The benefits of full-dose heparin in certain COVID-19 patients were identified

Therapeutic doses of heparin were associated with an increased survival probability in non-severe COVID-19 patients compared to thromboprophylaxis in conventional care, but in the most severe patient population, REMAP-CAP, ACTIV- 4a, and ATTACC multi-platform trials were shown.

In non-severe cohorts, heparin-treated dose anticoagulant therapy was superior to conventional care prevention and was more likely to increase organ support-free days in patients admitted with moderate COVID-19 (adjusted odds ratio). ) [aOR] 1.27, 95% confidence interval [CrI] 1.03-1.58), reported by Ryan Zarychanski, MD and his colleagues at the University of Manitoba in Winnipeg, Canada.

This advantage is high D-dimer (aOR 1.31, 95% CrI 1.00-1.76), low D-dimer (aOR 1.22, 95% CrI 0.93-1.57), and unknown D-dimer, regardless of the level of D-dimer. It seemed to last. Dimeric levels (aOR 1.32, 95% CrI 1.00-1.86) indicate a high probability of a therapeutic dose of anticoagulant therapy superiority compared to thromboprophylaxis with conventional care. New England Journal of Medicine (((NEJM).

The authors stated that the median adjusted absolute group-to-group survival rate before discharge without organ support was 4.0 percentage points (95% CrI 0.5-7.2).

However, The second NEJM study The same benefits were not found in this multi-platform trial in critically ill patients.

So why are the reactions of each group different?and Ancillary editorial“It is possible that the underlying thrombotic and inflammatory injuries were too advanced to be affected by high doses of heparin,” said Hugotenkate, MD, MD, of the Gutenberg University Medical Center in Mainz, Germany. I guessed.

He also said that the majority of critically ill patients were from REMAP-CAP in the United Kingdom, and the majority of patients with moderate illness were from ATTACC and ACTIV-4 in the United States and Brazil, patients across three platforms. I also mentioned the differences between groups.

Ultimately, 10 Cates did not support the use of heparin to prevent thrombosis in critically ill patients, but “may justify other thrombosis or fibrinolysis-promoting strategies. There is. ” He also argued that the jury had not yet used heparin for moderate illness and said the benefits and risks needed to be weighed.

“Physicians need to address key issues regarding the lack of insight into the mechanism of heparin. […] The question of providing (or not providing) protection and whether the risk of bleeding in an individual patient outweighs the benefits, “writes 10 Kate.

Non-severe patients see benefits

Previous results from three platforms (combined into one multi-platform randomized trial) were published twice in January 2021. Top line results and, Slide deck..

After the top-line results are published, adaptive analysis defines a 99% probability of a pre-specified criterion of superiority (> 1.0 “odds ratio in both the high-D-dimer group and the low-D-dimer group. ) Was discontinued. High D-dimer levels were at least twice the upper limit of the normal range, while lower D-dimer levels were twice the upper limit of the normal range. Overall, the primary analysis included 2,219 patients enrolled between April 2020 and January 2021.

The study included patients from 121 institutions in 9 countries admitted with moderate COVID-19, but did not require respiratory or cardiovascular organ support in the ICU setting. They were randomized to receive either therapeutic doses of anticoagulant therapy with heparin or thrombosis prevention with conventional treatment, and stratified by D-dimer levels (high, low, or unknown).

The primary outcome was organ-free support days based on an ordinal scale that combined in-hospital death of patients who survived to discharge with days without cardiovascular or respiratory support by day 21.

The average age of patients was about 59 years, 57% to 60% were male and about two-thirds were Caucasian. Patients in the high-D-dimer group were generally older and had more comorbidities. Approximately 62% of patients received glucocorticoids at baseline, 36% received remdesivir (Veklury), and 12% received antiplatelet drugs.

Overall, 80.2% of patients in the treatment dose group survived to discharge without organ support, compared to 76.4% of patients in the regular care group. The median number of days without organ support was 22 days in both groups.

Major bleeding occurred in 1.9% of the treatment dose group and 0.9% of the usual care group. Fatal bleeding occurred in 3 patients in the therapeutic dose group and 1 patient in the usual care group.

“Based on these findings, for every 1,000 patients hospitalized for moderate disease, the initial strategy for therapeutic doses of anticoagulant therapy. […] It is expected to result in the survival of 40 additional patients until they are discharged without organ support at the expense of seven additional major bleeding events, “the authors wrote.

There is no benefit to the seriously ill population

In severely ill COVID-19 patients, there was no difference in the number of days without organ support or survival time to discharge between the two treatment groups, and the study was discontinued in December 2020 due to futileness.

Uselessness was defined as an odds ratio of less than 1.2, with odds in which the treatment dose group increased the number of organ support-free days was lower than in the normal care group (aOR 0.83, 95% CrI 0.67-1.03). The proportion of patients who survived to discharge was similar, with approximately 63% in the treatment dose group versus approximately 65% ​​in the conventional treatment group (aOR 0.84, 95% CrI 0.64-1.11).

This population consisted of 1,103 patients from 393 sites in 10 countries. They were hospitalized with COVID-19 and required ICU-level respiratory or cardiovascular support, including non-invasive or invasive mechanical ventilation.

The median number of organ support-free days in the treatment dose group was 1, compared with 4 in the regular care group.

Major bleeding events occurred in 3.8% of the therapeutic dose group compared to 2.3% in the normal care group, and approximately 40% of patients in both groups showed major thrombotic events or death.