Study Shows That Use of Antithrombotics Such As Aspirin And Apixaban Does Not Help Non-Hospitalized COVID-19 Patients With Mild Or Moderate Symptoms
A new multi-institutional clinical study has shown that antithrombotic therapy involving drugs like aspirin or apixaban is not warranted in COVID-19 outpatients.
The researchers from Brigham and Women’s Hospital-Massachusetts, University of Pittsburgh-Pennsylvania, University of Illinois-Chicago, Intermountain Healthcare-Utah, National Heart, Lung, and Blood Institute-Maryland, SOCAR Research SA-Switzerland, University of Florida-Gainesville, University of South Florida and Tampa General Hospital-Florida had found that antithrombotic therapy in clinically stable, non-hospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.
The clinical study was conducted to assess whether anticoagulant or antiplatelet therapy can safely reduce major adverse cardiopulmonary outcomes among symptomatic but clinically stable outpatients with COVID-19.
The randomized trial of 657 symptomatic outpatients with COVID-19 conducted in the US was stopped early because of an unanticipated low event rate. Among randomized participants who initiated trial treatment with aspirin (81 mg once daily), apixaban (2.5 mg twice daily), apixaban (5.0 mg twice daily), or placebo, the rates of an adjudicated composite outcome (all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause) after 45 days were 0.0%, 0.7%, 1.4%, and 0.0%, respectively; there were no significant differences between the active groups and the placebo group.
Hence the study data did not support the use of aspirin or apixaban in the outpatient setting to reduce the major adverse cardiovascular or pulmonary consequences associated with symptomatic but clinically stable SARS-CoV-2 infection.
The study findings were published in the peer reviewed journal: JAMA Network. https://jamanetwork.com/journals/jama/fullarticle/2785218
Although antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, this study findings showed that treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.
Corresponding author, Dr Paul M Ridker, MD, Divisions of Preventive Medicine and Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School told Thailand Medical news, "Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome. However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated."
clinical research which was led by Dr Jean M. Connors, MD, Brigham and Women's Hospital.
This clinical trial known as the ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled tri
al that sought to compare anticoagulant and antiplatelet therapy among 7000 symptomatic but clinically stable outpatients with COVID-19.
The randomized clinical trial was conducted at 52 sites in the United States between September 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.
The study participants were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.
The study’s primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.
The clinical trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled. The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.
Importantly the median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.
The clinical trial's primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.
The study findings showed that among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.
The study team found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% CI not calculable) in the aspirin group, 0.7% (95% CI, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.
Also, no major bleeding events were reported.
Importantly the absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.
It was noted that safety and efficacy results were similar in all randomly assigned patients.
The study team speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.
Dr Ridker added, "First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation. As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined. Second, at least within the US where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic.”
The study team noted that further, COVID-19 testing was quite limited early in the pandemic, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (ie, the number of infected individuals overall) was essentially unknown."
Dr Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told media, "The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19.”
He wrote in an accompanying editorial in the same journal, "It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power. The ACTIV-4B trial has immediate implications for clinical practice. In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended."
He added that ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized.
He said, "In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions.”
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