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No reduction in cardiopulmonary events in symptomatic outpatients with COVID-19

Cardiopulmonary events in symptomatic COVID-19 patients were unaffected by antithrombotic therapy however the trial was terminated early.

The level of cardiopulmonary events including deep vein thrombosis, pulmonary embolism, myocardial infarction and ischaemic stroke did not appear to be affected with the use of antithrombotic therapy according to a study by a group from the Brigham and Women’s Hospital, Boston, Massachusetts, US. The risk of a thromboembolic event in patients with COVID-19 is high and linked with a greater mortality risk. Although some data shows how the use of heparins among non-critically ill hospitalised patients with COVID-19 increases  the probability of survival, there is a paucity of data on the use of antithrombotic therapy among symptomatic outpatients. The Brigham researchers therefore performed a randomised, double-blind, placebo-controlled trial among symptomatic outpatients infected with COVID-19.

Their ACTIV-4B COVID-19 Outpatient Thrombosis Prevention Trial examined whether symptomatic patients infected with the virus but not hospitalised, would experience a slowing of disease progression from either anti-platelet or anticoagulant (i.e., antithrombotic) therapy. The researchers enrolled patients aged between 40 and 80 years of age with a PCR or antigen confirmed diagnosis of COVID-19 and randomised them 1:1:1:1, to aspirin 81 mg daily (and matching placebo), apixaban 2.5 mg twice daily, apixaban 5 mg twice daily or placebo twice daily for a period of 45 days. The team set their primary outcome as a composite of cardiopulmonary events which included symptomatic deep vein thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, ischaemic stroke, hospitalisation for cardiovascular or pulmonary events and all-cause mortality, over the next 45 days after randomisation.


A total of 657 patients with a median age of 54 years (59.1% women) were randomised between one of the four arms. The median time from diagnosis to randomisation was 7 days and 3 days between randomisation and the start of therapy. During this period of time, some patients were hospitalised and complete, 45-day follow-up was available for only 556 individuals. However, the overall incidence of cardiopulmonary events in the study was very low, with only 5 events. This included 1 deep vein thrombosis in the aspirin group, 3  cardiopulmonary events (all hospitalisations), two in the apixaban 5 mg group, one in apixaban 2.5 mg group) and one in the placebo group. On a positive note, although the event rate was very low, the study observed no deaths or major bleeding events, but there were 14 non-major bleeds; 4 in the aspirin group with 6 and 4 in the low and high apixaban groups respectively.

As a result of the low event rate, the authors had to terminate the trial early and concluded that among clinically stable symptomatic outpatients, treatment with aspirin or apixaban did not reduce the rate of cardiopulmonary events. Nevertheless, the overall generalisability of these findings are somewhat limited because of the low incidence of primary events.


Connors JM et al. Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19. The ACTIV-4B Randomized Clinical Trial. JAMA 2021

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