudicated if the …

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Footnotes

  • Contributors AD and GD participated in the writing and editing of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests AD discloses the following: research grants from Abbott and travel fees by AlviMedica and Bayer. GD discloses speaker’s and/or consulting fees from Amgen, AstraZeneca, Bayer, BMS, Janssen, Sanofi and Terumo.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; externally peer reviewed.

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