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Preemptive therapeutic-level heparin appeared futile and possibly unsafe for COVID-19 patients in three large-scale international trials.

Interim analyses comparing that strategy against typical prophylactic dosing reached the prespecified threshold for futility among patients enrolled from the ICU in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored trial, showing no reduction in the need for organ support.

The data safety monitoring boards of the three adaptive platform trials -- the National Heart, Lung, and Blood Institute (NHLBI)-sponsored trial, , and -- "also indicated concerns regarding the overall safety of therapeutic anticoagulation in the severe illness at enrollment cohort," a letter to ACTIV-4 enrolling sites noted, so enrollment in that group is on "pause."

"The trials are working urgently to undertake additional analyses which will be made available as soon as possible," according to a from the University of Manitoba, which is leading the ATTACC trial.

While the specifics weren't disclosed, decades of experience with heparin suggest those concerns would likely relate to excess bleeding -- major bleeds, clinically relevant bleeds, and intracranial hemorrhage -- or thrombocytopenia, commented Behnood Bikdeli, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, who is not part of ACTIV-4 but has been involved in COVID-19 anticoagulation consensus recommendations and other similar trials.

Meanwhile, ACTIV-4 sites were advised to stop therapeutic anticoagulation as soon as practicable for severe COVID-19 patients in that trial arm unless otherwise indicated.

Severe COVID-19 represents a subset of the inpatient arm of the pragmatic trials, so the less severe hospitalized cases will continue to be randomized to prophylactic versus full therapeutic-dose heparin, a statement from the NHLBI said. Also, the has outpatient and post-discharge arms ongoing to evaluate antithrombotic strategies in COVID-19; REMAP-CAP has a number of other therapy arms still enrolling as well.

The three trials to look at therapeutic anticoagulation with heparin.

Observational data available so far have been all over the map, with some noting a survival advantage to therapeutic anticoagulation in the ICU, but others finding harm. A pilot trial suggested that therapeutic dosing of enoxaparin (Lovenox) improved respiratory outcomes in severe COVID-19, but was far from conclusive.

Clinical practice varies widely as well, Bikdeli noted.

"The academic community is so split on how they've been thinking about this," he said. "Many of the hospitals made acute changes to their protocols and treatment guidelines. Some of them considered some form of intensified antithrombotic therapy as standard of care. Some of them even went above and beyond for sicker patients, considering thrombolytic therapy as standard of care."

In that sense, no matter what the trials show, they are important and useful, said Stephan Moll, MD, of the University of North Carolina at Chapel Hill.

"It is terrific gain of knowledge to have results from randomized trials, even if they have to be stopped early, such as this one," he said. "These studies provide so much more meaningful data compared to the initial retrospective case series. I am thrilled that this study provides solid clinical data that will help us with our clinical management."

His center's anticoagulation management algorithm for inpatient COVID-19 may be revised, but only "once we see the full data and report," he said.

Bikdeli, too, cautioned against reactionary changes in clinical management based just on the announcement and urged colleagues to enroll patients in the many ongoing trials and prospective studies for anticoagulation management in COVID-19. "Physicians argue 'we can't sit and do nothing.' That's true, but also doing things without sufficient knowledge is not necessarily a fix."

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