Anticoagulation and Antiplatelet Strategies in Non-Critically Ill Patients with Covid-19

Background Optimal thromboprophylaxis for hospitalized patients with Covid-19 is uncertain. Most published clinical trials comparing different anticoagulation protocols in hospitalized patients with Covid-19 have recruited patients in high-income countries (HIC) and results may not be generalizable to patients in low and middle-income countries (LMIC). Furthermore, the incidence of VTE varies by ethnic background with higher rates reported amongst Caucasian compared to diverse Asian populations. We report the results of an international (incorporating both HIC and LMIC regions) adaptive platform randomized trial in hospitalized non-critically ill patients with Covid-19 comparing the effectiveness of low-dose, intermediate-dose, therapeutic-dose anticoagulation, and low-dose plus aspirin on survival and need for organ support.

Methods The Australasian COVID-19 Trial (ASCOT) is an investigator-initiated, open-label, pragmatic adaptive platform randomized clinical trial of therapeutics (anticoagulation, antiviral, and therapeutic antibody domains) for non-critically ill patients hospitalized with Covid-19. In our anticoagulation trial, we initially randomly assigned patients to low-dose low-molecular-weight heparin (LMWH) thromboprophylaxis, intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary endpoint was death or the requirement for new organ support by day-28, analyzed with a Bayesian logistic model. Enrolment was closed due to operational constraints.

Results Between February 2021 and April 2022, we screened 2,203 patients in 32 hospitals (15 in Australia, 4 in New Zealand, 11 in India, and 2 in Nepal) and enrolled 1574 into the anticoagulation domain (619 assigned to low-dose, 620 to intermediate-dose, 285 to low dose plus aspirin, and 50 to therapeutic-dose). Eighteen participants withdrew consent and 30 were lost to follow-up leaving 1526 included in the primary analysis population (1273 from India, 138 from Australia and New Zealand, 115 from Nepal).

The median age of participants was 49 years, 633 (41%) were female, 1291 (83%) were Indian, 480 (31%) were vaccinated against SARS-CoV-2, and 629 (40%) had one or more comorbidities. Adherence to the trial protocol was 98% in the low-dose, 98% in the intermediate-dose, 97% in the low-dose plus aspirin and 92% in the therapeutic-dose anticoagulation arms. All participants received enoxaparin except for one participant in the intermediate group who received tinzaparin.

At 28 days after randomization, 35/596 (5.9%) participants assigned to low-dose, 25/601 (4.2%) intermediate-dose, 20/279 (7.2%) low-dose plus aspirin, and 7/50 (14%) therapeutic-dose anticoagulation had died or required organ support. Compared to low-dose thromboprophylaxis, the median adjusted odds ratio (aOR) for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI] 0.43 to 1.27, posterior probability of effectiveness [aOR < 1] [Pr] 86%), for low-dose plus aspirin 0.88 (95% CrI 0.47 to 1.64, Pr 65%) and for therapeutic-dose 2.22 (95% CrI 0.77 to 6.20, Pr 7%). The results were consistent in a number of sensitivity analyses including when restricting the analysis populations to concurrent randomizations. The results were also broadly consistent across the predefined subgroups, with the posterior probability of effectiveness for intermediate-dose compared to low-dose ranging from 56% (corticosteroid exposure) to 94% (>7 days of symptom onset to hospitalization). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively.

Conclusions In hospitalized adults with Covid-19, compared to low-dose, there was an 86% posterior probability that intermediate-dose, and 7% posterior probability that therapeutic-dose, reduced the odds of death or requirement for organ support by day 28. No treatment strategy met pre-specified statistical stopping criteria prior to trial closure.

Trial registration number: NCT04483960

McQuilten:Sanofi: Research Funding; Novartis: Research Funding; Janssen: Research Funding; GSK: Research Funding; BMS/Celgene: Research Funding; CSL: Research Funding; Beigene: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Jha:GSK: Research Funding; Baxter Health: Research Funding; Biocon: Research Funding; Bayer: Honoraria; AstraZeneca: Honoraria; Boeringer Ingelheim: Honoraria; NephroPlus: Honoraria; Zydus Cadilla: Honoraria. Roberts:Gilead: Consultancy; Summit: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Sandoz: Consultancy; MSD: Consultancy, Speakers Bureau; Cipla: Speakers Bureau; Biomerieux: Research Funding; QPEX: Research Funding. Lewin:Gilead: Honoraria, Research Funding, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Viiv: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Vaxxinity: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Esfam: Membership on an entity's Board of Directors or advisory committees. Sasadeusz:Gilead: Honoraria; GSK: Honoraria; AstraZeneca: Honoraria; Merck: Honoraria. Tran:Sanofi: Research Funding; AstraZeneca, CSL Behrig: Honoraria; Pfizer, Takeda: Speakers Bureau.