Dr Michelle Sholzberg

Early initiation of therapeutic heparin should be considered in moderately ill hospitalised patients admitted for COVID-19, according to Canadian researchers whose trial showed it reduced the risk of death by almost 80%.

While previous studies have not shown a benefit for therapeutic anticoagulation with DOACs in COVID-19, the researchers said heparin had additional anti-inflammatory and anti-viral properties that could potentially decrease the thrombo-inflammatory process and reduce the risk of critical illness or death.

They therefore conducted the Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID) trial in 465 patients with Covid-19 and elevated D-dimer level.

The 228 patients assigned to therapeutic heparin received therapeutic doses of low molecular weight heparin (LMWH) or unfractionated heparin, while 237 patients allocated to prophylactic heparin received dose-capped prophylactic subcutaneous heparin (LMWH or UFH) adjusted for body mass index and creatinine clearance.

Treatment was continued until the first of hospital discharge, day 28, study withdrawal or death.

The results, published on pre-print server MedRvx, showed there was no difference between groups in the primary outcome, a composite of ICU admission, non-invasive/ invasive mechanical ventilation or death up to 28 days. This occurred in 16.2% of patients in the therapeutic heparin group vs 21.9% for prophylactic heparin (OR, 0.69; 95% CI, 0.43-1.10; p=0.12).

However there were significant differences in all-cause mortality between groups. Four patients (1.8%) assigned to therapeutic heparin died compared with 18 patients (7.6%) assigned to prophylactic heparin (odds ratio, 0.22; 95%-CI, 0.07 to 0.65).

There was also a benefit for therapeutic heparin in the composite outcomes of all-cause mortality or any mechanical ventilation compared to the prophylactic heparin group ( (10.1% vs 16.0%, OR 0.59; 95%- CI, 0.34 to 1.02).

Differences in outcomes for mechanical ventilation and ICU admission were smaller and non-significant for therapeutic and prophylactic heparin.

Major bleeding occurred in 0.9% of patients with therapeutic heparin and 1.7% of patients with prophylactic heparin (odds ratio, 0.52; 95%-CI, 0.09 to 2.85).

We believe that the findings of these trials taken together should result in a change in clinical practice for moderately ill ward patients with COVID-19. 8/10

— Michelle Sholzberg (@sholzberg) July 9, 2021

The researchers, led by Dr Michelle Sholzberg,  Head, Division of Hematology/Oncology, St. Michael’s Hospital, Toronto, said the RAPID trial results should be interpreted in conjunction with the available COVID-19 trials of therapeutic heparin. These clearly indicated that therapeutic heparin was beneficial in moderately ill but not in the severely ill patients, she noted, citing an accompanying meta-analysis of randomised evidence.

One previous study, the Anticoagulation Coronavirus (ACTION) trial used 15 to 20 mg of rivaroxaban in 94% of patients assigned to therapeutic anticoagulation and found no benefit, she noted.  However the DOAC was unlikely to have the anti-inflammatory and antiviral effects of heparin.

“Early initiation of therapeutic heparin could therefore decrease the thrombo-inflammatory process, and reduce the risk of critical illness or death. Randomized trials indicated that therapeutic heparin anticoagulation therefore may be beneficial in moderately, but not critically ill patients with Covid-19, suggesting that the time of initiation of therapeutic heparin is indeed important,” the study authors concluded.