麻豆传媒

Therapeutic anticoagulation for thromboembolic prophylaxis improved outcomes and possibly survival in a hospitalized but not critically ill COVID-19 population, according to topline results of three large platform trials released today.

The full-dose strategy proved superior to prophylactic dosing in reducing the proportion of patients who progressed to needing ventilation and other vital organ support across the three adaptive platform trials -- the National Heart, Lung, and Blood Institute (NHLBI)-sponsored , , and .

"A trend in possible reduction of mortality was also observed and is being further studied," noted a from the NHLBI.

If confirmed, it would be only the second such treatment proven to provide a survival benefit for COVID-19 patients. The steroid dexamethasone cut mortality by 27% in hospitalized COVID-19 patients in the RECOVERY trial.

"This is groundbreaking," said Jeffrey Berger, MD, co-primary investigator on the ACTIV-4a trial. "For hospitalized patients with COVID-19, I think we are going to enter a new era."

Therapeutic dosing was safe in this moderately ill COVID-19 population, unlike in the critically ill population for which the trials halted the full-dose strategy after seeing signals of harm.

Anticoagulation practice has typically included at least prophylactic dosing for hospitalized COVID-19 patients, due to the excess clotting risk seen with the coronavirus. However, centers have tried intermediate and full therapeutic doses as well, but with little data and only consensus recommendations to go on.

"This will define a for patients with COVID-19 in hospital but not on life support," tweeted ATTACC principal investigator Ryan Zarychanski, MD, of the University of Manitoba in Winnipeg.

Full results of the three trials will be released later, with a from his institution noting that "trial investigators are now working as fast as possible to make the full results of the study available so clinicians can make informed decisions about treating their COVID-19 patients."

"But based on the very stringent criteria used to stop the trial, I would change my practice. In other words, it is unlikely there would be a reversal of the finding," argued Mary Cushman, MD, of the University of Vermont in Burlington and an ACTIV 4 trial investigator, in an email to 麻豆传媒.

As with dexamethasone, heparin is not very expensive and readily available, noted Berger. "Any hospital can begin making changes immediately."

However, effects of COVID-19 treatments have varied by phase of the disease, so there's still good reason to await further trial results, noted Behnood Bikdeli, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston. "It's very possible that we don't have one-size-fits-all interventions."

His group's turned up 75 randomized trials on antithrombotics for COVID-19, including antiplatelet agents, direct oral anticoagulants, and in pre- and post-discharge settings. "We're going to learn from all of them," he said.

The three trials' interim results spanned more than 1,300 moderately ill patients in general wards who did not receive organ support such as mechanical ventilation at trial enrollment.

All three trials halted their therapeutic anticoagulation study arms for efficacy based on the interim results, although other treatments continue to be studied across the platforms.

While their findings agree with those of the small phase II HESA COVID trial that showed therapeutic-level dosing of enoxaparin (Lovenox) improved respiratory outcomes in severe COVID-19, it will be important to see the signal corroborated across larger trials, Bikdeli said.

He contrasted the case of dexamethasone quickly becoming standard of care with that of tocilizumab (Actemra), for which benefits haven't been consistent.

Antithrombotic guidelines, too, will have to wait, Bikdeli noted.

"I think it's almost time," he told 麻豆传媒. "We will have the results of [on intermediate-dose prophylaxis] in a week or two. With these trials coming out, then I think it is going to be time to revise the consensus recommendations toward evidence-based guidelines."

In fact, Bikdeli's group released a Tuesday with topline results from the 600-patient INSPIRATION trial. Intermediate dose enoxaparin yielded no significant advantage for the primary composite endpoint of incident venous thromboembolism, need for extracorporeal membrane oxygenation, or death from any cause compared with standard doses (45.7% vs 44.1%). Major bleeding occurred in more intermediate-dose group patients (2.5% vs 1.4%), and all six cases of severe thrombocytopenia were in the higher dose group.

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