Escalated Anticoagulation Shows No Benefit Over Standard Dosing for COVID-19 Patients in ICU

Upping the dose of prophylactic anticoagulation for patients with coronavirus disease 2019 (COVID-19) in intensive care did not result in improvements in mortality or venous or arterial thrombosis, a new study found.

The INSPIRATION study, published in JAMA, included 562 patients with COVID-19 admitted to ICUs at 10 academic centers in Iran between July 29 and Nov. 19. Patients (276 of them) in the intermediate-dose group were given 1 mg/kg daily of enoxaparin, while 286 in another group were given the standard 40 mg dose of the prophylactic anticoagulation treatment.

“Since last year, out of concern for excess of blood clots, many clinicians have been using higher than usual doses of preventative (prophylactic) blood thinners in ICU patients with COVID-19. This multicenter randomized trial shows that an escalated (intermediate-dose) regimen did not lead into patient benefit for mortality or venous or arterial thrombosis,” Behnood Bikdeli, MD, MS, Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School; Center for Outcomes Research and Evaluation (CORE), Yale University School of Medicine; Cardiovascular Research Foundation (CRF), told Contagion®.

The study found that 45.7% (126) of patients in the intermediate-dose group met the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. Compared with 44.1% (126) of those in the standard-dose group, the difference was not statistically significant (absolute risk difference, 1.5% [95% CI, −6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70).

“We were wondering about the potential benefit of escalated anticoagulation,” Bikdeli said. “So, lack of an efficacy signal for any of the primary or secondary outcomes was surprising –but it is helpful to turn attention to other therapies that may confer benefit. In fact, there are several other trials of blood thinners ongoing for COVID-19, as we recently summarized.”

All-cause mortality at the 30-day follow-up was not significantly different between the intermediate-dose group (119 [43.1%]) and the standard-dose group (117 [40.9%]). Seven patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose group experienced major bleeding, and 6 patients in the intermediate-dose group experienced severe thrombocytopenia compared with none in the standard-dose group.

“I think the take home message is that routine use of intermediate-dose anticoagulation in ICU patients with COVID-19 should be discouraged,” Bikdeli said.

The study offered possible explanations for the lack of benefit of intermediate-dose anticoagulation, including the possibility of insufficient intensity, timing of administration, the population of patients studied being broad rather than targeted, and a low number of patients requiring mechanical ventilation.

Limitations included that the study excluded the most severely ill patients, anticoagulation assignment was open-label, venous thromboembolism rate was lower than in other studies, the confidence interval for the primary outcome was relatively wide, and there were not enough patients with high body weight to generalize the results to patients with obesity.

“We remain excited to see how the results of other antithrombotic therapy trials will plan out,” Bikdeli said. “Also, several other studies are assessing whether medications with anti-inflammatory properties may impact the so-called thromboinflammation. For example, a separate randomization in our trial (INSPIRATION-S) is assessing whether statin therapy, compared with placebo, confers benefit in these patients –the results will be presented at the American College of Cardiology annual meeting in May 2021.”

A previous study including three clinical trial platforms involving more than 1000 patients reported by the National Institutes of Health found that full-dose blood thinners improved outcomes for patients hospitalized with moderate COVID-19 and were found to be safe and superior to standard dosing for preventing blood clots among hospitalized patients.

A study of data from the Mount Sinai COVID Information Center involving 2500 patients found that patients receiving anticoagulants had a lower rate of in-hospital mortality than those who didn’t receive the treatment.

Investigators at Rensselaer Polytechnic Institute (RPI) have examined whether heparin, which is also available in non-anticoagulant formulations, could interfere with SARS-CoV-E infection by binding to the coronavirus’ surface spike protein.