麻豆传媒

Increasing the dose of prophylactic anticoagulation didn't help critically ill COVID-19 patients in the randomized .

Intermediate-dose prophylaxis with enoxaparin (Lovenox) yielded a similar composite rate of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days as seen with standard-dose prophylaxis (45.7% vs 44.1%, OR 1.06, P=0.70).

The higher dose -- 1 mg/kg versus the standard, flat 40 mg daily for all but the most obese patients -- increased major bleeding (2.5% vs 1.4%, P>0.99 for noninferiority) and severe thrombocytopenia (2.2% vs 0%, P=0.01), albeit with small numbers of cases among the 600 patients in the trial.

"These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19," concluded Behnood Bikdeli, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues .

These findings follow those of the ACTIV-4a, REMAP-CAP, and ATTACC platform trials showing that therapeutic-dose anticoagulant prophylaxis wasn't better, and possibly worse, for outcomes in ICU patients than standard dose levels.

In moderate COVID-19 patients in the hospital but not critically ill, full-dose prophylaxis has proved superior in those trials.

While yet to be published with peer review (just a for the ICU data), those pooled results along with INSPIRATION are filling in the puzzle of how to handle the excessive coagulation seen in COVID-19 hospitalizations since the early days of the pandemic.

"All taken together," commented Jeffrey Berger, MD, of NYU Langone Medical Center in New York City, "this really suggests that a prophylactic dosing strategy is seemingly the best strategy for these patients."

Some centers have been using an elevated-dose strategy despite "not great data" supporting it, so the findings may prompt a change in clinical care, although there should still be a discussion about what is best for the individual patient, noted Berger, who is co-primary investigator on the ACTIV-4a trial.

"This study nearly closes the question on whether intermediate dose anticoagulation with enoxaparin 1 mg/kg once daily helps among ICU level of care patients with COVID-19 who would be eligible for this trial," commented Mary Cushman, MD, of the University of Vermont in Burlington and an ACTIV-4a trial investigator, in an email to 麻豆传媒.

The open-label trial included 600 adults admitted to the ICU at 10 centers in Iran with PCR-confirmed COVID-19 and no indication for therapeutic anticoagulation, need for ECMO, or less than 24-hour life expectancy. Among them, the 562 patients recruited from July 29 to Nov. 19, 2020 and who got at least one dose were included in the prespecified primary analysis.

An , however, sounded some notes of caution about the study.

The trial included higher anticoagulant doses for body weights of 120 kg (265 lb) or BMI of 35 or greater: 0.6 mg/kg twice daily in the intermediate-dose group and 40-mg twice daily in the standard-dose group, Hanny Al-Samkari, MD, of Massachusetts General Hospital in Boston, pointed out.

"Therefore, describing the trial as a comparison between intermediate-dose and standard-dose thromboprophylaxis is somewhat of an oversimplification; the authors actually compared two weight-based [low molecular weight heparin] thromboprophylaxis dosing protocols," Al-Samkari wrote. "For the clinician practicing at a center that does not routinely use weight-based thromboprophylaxis dosing, this is a critical distinction."

The trial only included four such patients who needed a dose adjustment due to their weight, Bikdeli noted. Based on such a low prevalence of obesity, he said, "Our results cannot be extrapolated to those patients (or others not meeting the eligibility criteria)."

The study turned up no subgroups that appeared to benefit from an escalated dose.

Al-Samkari also noted that the overall low thrombotic event rate in both dosing groups raised the "possibility of a significant number of uncaptured events." Studies like INSPIRATION that haven't used universal VTE screening generally have had lower rates than seen in those with it (up to 80% in some ICU cohorts), he added, "although the relevance of clinically occult VTE in these patients is not known."

Berger also noted the "extraordinarily low" bleeding rate.

Another question was the generalizability to U.S. patients, Berger said, as practice patterns can differ around the world.

"In pandemic times we must move to other treatments that are likely to work, and optimally enroll as many patients as possible in clinical trials testing other interventions, including antithrombotic interventions," said Cushman in arguing against a need for more trials on this particular question. "It would appear that once a person is at ICU level of care, it is too late for heparins to exert an important effect on outcomes in COVID-19."

However, "This study really reminds us that sometimes doing what seems best is not actually the best thing to do," Berger said. "We should be using evidence-based strategies."

What the best thromboprophylaxis strategy is after discharge and for outpatients with mild COVID-19 not requiring hospital admission remain under study, Al-Samkari concluded.

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