Infectious Disease

Therapeutic heparin may improve the survival of non-critically ill patients with COVID-19. to enhance

August 04, 2021

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Goligher reports that he has received personal fees and non-financial assistance from Getinge and non-financial assistance from Timpel. ten Cate reports that he served as a consultant to Alveron and STAGO, a coagulation Profile shareholder, on an advisory board for Portola / Alexia, has a research contract with Bayer and PPS Health Holland, has received research support from Pfizer, and personal fees from Daiichi. receives, Gilead / Galapagos, Leo Pharma, Pfizer and STAGO outside of the submitted work. Please refer to the studies for all relevant financial information from the other authors.

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Therapeutic anticoagulation with heparin increased the likelihood of survival in non-critically ill patients hospitalized with COVID-19, according to a new study in The New England Journal of Medicine.

However, a second study published at the same time showed that the same treatment did not bring any survival benefit in critically ill patients.

Therapeutic anticoagulation with heparin, according to two recent studies, increased the likelihood of survival in non-critically ill patients hospitalized with COVID-19, but not in critically ill patients hospitalized with COVID-19.
Source: Adobe Stock

“Patients admitted to hospital with COVID-19 often have macrovascular and microvascular thrombosis and inflammation, which are associated with poor clinical outcomes.” Ewan C. Goligher, MD, PhD, an assistant professor in the Interdepartmental Intensive Care Unit at the University of Toronto, and colleagues wrote. “Given the antithrombotic, anti-inflammatory and possibly antiviral properties of heparins, it has been hypothesized that anticoagulation with heparin, which is administered in higher doses than conventionally used for venous thromboprophylaxis, can improve results.”

Researchers from three international adaptive platform studies standardized their protocols and analyzes to collectively examine the effects of therapeutic dose anticoagulation with heparin in patients admitted to hospital with COVID-19. Platforms included the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), a multicenter, adaptive, randomized controlled platform study of the safety and effectiveness of antithrombotic strategies in hospitalized adults with COVID-19 (ACTIV-4a) and Antithrombotic Therapy to Relieve Complications of COVID-19 (ATTACC). The researchers then conducted two open, adaptive, cross-platform, randomized clinical trials.

An analysis included 2,219 hospitalized patients with COVID-19 who were not critically ill, defined as the lack of ICU level organ support upon admission. At random, the patients received either therapeutically dosed anticoagulation with heparin (n = 1,181) or standard pharmacological thromboprophylaxis. They were also subjected to a d-dimer level test with the results rated as high (2 times the upper limit of the normal range), low (2 times the upper limit of the normal range), or unknown.

The other analysis included 1,098 hospitalized patients with COVID-19 who were critically ill, defined as a serious illness that resulted in respiratory or cardiovascular support at the ICU level. These patients were also randomly assigned to heparin treatment (n = 534) or pharmacological thromboprophylaxis.

The primary result of both analyzes were organ support-free days up to 21 days in those who survived to discharge. Patients receiving heparin received therapy for up to 14 days or until recovery (discharge or discontinuation of supplemental oxygen for at least 24 hours). Those receiving thromboprophylaxis were given a dosage and duration determined by the treating clinician.

The mean age of the non-critically ill patients under heparin or thromboprophylaxis was 59 years and 58.8 years, respectively, in 60.4% and 56.9% men. The mean age of critically ill patients under heparin or thromboprophylaxis was 60.4 years and 61.7 years, respectively, in 72.2% and 67.9% men. The non-critically ill patients were admitted from April 21, 2020 to January 22, 2021 and the critically ill patients were admitted from April 21, 2020 to December 19, 2020.

Response of non-critically ill patients

Among the non-critically ill patients, there was a 98.6 percent probability that therapeutic doses of heparin increased the days without organ support compared to thromboprophylaxis in standard care (OR = 1.27; 95% CI, 1.03-1 , 58), according to the researchers. The likelihood of heparin superiority over thromboprophylaxis was 92.9% in those with low d-dimer values ​​and 97.3% in those with either high or unknown d-dimer values.

According to the researchers, 1.9% of patients who received heparin and 0.9% of patients who received thromboprophylaxis experienced major bleeding.

Overall, there was an 87.1% probability that heparin treatment increased survival to discharge compared to thromboprophylaxis (OR = 1.21; 95% CI, 0.87-1.68).

“On the basis of these results, it is to be expected that for every 1,000 hospitalized patients with moderately severe illness an initial strategy of therapeutically dosed anticoagulation compared to conventional thromboprophylaxis will ensure the survival of 40 additional patients until discharge from hospital without organ support at the expense of seven other major bleeding events”, wrote Goligher and colleagues.

Reaction of critically ill patients

In the critically ill patients, the proportion of those who survived to discharge was similar in the two treatment cohorts: 62.7% in the heparin group and 64.5% in the thromboprophylaxis group (OR = 0.84; 95% -KI 0.64 – 1.11). Major bleeding occurred in 3.8% of patients receiving heparin and 2.3% of patients receiving thromboprophylaxis.

According to the researchers, there was a 95% chance that heparin was inferior to thromboprophylaxis. In addition, there was an 89% chance that heparin treatment would reduce the chance of survival to discharge.

“The net effect of anticoagulation on clinical outcomes in patients with COVID-19 may depend on the time of onset in relation to the course of the disease and may vary with the severity of the disease (and the degree of clotting or inflammation) at the time of therapy recommended”, wrote Goligher and colleagues. “Despite the demonstrable activation of coagulation in several organ systems in patients with severe COVID-19, it is possible that the start of therapeutically dosed anticoagulation after the development of severe COVID-19 is too late to change the consequences of established disease processes.”

“The jury is still pending”

In a related editorial Hugo ten Cate, MD, PhD, of the Thrombosis Expertise Center and the Department of Internal Medicine at Maastricht University Medical Center in the Netherlands, responded to the conflicting results in non-critically vs. critically ill patients.

“How can we reconcile these different outcomes in different populations?” He wrote. “One factor could be that the critically ill patients may have had underlying thrombotic and inflammatory damage too advanced to be affected by higher doses of heparin.”

ten Cate also theorized that the geographic location of the patients may have been a factor in the different results; Most of the critically ill patients in the REMAP-CAP platform were from the UK, while most of the non-critically ill patients in the ATTACC and ACTIV-4a studies were from the US and Brazil.

“Despite the benefit signals of anticoagulation in non-critically ill patients with COVID-19, the doctors have to deal with the central questions of the lack of insight into the mechanisms by which heparin or [low-molecular-weight heparin] provides (or not) protection and the question of whether the individual patient’s risk of bleeding outweighs the benefit, ”wrote ten Cate. “As the late one Ed Salzmann in the early stages of clinical research with [low-molecular-weight heparin]: ‘A promising innovation in antithrombotic treatment, but the jury has not yet decided.’ “

References:

Goligher EC, et al. N Engl J Med. 2021; doi: 10.1056 / NEJMoa2103417.

Goligher EC, et al. N Engl J Med. 2021; doi: 10.1056 / NEJMoa2105911.

ten Cate H. N Engl J Med. 2021; doi: 10.1056 / NEJMe2111151.

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