First RCT in COVID Anticoagulation Says Go Full Dose


Therapeutic-level dosing of enoxaparin (Lovenox) improved respiratory outcomes in severe COVID-19, a pilot randomized trial showed.

Gas exchange measured by the PaO2/FiO2 ratio improved significantly over time in the 10-patient therapeutic group (from 163 at baseline to 209 at 7 days and 261 at 14 days, P=0.0004) but not in the 10-patient control group receiving lower prophylactic-level doses in the open-label study (184, 168, and 195, respectively, P=0.487).

Compared with prophylactic dosing of the drug, therapeutic dosing also led to four-fold more patients being weaned off of mechanical ventilation (P=0.031) and more ventilator-free days (15 vs 0 days, P=0.028), Carlos Henrique Miranda, MD, PhD, of São Paulo University in Brazil, and colleagues reported in Thrombosis Research.

Three patients died within 28 days with therapeutic anticoagulation (two secondary to healthcare-associated infections) versus one with prophylactic dosing, but the difference wasn’t statistically significant. The study wasn’t powered for clinical outcomes, the researchers noted.

There were no major bleeding events, but numerically more minor bleeding with the higher dose anticoagulation.

“It’s a remarkable step forward in the sense that now for the first time we are having randomized trial data related to antithrombotic therapy for COVID-19,” commented Behnood Bikdeli, MD, of Brigham and Women’s Hospital and Harvard in Boston.

While the study couldn’t address the mechanism, “hypothetically, it’s reducing the risk and/or severity of macrothrombi and microthrombi in the lung,” he told MedPage Today.

However, “this study is far, far, far from being conclusive,” Bikdeli cautioned. “As enthusiastic as I am to see the results, we have to be honest with respect to their research design and limitations.”

“It’s such a heated debate,” he said. Proponents cite mechanistic reasons for why low molecular weight heparin like enoxaparin should help in COVID-19 (one recent study showed it blocks SARS-CoV-2 from binding with cells) and observational studies that have suggested better mortality outcomes with it. Opponents cite retrospective data like that from a small study suggesting higher mortality with preemptive therapeutic dose anticoagulation.

Miranda and colleagues’ single-center study randomly assigned 20 patients with severe COVID-19 and elevated D-dimer (>1,000 μg/L) who required mechanical ventilation to receive standard prophylactic anticoagulation versus therapeutic anticoagulation, both utilizing subcutaneous unfractionated enoxaparin.

Enoxaparin doses in the therapeutic-level group were set according to age and estimated creatinine clearance, generally ranging from 0.75 mg/kg once daily to 1 mg/kg twice daily, up to a maximum of 140 mg twice daily. The control group received 40 mg of enoxaparin once or twice daily or 5,000-7,500 IU of unfractionated heparin three times daily — for both, the higher dose was for patients weighing more than 120 kg.

A third arm with therapeutic IV unfractionated heparin “was abandoned due to difficulties in adjusting the activated partial thromboplastin time (aPTT) during the pandemic,” the researchers noted.

The small size and open-label design make the choice of a “softer” surrogate measure (gas exchange vs mortality as a hard endpoint) as the primary endpoint more challenging, Bikdeli noted. And the endpoint of liberation from mechanical ventilation is to some extent discretionary, he added.

Still, the question of how to dose and which agent to use for thromboprophylaxis are going to be more definitively answered soon, noted Bikdeli, whose INSPIRATION trial protocol for intermediate versus prophylactic dose anticoagulation was published alongside the Brazilian study in Thrombosis Research.

“As of now there are more than 20 ongoing or registered randomized studies to address the questions of optimal anticoagulation in various subgroups of patients with COVID-19 — from outpatients to inpatients or critically-ill patients,” he said.

Disclosures

The researchers disclosed no relevant relationships with industry.

Bikdeli disclosed serving as a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters.

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