Higher anticoagulation dose associated with lower mortality in hospitalized COVID-19 patients

Patients hospitalized with COVID-19 appeared to do better with higher versus lower doses of anticoagulation, a recent meta-analysis found.

Researchers reviewed randomized trials from the World Health Organization's International Clinical Trials Data Registry Platform and ClinicalTrials.gov that assigned hospitalized COVID-19 patients to receive higher-dose or lower-dose anticoagulation. The study's primary objective was estimating the intention-to-treat effects of therapeutic- versus prophylactic-dose, therapeutic- versus intermediate-dose, and intermediate- versus prophylactic-dose anticoagulation in hospitalized patients with suspected or confirmed COVID-19. All-cause mortality 28 days after randomization was the primary outcome, while secondary outcomes were progression to invasive mechanical ventilation or death, thromboembolic events, and major bleeding. The results were published Dec. 24 by Annals of Internal Medicine.

Twenty-two trials were included in the study. In 11 trials involving 6,297 patients, 5,456 who required low or no oxygen at randomization, therapeutic doses of anticoagulation with heparin appeared to reduce 28-day mortality rates compared with prophylactic doses (odds ratio [OR], 0.77; 95% CI, 0.64 to 0.93). ORs for 28-day mortality were 1.21 (95% CI, 0.93 to 1.58) for therapeutic doses of anticoagulation versus intermediate doses (six trials involving 1,803 patients, 843 receiving noninvasive ventilation at randomization) and 0.95 (95% CI, 0.76 to 1.19) for intermediate versus prophylactic doses of anticoagulation (10 trials involving 3,897 patients, 2,935 receiving no or low oxygen at randomization). Analyses of predefined patient subgroups, some limited in power, found that treatment effects were broadly consistent. Based on 11 studies, thromboembolic events were less common with higher doses of anticoagulation than with lower doses (summary OR, 0.48; 95% CI, 0.36 to 0.64), but risk for major bleeding was greater (summary OR, 1.90; 95% CI, 1.19 to 3.05).

The researchers noted that only one of the included trials used direct-acting anticoagulants so the results apply only to anticoagulation with heparin, and that reporting of adverse events was inconsistent, among other limitations.

“In conclusion, in this prospective meta-analysis of clinical trials examining doses of anticoagulation for hospitalized patients with COVID-19, therapeutic compared with prophylactic-dose anticoagulation reduced 28-day mortality. By contrast, mortality was higher for therapeutic- compared with intermediate-dose anticoagulation, although this comparison was not estimated precisely, and was similar for intermediate compared with prophylactic-dose anticoagulation,” the authors wrote. “For each comparison, higher- compared with lower-dose anticoagulation was associated with fewer thromboembolic events but a greater risk for major bleeding.”

An accompanying editorial said that while the study's central conclusion is positive, the full results are more nuanced. For example, the benefits with higher-dose anticoagulation were not seen in any dose comparisons other than therapeutic versus prophylactic, and the differences in effect estimates did not indicate a causal dose-dependent relationship, the editorialists said. They noted that the study is not likely to drastically change practice, in part because it was conducted during a period when the SARS-CoV-2 pathogen evolved significantly, when immunity became widespread, when a pharmacologic standard of care was established, and when hospitalization and mortality rates for COVID-19 decreased.

“Even if the results provided clear direction about the benefits of higher-dose anticoagulation for a particular patient subgroup, whether the results would be appropriately applied to the patients admitted with COVID-19 today is not assured,” the editorialists wrote.