RECOVERY results do not support aspirin use in this setting

Treatment with aspirin did not bring about any clinically meaningful improvements in outcomes among patients hospitalized with Covid-19 in the large, randomized, open-label RECOVERY trial.

Aspirin was not associated with reductions in 28-day mortality or in the risk of progression to invasive mechanical ventilation in the study, published online in The Lancet, but was associated with a very slight increase in being discharged alive within 28 days. RECOVERY researchers concluded that the results of the trial “do not support the addition of aspirin to standard thromboprophylaxis or therapeutic anticoagulation in patients hospitalized with Covid-19.”

Furthermore, according to RECOVERY co-chief investigator Peter W. Horby, MBBS, PhD, of Oxford University, Oxford, U.K., and colleagues, “As expected, allocation to aspirin was associated with an increased risk of major bleeding and a decreased risk of thromboembolic complications, such that for every 1,000 patients treated with aspirin, approximately six more patients would have a major bleeding event and approximately six fewer patients would have a thromboembolic event.”

The ongoing Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial was designed to identify and evaluate potential treatments for patients hospitalized with Covid-19, and the investigators have previously published results from the open-label trial for a range of therapies, including lopinavir-ritonavir, hydroxychloroquine, dexamethasone, and convalescent plasma. Aspirin was included in the study, researchers explained, because thrombosis is common in patients hospitalized with Covid-19.

“Anti-platelet therapy might have beneficial effects in severe Covid-19 through several mechanisms, including inhibition of platelet aggregation, reduction in platelet-derived inflammation, and blocking of thrombogenic neutrophil extracellular traps,” they wrote, adding that seven other clinical trials evaluating aspirin as a treatment for Covid-19 are ongoing, but none have yet reported final results.

The RECOVERY aspirin comparison trial, conducted at 177 hospitals in the United Kingdom, two in Indonesia, and two in Nepal, included patients randomized from Nov. 1, 2020, through March 21, 2021, to treatment with either usual care plus 150-mg aspirin once a day until discharge (n=7,351) or usual care without aspirin (n=7,541).

Twenty-eight day mortality was similar in both groups. Within 28 days, 1,222 (17%) of the patients allocated to aspirin died compared with 1,299 (17%) of those in the usual care group (rate ratio 0.96, 95% CI 0.89–1.04; P=0.35).

Among the main findings:

  • Aspirin-treated patients had a slightly shorter duration of hospitalization (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 compared with aspirin non-use was associated with a reduction in thrombotic events (4.6% vs 5.3%, respectively; absolute reduction 0.6%, SE 0.4%), but also with an increase in major bleeding events (1.6% vs 1.0%; absolute increase 0.6%, SE 0.2%).
  • The incidence of new cardiac arrhythmias was similar in the two groups, and there were 18 reported serious adverse bleeding events in the aspirin users.

The rate of thromboembolic events was low in the study population, and Horby and colleagues hypothesized that “aspirin might have a more meaningful benefit in populations with higher thrombolytic risk, although there would also probably be a corresponding increase in bleeding risk.”

They added: “Although there are no other published randomized trial data on the use of aspirin in Covid-19, the REMAP-CAP, ACTIV-4a and ATTAC report does suggest that antithrombotic therapy might be important in some patients.”

Antithrombotic therapy appeared to benefit patients with less severe disease in the analysis of data from the three trials, but it did not appear to benefit patients who had progressed to severe Covid-19.

“The absence of meaningful benefit from aspirin in our trial could be because anti-platelet therapy confers no clinically significant additional benefit on top of high rates of anti-thrombotic therapy with low-molecular weight heparin and corticosteroid treatment diminishing thrombo-inflammatory stimulation,” Horby and colleagues wrote, and added that earlier treatment with aspirin may benefit patients with Covid-19, as suggested by the combined REMAP-CAP, ACTIV-4a and ATTAC findings.

“The RECOVERY trial only studied patients with Covid-19 who were hospitalized, and therefore is not able to provide evidence on the safety and efficacy of aspirin used in other patient groups,” Horby et al. concluded. “Further studies to identify the safety and efficacy of aspirin in patients with Covid-19 who are not hospitalized are needed and are ongoing.”

In commentary published with the study, vascular medicine specialists Alex Spyropoulos, MD, of Northwell Health at Lenox Hill Hospital, New York City, and Marc Bonaca, MD, of the University of Colorado, Aurora, wrote that the study design may have also played a role in the lack of observed efficacy.

“Have we set too high a bar in the design of antithrombotic clinical trials in Covid-19?” they queried.

Spyropoulos and Bonaca noted that traditional antithrombotic clinical trial designs in patients who are hospitalized have used a composite of thromboembolic disease and mortality as primary endpoints.

“Whether antithrombotics reduce thrombotic microangiopathy is still a matter of debate. And yet, the entire premise of many Covid-19 antithrombotic clinical trial designs, which are based on primary endpoints of mortality or disease severity, is that they would have potential to reduce thrombotic microangiopathy and ameliorate the course of disease on the basis of thrombo-inflammatory mechanisms,” they wrote. “It can indeed be a slippery slope to base an entire clinical trial design on an unproven hypothesis.”

Both editorialists were investigators in the HEP-COVID randomized clinical trial, which used a traditional antithrombotic clinical trial design and showed therapeutic-dose heparin reduced thromboembolism and death compared to standard heparin doses in hospitalized Covid-19 patients with elevated D-dimer levels.

“Although it can be argued that the urgency of the pandemic required broader outcomes to speed up discovery perhaps the time has come for us to rethink how we study the coagulopathy of Covid-19, returning to principles that led to traditional antithrombotic clinical trial designs,” they concluded.

  1. Treatment with aspirin was not associated with clinically meaningful improvements in outcomes among patients hospitalized with Covid-19 in the large, randomized, open-label RECOVERY trial.

  2. RECOVERY researchers concluded that the results of the trial “do not support the addition of aspirin to standard thromboprophylaxis or therapeutic anticoagulation in patients hospitalized with Covid-19.”

Salynn Boyles, Contributing Writer, BreakingMED™

Funding for this study was provided by UK Research and Innovation, the National Institute of Health Research and the Wellcome Trust through the Covid-19 Therapeutics Accelerator. The researchers declared “no competing interests or financial relationships relevant to the submitted work.” Commentary writer Alex Spyropoulos declared research grants and consulting fees from Janssen Research & Development LLC, Bayer, Prtola, Boehringer ingelheim and others unrelated to this study. Marc Bonaca receiving grants from Janssen, Amgen, AstraZeneca, Bayer, Janssen, Merck, Novo Nordisk and Pfizer unrelated to this study.

Cat ID: 190

Topic ID: 79,190,730,933,118,190,926,192,927,151,928,195,929,925,934