Findings from a study in the Journal of Thrombosis and Haemostasis dispute the currently adopted strategy of giving weight-adjusted doses of anticoagulants to non-critically ill patients with COVID-19 in the absence of thromboembolic complications.
Researchers led by Raffaele Pesavento, MD, Department of Medicine, University of Padua, Padua, Italy, noted that “the increasing awareness that low-dose anticoagulants may be ineffective for prevention of thrombotic complications in the course of COVID-19, including the development of micro-thrombosis in the lung vessels, has induced several clinicians to consider the use of sub-therapeutic or even therapeutic doses of antithrombotic agents in all admitted patients, challenging their hemorrhagic potential. The results of our retrospective cohort study do not support this strategy.”
The study included consecutive patients with laboratory-confirmed SARS-CoV-2 infection who were admitted between February 26 and April 6, 2020 to the non-intensive COVID-19 Unit of the University Hospital of Padua and the COVID-19 Hospital of the Padua Province, Ospedali Riuniti Padova Sud, both in Northern Italy. The median age was 71 years (IQR 59-82) years and 181 were men (55.9%). Patients with critical disease were excluded.
The choice of the antithrombotic agent was left to attending physicians, who decided to use prophylactic or higher doses based on perceived thromboembolic risk. From clinical charts, researchers retrieved information on each of the three antithrombotic drugs that had been administered (unfractionated heparin, enoxaparin or fondaparinux), and predefined the dose intensity as being prophylactic or higher.
Daily doses of unfractionated heparin up to 15,000 U, of enoxaparin up to 4000 U and of fondaparinux up to 2.5 mg were labelled as prophylactic (prophylaxis group). Higher daily doses, usually adjusted to body weight or laboratory parameters, were aggregated in one group [(sub)therapeutic group] regardless of the drug amount. The primary endpoint was the composite of major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) occurring in each of the two study groups during the administration of antithrombotic agents, up to two days after their discontinuation.
Of the 324 patients recruited, 240 had been treated with prophylactic doses and 84 with higher doses of anticoagulants. The rate of the composite endpoint of MB or CRNMB was 6.9 per 100 person-months in patients who had been given prophylactic doses, and 26.4 per 100 person-months in those who had been prescribed higher doses (HR 3.89; 95%CI, 1.90 to 7.97; p=<0.001).
Looked at individually, there were 8 cases each of MB events in the prophylactic and (sub)therapeutic dose groups (3.7 and 11.7 per 100 person-months, respectively), and there were 7 and 10 CRNMB cases (3.2 and 14.6 per 100 person-months, respectively).
Two fatal bleeding events occurred in patients who had received prophylactic doses (0.9 per 100 person-months) and two in patients prescribed higher doses (2.9 per 100 person-months). Venous thromboembolism developed in six patients given prophylactic doses (2.8 per 100 person-months) and in three patients who had been prescribed higher doses (4.4 per 100 person-months).
The corresponding rates for overall mortality were 12.2 and 20.1 per 100 person-months, respectively. Age > 80 years, high Padua Prediction Score (PPS), COVID phenotype, and moderate-to-severe renal impairment were found to be independent predictors of all-cause mortality.
In a multivariable analysis, use of (sub)therapeutic doses of anticoagulants (HR 3.89; 95% CI, 1.90 to 7.97; p=<0.001), age older than 80 years (HR 3.40; 95% CI, 1.51 to 7.65; p=0.003) and concomitant dual antiplatelet therapy (HR 9.4; 95% CI 2.6 to 33.7; p<0.001) were found to be independent predictors of major or clinically relevant non-major bleeding.
“The rate of symptomatic complications occurring during the clinical course of patients who received (sub)therapeutic doses of heparins or fondaparinux did not differ from that of patients given conventional preventive doses, nor did the rate of overall mortality, which was even higher in the former group, most likely because of the recruitment of patients who were on average older and had a higher thromboembolic risk,” the authors said.
By contrast, they noted that the rate of clinically relevant bleeding complications among those allocated to (sub)therapeutic doses “exceeded by far” that recorded among those on preventive doses, with anticoagulant dose being the strongest determinant of bleeding risk. “As (sub)-therapeutic doses of antithrombotic drugs failed to reduce the risk of fatal or non-fatal thrombotic complications while simultaneously increasing the haemorrhagic risk, their use in patients with non-critically ill COVID-19 should be discouraged,” the authors said.