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Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Background
Aspirin has been proposed as a treatment for COVID-19 on the basis of its anti-thrombotic properties. We aimed to evaluate the efficacy and safety of aspirin in patients admitted to hospital with COVID-19.
Methods
In this randomised, controlled, open-label, platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. The trial took place at 177 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care plus 150 mg aspirin once per day until discharge or usual standard of care alone using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28 day mortality. All analyses were done by intention to treat. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).
Findings
Between Nov 1, 2020, and March 21, 2021, 14 892 (66%) of 22 560 patients enrolled into the RECOVERY trial were eligible to be randomly allocated to aspirin. 7351 patients were randomly allocated (1:1) to receive aspirin and 7541 patients to receive usual care alone. Overall, 1222 (17%) of 7351 patients allocated to aspirin and 1299 (17%) of 7541 patients allocated to usual care died within 28 days (rate ratio 0·96, 95% CI 0·89–1·04; p=0·35). Consistent results were seen in all prespecified subgroups of patients. Patients allocated to aspirin had a slightly shorter duration of hospitalisation (median 8 days, IQR 5 to >28, vs 9 days, IQR 5 to >28) and a higher proportion were discharged from hospital alive within 28 days (75% vs 74%; rate ratio 1·06, 95% CI 1·02–1·10; p=0·0062). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs 22%; risk ratio 0·96, 95% CI 0·90–1·03; p=0·23). Aspirin use was associated with a reduction in thrombotic events (4·6% vs 5·3%; absolute reduction 0·6%, SE 0·4%) and an increase in major bleeding events (1·6% vs 1·0%; absolute increase 0·6%, SE 0·2%).
Interpretation
In patients hospitalised with COVID-19, aspirin was not associated with reductions in 28 day mortality or in the risk of progressing to invasive mechanical ventilation or death, but was associated with a small increase in the rate of being discharged alive within 28 days.
Funding
UK Research and Innovation (Medical Research Council), National Institute of Health Research, and the Wellcome Trust through the COVID-19 Therapeutics Accelerator.
Introduction
Thrombosis is a key feature of severe COVID-19, with 5–30% of hospitalised patients (depending on illness severity) having a major venous thromboembolic event (mostly pulmonary embolism) and up to 3% of patients having an arterial thromboembolic event, particularly myocardial infarction and ischaemic stroke.
The risk of thromboembolic complications is reported to be higher in COVID-19 than in other acute medical illnesses and viral respiratory infections, and is associated with worse prognosis.
Anti-platelet therapy might have beneficial effects in severe COVID-19 through several mechanisms, including inhibition of platelet aggregation, reduction of platelet-derived inflammation, and blocking of thrombogenic neutrophil extracellular traps.
Aspirin is an affordable, globally available drug which at low doses irreversibly inhibits the cyclooxygenase-1 enzyme, which is responsible for production of thromboxane A2 and proinflammatory prostaglandins. Aspirin can reduce both arterial and venous thrombotic events and has been shown to prevent in-vitro hyperactivity in platelets from patients with SARS-CoV-2.
Existing evidence from randomised trials has shown that 75–150 mg aspirin per day is as effective as higher doses in preventing cardiovascular events.
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Seven clinical trials of aspirin in COVID-19 are registered, but none have yet reported on the effect of aspirin therapy in COVID-19. Here we report the results of a large randomised controlled trial of aspirin in patients hospitalised with COVID-19.
Research in context
Evidence before this study
Patients with COVID-19 are at risk of thromboembolic complications. Anti-thrombotic therapies such as aspirin might be useful to prevent vascular events and improve outcomes. We searched MEDLINE, Embase, bioRxiv, medRxiv, and the WHO International Clinical Trials Registry Platform (ICTRP), from Sept 1, 2019, up to Feb 25, 2021, for completed published randomised clinical trials establishing the effect of aspirin in patients with COVID-19. For MEDLINE and Embase, we used the search terms “Coronavirus infections/”, “SARS-CoV-2.mp.”, “Coronavirus/” or “CORONAVIRUS.mp”, “COVID.mp.”, “COVID-19.mp.”, “2019-nCoV.mp.”, “COVID19.mp”, “SARSCoV2.mp”, or “SARS-Cov2.mp” and “aspirin.mp”, “aspirin/”, or “acetylsalicylic acid/”, filtered by randomised controlled trials according to validated filters. For medRxiv and bioRxiv, we used the search term “aspirin”. We identified no published randomised controlled trials assessing aspirin as a treatment for patients with COVID-19 in any clinical scenario. The WHO ICTRP database listed seven ongoing randomised trials of aspirin, two in outpatients and five in inpatients.
Added value of this study
To the best of our knowledge, the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is the first randomised controlled trial to report on the effect of aspirin as a treatment for hospitalised patients with COVID-19. We found that in 14 892 adults hospitalised with COVID-19, 150 mg aspirin did not reduce 28 day mortality, and among patients who were not receiving invasive mechanical ventilation at randomisation, did not reduce the probability of progression to the composite outcome of invasive mechanical ventilation or death. Allocation to aspirin was associated with an increase in the rate of being discharged alive within 28 days, but the magnitude of the effect was small (1% absolute difference).
Implications of all the available evidence
Our findings do not support the use of aspirin as a treatment for hospitalised patients with COVID-19.
Methods
Study design and participants
The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial is an investigator-initiated, individually randomised, controlled, open-label, platform trial to evaluate the effects of potential treatments in patients hospitalised with COVID-19. Details of the trial design and results for other treatments evaluated (including lopinavir–ritonavir, hydroxychloroquine, dexamethasone, azithromycin, tocilizumab, convalescent plasma, and colchicine) have been published previously.
Aspirin comparison was conducted at 167 hospitals in the UK, two hospitals in Indonesia, and two hospitals in Nepal (appendix pp 5–26), and is supported in the UK by the National Institute for Health Research Clinical Research Network. The trial was coordinated by the Nuffield Department of Population Health at the University of Oxford (Oxford, UK), the trial sponsor. The trial was done in accordance with the principles of the International Conference on Harmonisation Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency and the Cambridge East Research Ethics Committee (reference 20/EE/0101). The protocol, statistical analysis plan, and additional information are available on the study website.
Patients admitted to hospital were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at substantial risk if they were to participate in the trial. Children younger than 18 years were not eligible for random assignment to aspirin. Patients with known hypersensitivity to aspirin, a recent history of major bleeding, or currently receiving aspirin or another anti-platelet treatment were excluded. Written informed consent was obtained from all patients, or a legal representative if they were too unwell or unable to provide consent.
Randomisation and masking
Baseline data were collected using a web-based case-report form that included demographics, amount of respiratory support, major comorbidities, suitability of the study treatment for a particular patient, and treatment availability at the study site (appendix pp 33–34). Eligible and consenting adult patients were assigned in a 1:1 ratio to either usual standard of care or usual standard of care plus aspirin using web-based simple (unstratified) randomisation with allocation concealed until after randomisation (appendix p 30). For some patients, aspirin was unavailable at the hospital at the time of enrolment or was considered by the managing physician to be either definitely indicated or definitely contraindicated. These patients were excluded from the randomised comparison between usual care plus aspirin and usual care alone.
As a platform trial, and in a factorial design, patients could be simultaneously randomly assigned to the following other treatment groups: azithromycin, colchicine, or dimethyl fumarate versus usual care; convalescent plasma or casirivimab and imdevimab versus usual care; and baricitinib versus usual care (appendix p 30). Until Jan 24, 2021, the trial also allowed a subsequent randomisation for patients with progressive COVID-19 (evidence of hypoxia and a hyperinflammatory state) to tocilizumab versus usual care. Participants and local study staff were not masked to the allocated treatment. The trial steering committee, investigators, and all other individuals involved in the trial were masked to aggregated outcome data during the trial.
Procedures
Patients allocated to aspirin received 150 mg by mouth (or nasogastric tube) or by rectum every day until discharge. The 150 mg dose of aspirin once per day was chosen to ensure sufficient inhibition of platelet cyclooxygenase-1 activity in all participants, including those who were overweight.
A single online follow-up form was completed when participants were discharged, had died, or 28 days after randomisation, whichever occurred earliest (appendix pp 35–41). We recorded information on adherence to allocated study treatment, receipt of other COVID-19 treatments, duration of admission, receipt of respiratory or renal support, and vital status (including cause of death). In addition, in the UK, we obtained routine health-care and registry data, including information on vital status (with date and cause of death), discharge from hospital, receipt of respiratory support, or renal replacement therapy.
Créditos: Comité científico Covid
