麻豆传媒

Antiplatelet therapy didn't appear to help critically ill COVID-19 patients recover quicker, the randomized REMAP-CAP platform trial showed.

The aspirin and P2Y12 inhibitor arms were stopped early for futility, due to greater than 95% posterior probability of less than a 20% relative benefit in days alive and free of respiratory or cardiovascular organ support in the ICU to 21 days.

The number of organ support-free days didn't suggest a benefit for either type of antiplatelet alone or when pooled (median 7 in both groups, adjusted OR [aOR] 1.02, 95% credible interval [CrI] 0.86-1.23), reported Charlotte Bradbury, MD, PhD, of the University of Bristol in England, and colleagues in in conjunction with a presentation at the International Symposium on Intensive Care and Emergency Medicine in Brussels.

However, survival to hospital discharge was numerically more common with the antiplatelet agents considered together (71.5% vs 67.9% among controls, aOR 1.27, 95% CrI 0.99-1.62). While not statistically significant, it did have a 97% posterior probability of efficacy in the Bayesian analysis, which rose to 99.7% when considering 90-day survival.

"As recruitment occurred in 8 countries and antiplatelet therapy is inexpensive, widely available, and easy to administer and dose, these results are expected to have global applicability," Bradbury's group suggested.

The number of patients on short durations of organ support counterbalanced that survival difference, yielding the neutral results, they pointed out. "It is possible that antiplatelet therapy may reduce fatal complications of COVID-19 in critically ill patients while potentially increasing the need for organ support, possibly through bleeding that may or may not be clinically evident, such as alveolar hemorrhage."

As expected, there was a cost in major bleeding (2.1% vs 0.4% of controls, aOR 2.97, 95% CrI 1.23-8.28), with a 99.4% probability of harm.

There was a "compelling" rationale for trying antiplatelet therapy in this disease known to make platelets hyperreactive and to cause systemic endothelial damage and coagulopathy, noted Jean Connors, MD, and Paul Ridker, MD, MPH, both of Brigham and Women's Hospital in Boston, in an .

Along with the REMAP-CAP results, the trial in largely noncritically ill inpatients, the ACTIV-4A trial in general-ward inpatients, and the trial in symptomatic outpatients have all weighed in against antiplatelet agents for COVID-19, they pointed out.

Other trials looking at antithrombotic agents ranging in setting have shown that efficacy "may vary by mechanism of action, illness severity, dose, and duration," Bradbury's group wrote.

For critically ill patients, though, standard prophylactic heparin alone has proven best in the trials.

"First and foremost, the accumulated data should provide physicians with the rare confidence to do less rather than more, a finding that also has become apparent with anticoagulation therapy," Connors and Ridker noted.

"At this juncture in the global pandemic, all hospitalized patients with COVID-19 and low risk of bleeding should receive at least prophylactic-dose anticoagulation with a heparin anticoagulant, with consideration of therapeutic-dose heparin in some cases, but there is no proven efficacy supporting the addition of traditional antiplatelet therapies to prevent progressive thromboinflammatory complications of COVID-19," they added.

REMAP-CAP's antiplatelet domain had randomized critically ill COVID-19 patients to open-label use of aspirin 75 to 100 mg daily, a P2Y12 inhibitor (89% clopidogrel, 8.8% unknown), or no antiplatelet therapy while in the hospital for up to 14 days. This was given atop prophylactic anticoagulation (98% low-molecular-weight heparin, 59% at an intermediate dose).

Before the trial was discontinued due to futility, 1,549 patients completed treatment (median age 57, 33.6% female).

The protocol recommends gastric protection with a proton pump inhibitor or H₂ receptor antagonist for the antiplatelet groups. Elevated risk of bleeding, including severe kidney failure, was cause for exclusion.

Limitations beyond the open-label design included heterogeneity in anticoagulation regimens and antiplatelet agents used, "limiting ability to draw firm conclusions for any given combination," the researchers noted.

They pointed to the ongoing with a domain testing P2Y12 inhibitors added to prophylactic-dose heparin for critically ill patients.

"The clinical goal, however, should be to avoid thromboinflammation and hospitalization in the first place, an objective largely achievable through aggressive vaccination," the editorialists concluded.

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