A therapeutic dose of heparin was associated with increased probability of survival for non-critically ill COVID-19 patients versus usual-care thromboprophylaxis, but not for the most severe patient population, peer-reviewed results from the REMAP-CAP, ACTIV-4a, and ATTACC multi-platform trial showed.
In the non-critically ill cohort, therapeutic dose anticoagulation with heparin was superior to usual care prophylaxis, with higher odds of increasing organ support-free days in patients hospitalized with moderate COVID-19 (adjusted odds ratio [aOR] 1.27, 95% credible interval [CrI] 1.03-1.58), reported Ryan Zarychanski, MD, of the University of Manitoba in Winnipeg, Canada, and colleagues.
This benefit seemed to persist, regardless of D-dimer level, with high D-dimer (aOR 1.31, 95% CrI 1.00-1.76), low D-dimer (aOR 1.22, 95% CrI 0.93-1.57), and unknown D-dimer levels (aOR 1.32, 95% CrI 1.00-1.86) showing higher odds of superiority for therapeutic-dose anticoagulation versus usual care thromboprophylaxis, they wrote in the New England Journal of Medicine (NEJM).
The median adjusted absolute between-group difference in survival until hospital discharge without organ support was 4.0 percentage points (95% CrI 0.5-7.2), the authors noted.
However, a second NEJM study from this multi-platform trial in a critically ill population did not find the same benefits.
So why did each population respond differently? In an accompanying editorial, Hugo ten Cate, MD, PhD, of Gutenberg University Medical Center in Mainz, Germany, speculated that "the underlying thrombotic and inflammatory damage may have been too advanced to be influenced by higher doses of heparin" in the critically ill group.
He also noted the differences in patient populations between the three platforms, where the majority of critically ill patients were from REMAP-CAP in the U.K, while the majority of patients with moderate disease were from ATTACC and ACTIV-4 in the U.S. and Brazil.
Ultimately, ten Cate concluded the data do not support use of heparin to prevent thrombosis in critically ill patients, but that "other thrombotic or even profibrinolytic strategies may be warranted." He also argued that the jury is still out on heparin even in the moderately ill, saying the benefits and risks should be weighed.
"Physicians must deal with the key issues regarding the lack of insight into the mechanisms by which heparin [...] does (or does not) provide protection and the question of whether the individual patient's bleeding risk outweighs the benefit," ten Cate wrote.
Non-Critically Ill Patients See Benefit
Earlier results from the three platforms -- rolled into one multi-platform, randomized trial -- were presented twice in January 2021, as topline results and then as a slide deck.
After topline results were released, enrollment was discontinued when an adaptive analysis showed prespecified criteria for superiority (defined as ">99% probability of an odds ratio of >1.0") were met for both high and low D-dimer groups. High D-dimer level was at least two times the upper limit of the normal range, while low D-dimer level was less than two times the upper limit of the normal range. Overall, the primary analysis included 2,219 patients, enrolled from April 2020 to January 2021.
The trial included patients from 121 sites in nine countries hospitalized with moderate COVID-19, but who did not need respiratory or cardiovascular organ support in an ICU setting. They were randomized to receive either therapeutic-dose anticoagulation with heparin or usual-care thromboprophylaxis, and were stratified by D-dimer level: high, low, or unknown.
Primary outcome was organ-free support days based on an ordinal scale combining in-hospital death and days free of cardiovascular or respiratory support through day 21 among patients surviving to hospital discharge.
Patients had a mean age of about 59 years, 57% to 60% were men, and about two-thirds were white. Patients in the high D-dimer group were generally older and had more comorbidities. About 62% of patients were receiving glucocorticoids at baseline, 36% were receiving remdesivir (Veklury), and 12% were receiving antiplatelet agents.
Overall, 80.2% of patients in the therapeutic-dose group survived to hospital discharge without receiving organ support versus 76.4% of those in the usual care group. Median organ support-free days was 22 for both groups.
Major bleeding occurred in 1.9% of the therapeutic dose group and 0.9% of the usual care group. Fatal bleeding occurred in three patients in the therapeutic dose group and one in the usual care group.
"On the basis of these findings, for every 1,000 hospitalized patients with moderate disease, an initial strategy of therapeutic-dose anticoagulation [...] would be anticipated to result in the survival of 40 additional patients until hospital discharge without organ support at the expense of 7 additional major bleeding events," the authors wrote.
No Benefit in Critically Ill Population
In critically ill COVID-19 patients, there was no difference in organ support-free days or survival to hospital discharge between the two treatment groups, and the trial was stopped for futility in December 2020.
Futility was defined as an odds ratio less than 1.2, and odds that the therapeutic dose group increased organ support-free days was lower than the usual care group (aOR 0.83, 95% CrI 0.67-1.03). The percentage of patients surviving to hospital discharge was also similar, with about 63% in the therapeutic dose group versus about 65% in the usual care group (aOR 0.84, 95% CrI 0.64-1.11).
This population consisted of 1,103 patients from 393 sites in 10 countries. They were hospitalized with COVID-19 and required ICU-level respiratory or cardiovascular organ support, such as non-invasive or invasive mechanical ventilation.
The median value for organ support-free days for the therapeutic dose group was 1, while it was 4 for the usual care group.
A major bleeding event occurred in 3.8% of the therapeutic dose group versus 2.3% of the usual care group, and about 40% of patients in both groups had major thrombotic events or death.
Disclosures
The views expressed in this article are those of the authors and do not necessarily reflect the view of the National Health Service, the National Institute for Health Research, the U.K. Department of Health and Social Care, or the NIH.
Zarychanski disclosed support from Canadian Institutes of Health Research, LifeArc Foundation, Research Manitoba, Peter Munk Cardiac Centre, Thistledown Foundation, and NIH.
Other co-authors disclosed support from the NIH, as well as various ties to industry.
ten Cate disclosed support from Coagulation Profile, Portola/Alexia, PPS Health Holland, Bayer, Pfizer, STAGO, Leo Pharma, Daiichi, and Gilead/Galapagos.
