Meta-analysis finds intensified anticoagulation had no effect on short term mortality among hospitalized COVID-19 patients

Meta-analysis finds intensified anticoagulation had no effect on short term mortality among hospitalized COVID-19 patients

A recent systematic review and meta-analysis posted to the medRxiv* preprint server evaluated the safety and efficacy of intensified anticoagulation therapy in coronavirus disease 2019 (COVID-19) patients.

Study: Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis. Image Credit: tigerder/Shutterstock


COVID-19 pneumonia is associated with a hypercoagulable state that results from an intense prothrombotic inflammatory response and endothelial perturbation and progresses into COVID-19-associated coagulopathy. This syndrome is marked by elevated D-dimer and fibrinogen levels and pulmonary microvascular thrombosis, which is linked to the worst clinical outcome of COVID-19.

Studies have observed an increased risk of thrombosis in COVID-19 patients, particularly those with severe COVID-19. The risk of venous thrombosis is high even when standard prophylactic anticoagulation therapy is used. A few (non-comparative) studies suggested that the use of an intensified anticoagulant dose might lower thrombotic complications. Randomized controlled trials (RCTs) noted inconsistent effects of using intensified anticoagulation therapies on COVID-19 outcomes.

The review

The authors searched for RCTs that compared intensified anticoagulant dosing to standard prophylactic dosing for COVID-19 patients. The intensified dose was defined as a therapeutic or intermediate-dose viz, 1mg/kg enoxaparin once every day or equivalent. There was no bias in selecting papers, i.e., anticoagulant type, publication status (published or preprint), or language.

An electronic search was done on September 19, 2021, and January 19, 2022, using MEDLINE, Scopus, COVID-19 database of the World Health Organization (WHO), and Cochrane library. WHO trial registry network and clinical trials databases were screened to retrieve recently concluded or ongoing trials, while PROSPERO was used to obtain systematic reviews.

The core objective was studying all-cause mortality upon discharge or follow-up. Venous thromboembolism (VTE), arterial thrombosis, other thrombotic events, and death were included for assessing treatment efficacy. The critical safety outcome measured was non-major bleeding and other bleeding events. Moreover, the effects of intensified anticoagulation were analyzed on days when respiratory and organ support was required.

The researchers screened more than 2400 records and finalized 11 studies that matched the inclusion eligibility comprising data on 5873 adults with laboratory-confirmed COVID-19 diagnoses. Among these were five intensive care unit (ICU)-based studies on 1979 critically ill patients; five studies were on 3616 hospitalized (general ward) patients, and one study reported outcomes on 278 outpatients. Nine studies compared the use of unfractionated heparin (UFN), therapeutic low molecular weight heparin (LMWH), apixaban, or rivaroxaban to standard thromboprophylaxis, and two others were ICU-based studies which compared enoxaparin (intermediate dose) to a standard dose of enoxaparin.

Among the 11 studies, 41% were female; the median age ranged between 52 – 71 years. Of these, 38% received antiviral drugs at baseline, in contrast to 64% who received corticosteroids. People with diabetes constituted 30% of the sample, while 45% reported hypertension. Chronic cardiac disease was observed in 8%, while chronic lung disease was documented in 17%.

All-cause mortality was observed in 16.7% in the intensified anticoagulation cohort while 17.9% in the standard prophylactic group. The authors noted that intensified anticoagulation therapy was not associated with reduced mortality risk. VTE risk was low with intensified anticoagulation therapy compared to standard prophylaxis. Furthermore, intensified anticoagulation was associated with a reduced risk of composite thrombotic outcome or death.

Overall, thrombosis risk was lower with intensified therapy, but there was no evidence to suggest the same for arterial thrombosis. Major bleeding events were more with intensified therapy when compared to prophylaxis, with 1.3% in the intensified therapy cohort undergoing bleeding in contrast to 1.3% in the prophylactic group. Notably, other non-major bleeding and any bleeding events had elevated risks with intensified anticoagulation.

A slight mortality decrease was noted within the general ward inpatients with high heterogeneity and low precision. Intermediate and therapeutic dosing had no significant differences in mortality, although heterogeneity was substantial among trials with therapeutic dosing.


The current meta-analysis covering data from 11 RCTs on 5873 individuals observed that intensified anticoagulation therapy had no effect on mortality for hospitalized COVID-19 patients. Nonetheless, intensified therapy was associated with a reduced risk of VTE, including composite VTE outcomes and death, but with an elevated risk of major bleeding.

Despite a significant reduction in VTE events with an intensified anticoagulant dosing regimen, survival benefit was not observed. One of the plausible reasons for the lack of mortality reduction could be that the high risk of major bleeding associated with standard thromboprophylaxis and additional 74% elevation with intensified therapy could offset mortality reduction due to VTE. Based on the observations, it is not justifiable to introduce intensified anticoagulant therapy for non-critically ill COVID-19 patients.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Wills, N. et al. (2022) "Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with Covid-19: a systematic review and meta-analysis". medRxiv. doi: 10.1101/2022.03.05.22271947.

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Anticoagulant, Apixaban, Bleeding, Chronic, Coronavirus, Coronavirus Disease COVID-19, covid-19, D-dimer, Diabetes, Drugs, Efficacy, Heparin, Intensive Care, Laboratory, Language, Lung Disease, Mortality, Pneumonia, Prophylaxis, Respiratory, Rivaroxaban, Syndrome, Thromboembolism, Thrombosis, Venous Thromboembolism

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Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.

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