Therapeutic heparin may improve survival of noncritically ill patients with COVID-19

Therapeutic anticoagulation with heparin increased the likelihood of survival among noncritically ill patients who were hospitalized with COVID-19, according to a new study in The New England Journal of Medicine.

However, a second study that was simultaneously published showed that the same treatment did not produce a survival benefit in critically ill patients.

“Patients who are hospitalized with COVID-19 frequently have macrovascular and microvascular thrombosis and inflammation, which are associated with a poor clinical outcome,” Ewan C. Goligher, MD, PhD, an assistant professor in the interdepartmental division of critical care medicine at the University of Toronto, and colleagues wrote. “Given the antithrombotic, anti-inflammatory and possibly antiviral properties of heparins, it has been hypothesized that anticoagulation with heparin administered at doses higher than conventionally used for venous thromboprophylaxis may improve outcomes.”

Researchers from three international adaptive platform trials standardized their protocols and analyses to jointly study the effect of therapeutic-dose anticoagulation with heparin in patients hospitalized with COVID-19. The platforms included the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), a Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4a), and the Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC). The researchers then conducted two open-label, adaptive, multiplatform, randomized clinical trials.

One analysis included 2,219 hospitalized patients with COVID-19 who were not critically ill, defined as an absence of critical care-level organ support at enrollment. The patients were randomly administered either therapeutic-dose anticoagulation with heparin (n = 1,181) or usual-care pharmacologic thromboprophylaxis. They also underwent d-dimer level testing, with results classified as high ( 2 times the upper limit of the normal range), low ( 2 times the upper limit of the normal range) or unknown.

The other analysis included 1,098 hospitalized patients with COVID-19 who were critically ill, defined as severe disease that led to ICU-level respiratory or cardiovascular organ support. These patients were also randomly assigned the heparin treatment (n = 534) or pharmacologic thromboprophylaxis.

The primary outcome of both analyses was organ support-free days up to 21 days among those who survived to discharge. Patients on heparin received the therapy for up to 14 days or until recovery (discharge or discontinuation of supplemental oxygen for at least 24 hours). Those who received thromboprophylaxis were administered a dosage and duration that was set forth by the treating clinician.

The mean age of noncritically ill patients on heparin or thromboprophylaxis was 59 years and 58.8 years, with 60.4% and 56.9% men, respectively. The average age of critically ill patients on heparin or thromboprophylaxis was 60.4 years and 61.7 years, with 72.2% and 67.9% men. The noncritically ill patients were enrolled from April 21, 2020, to January 22, 2021, and the critically ill patients were enrolled from April 21, 2020, to December 19, 2020.

Response from noncritically ill patients

Among the noncritically ill patients, there was a 98.6% probability that therapeutic doses of heparin increased organ support-free days compared with usual-care thromboprophylaxis (OR = 1.27; 95% CI, 1.03-1.58), according to the researchers. The likelihood of heparin superiority over thromboprophylaxis was 92.9% for those with low d-dimer levels and 97.3% for those with either high or unknown d-dimer levels.

Major bleeding occurred in 1.9% of patients who received heparin and 0.9% of those who received thromboprophylaxis, according to the researchers.

Overall, there was an 87.1% probability that heparin treatment increased survival to discharge compared with thromboprophylaxis (OR = 1.21; 95% CI, 0.87-1.68).

“On the basis of these findings, for every 1,000 hospitalized patients with moderate disease, an initial strategy of therapeutic-dose anticoagulation, as compared with usual-care thromboprophylaxis, would be anticipated to result in the survival of 40 additional patients until hospital discharge without organ support at the expense of seven additional major bleeding events,” Goligher and colleagues wrote.

Response from critically ill patients

Among critically ill patients, the proportion of those who survived to discharge was similar in the two treatment cohorts: 62.7% in the heparin group and 64.5% in the thromboprophylaxis group (OR = 0.84; 95% CI, 0.64-1.11). Major bleeding occurred in 3.8% of patients who received heparin and 2.3% of those who received thromboprophylaxis.

There was a 95% probability that heparin was inferior to thromboprophylaxis, according to the researchers. Moreover, there was an 89% likelihood that heparin treatment lowered the chance of survival to discharge.

“The net effect of anticoagulation on clinical outcomes in patients with COVID-19 may depend on the timing of initiation in relation to disease course and may vary with the severity of illness (and the degree of coagulation or inflammation) at the time that therapy is commended,” Goligher and colleagues wrote. “Despite demonstrable activation of coagulation in multiple organ systems in patients with severe COVID-19, it is possible that initiation of therapeutic-dose anticoagulation after severe COVID-19 has developed may be too late to alter the consequences of established disease processes.”

‘The jury is still out’

In a related editorial, Hugo ten Cate, MD, PhD, of the Thrombosis Expertise Center and the department of internal medicine at Maastricht University Medical Center in the Netherlands, responded to the conflicting results in noncritically vs. critically ill patients.

“How can we reconcile these different outcomes in different populations?” he wrote. “One factor may be that in the critically ill patients, the underlying thrombotic and inflammatory damage may have been too advanced to have been influenced by higher doses of heparin.”

ten Cate also theorized that the geographic locations of the patients could have been a factor in the different outcomes; most critically ill patients in the REMAP-CAP platform were from the United Kingdom while most noncritically ill patients from the ATTACC and ACTIV-4a trials were from the U.S. and Brazil.

“In spite of the signals of benefit of anticoagulation in noncritically ill patients with COVID-19, physicians must deal with the key issues regarding the lack of insight into the mechanisms by which heparin or [low-molecular-weight heparin] does (or does not) provide protection and the question of whether the individual patient’s bleeding risk outweighs the benefit,” ten Cate wrote. “As the late Ed Salzman concluded in the early days of clinical research with [low-molecular-weight heparin]: ‘a promising innovation in antithrombotic treatment, but the jury is still out.’”

References:

Goligher EC, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2103417.

Goligher EC, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2105911.

ten Cate H. N Engl J Med. 2021;doi:10.1056/NEJMe2111151.