HEP-COVID RCT -Full Dose Anticoagulation for COVID-19?

Written by Seth Walsh-Blackmore

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In adult COVID-19 patients with high thrombosis risk, empiric therapeutic dose enoxaparin reduced a composite outcome incidence of thrombotic events or 30-day all-cause mortality relative to prophylactic regimens with no significant difference in major bleeding. The difference was driven by a reduction in venous thromboembolism (VTE) and was not observed in ICU patients.

Why does this matter?
Thrombotic events account for a clinically significant portion of morbidity and mortality in hospitalized COVID-19 patients. Is there a benefit to empirically treating those at the highest risk of thrombosis with therapeutic anticoagulation?

Careful with a composite outcome
This was a multicenter RCT of hospitalized non-pregnant adult COVID-19 patients requiring oxygen with a D-dimer greater than four times the upper limit of normal or a sepsis-induced coagulopathy score of 4 or greater. Two-hundred fifty-seven patients were randomized to receive therapeutic dose enoxaparin (1mg/kg BID) or the standard prophylactic regimen at their respective institution, which varied in dosing and agent used. ICU and non-ICU patients stratified the randomization. The composite primary outcome was any occurrence of VTE, Arterial thromboembolism (ATE, including MI and ischemic stroke), or death from any cause within 30 days.

Among all patients, the composite outcome incidence was 28.7% in the therapeutic group vs. 41.9% in the standard group; RR 0.68 (95% CI 0.49 – 0.96). Major bleeding occurred in 4.7% vs 1.6%; RR 2.88 (0.59-14.02). A reduction in symptomatic DVT drove the difference in the primary outcome: 5.4% vs. 15.3%; RR 0.35 (0.15-0.81), with no significant difference in other forms of VTE, any ATE, or death. In non-ICU patients the composite outcome occurred in 16.7% vs. 36.1%; RR 0.46 (0.27-0.81), while in ICU patients, the occurrence was 51.1% vs. 55.3%; RR 0.92 (0.62-1.39). There was no significant difference in major bleeds when compared by ICU status.

This study was designed to detect a composite outcome and finds clinical benefit with an NNT of 8 vs NNH of 33 using an empiric strategy. In applying these results to practice, it is important to realize the composite effect was driven by DVT reduction in non-ICU patients with no significant difference in ATE or mortality. Without a significant difference in major bleeding or other adverse events, the results support an empiric strategy if DVT prevention is the goal. However, a similar RCT found significantly higher bleeding risk using an empiric strategy and no benefit. There is a case to be made either way, but know what outcome you are buying with an empiric strategy.

Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern Med. 2021 Dec 1;181(12):1612-1620. doi: 10.1001/jamainternmed.2021.6203.

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