Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

Background. COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. Methods. We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. Findings. From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28.899 (34.8%) wins in the therapeutic group and 34.288 (41.3%) in the prophylactic group (win ratio 0.86 [95% CI 0.59–1.22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3.64 [95% CI 1.61–8.27], p=0.0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. Interpretation. In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

Age-adjusted D-dimer cutoffs to guide anticoagulation in COVID-19 – Authors' reply

Science, Medicine, and the Anesthesiologist

Therapeutic anticoagulation in COVID-19 patients

Funding Acknowledgements Type of funding sources: None. Background Several systematic reviews and meta-analyses have been conducted to evaluate the effects of anticoagulation on patients admitted with coronavirus infectious disease 2019 (COVID-19). However, since most of them consist of observational studies, the optimal dose still remains controversial. Purpose The purpose of this study was to investigate the efficacy and safety of therapeutic anticoagulation compared with prophylactic anticoagulation in patients admitted with COVID-19. Methods A meta-analysis was conducted on randomised controlled trials (RCTs) to minimise bias. PubMed and the Cochrane Central Register of Controlled Trials were queried for the terms "covid-19," "(anticoagulation OR thromboprophylaxis)," and "randomised." The same terms or relevant studies were also queried on the website of the ClinicalTrials.gov and relevant reviews. The clinical endpoints of interest were all-cause death, thromboembolism, and major bleeding. Pooled estimates were calculated using a random-effects model. Results A total of 7 RCTs were included in this study. The risk of thromboembolism was lower (odds ratio (OR) 0.54; 95% confidence interval (CI) 0.41-0.73; p < 0.001) and the risk of major bleeding was higher (OR 1.87; 95% CI 1.21-2.90; p = 0.005) in the therapeutic anticoagulation group than in the prophylactic anticoagulation group. On the other hand, the risk of all-cause death was similar (OR 0.92; 95% CI 0.65-1.31; p = 0.65) between the 2 groups. In a subgroup analysis, the risk of thromboembolism was also lower in the therapeutic anticoagulation group compared with the prophylactic anticoagulation group both in moderately and severely ill patients, respectively. However, the risk of major bleeding was more likely to higher (OR 1.85; 95% CI 0.98-3.49; p = 0.06) in the therapeutic anticoagulation group than the prophylactic anticoagulation group only in severely ill patients. Conclusions Therapeutic anticoagulation is associated with a lower risk of thromboembolism and a higher risk of major bleeding compared to prophylactic anticoagulation in patients hospitalised with COVID-19. Therapeutic anticoagulation may be more beneficial for moderately ill patients.

Efficacy and safety of therapeutic vs. prophylactic bemiparin in noncritically ill patients with COVID-19 pneumonia

Although patients with severe COVID-19 are known to be at high risk of developing thrombotic events, the effects of anticoagulation (AC) dose and duration on in-hospital mortality in critically ill patients remain poorly understood and controversial. The goal of this study was to investigate survival of critically ill COVID-19 patients who received prophylactic or therapeutic dose AC and analyze the mortality rate with respect to detailed demographic and clinical characteristics. We conducted a retrospective, observational study of critically ill COVID-19 patients admitted to the ICU at Stony Brook University Hospital in New York who received either prophylactic (n = 158) or therapeutic dose AC (n = 153). Primary outcome was in-hospital death assessed by survival analysis and covariate-adjusted Cox proportional hazard model. For the first 3 weeks of ICU stay, we observed similar survival curves for prophylactic and therapeutic AC groups. However, after 3 or more weeks of ICU stay, the therapeutic AC group, characterized by high incidence of acute kidney injury (AKI), had markedly higher death incidence rates with 8.6 deaths (95% CI = 6.2-11.9 deaths) per 1,000 person-days and about 5 times higher risk of death (adj. HR = 4.89, 95% CI = 1.71-14.0, p = 0.003) than the prophylactic group (2.4 deaths [95% CI = 0.9-6.3 deaths] per 1,000 person-days). Among therapeutic AC users with prolonged ICU admission, non-survivors were characterized by older males with depressed lymphocyte counts and cardiovascular disease. Our findings raise the possibility that prolonged use of high dose AC, independent of thrombotic events or clinical background, might be associated with higher risk of in-hospital mortality. Moreover, AKI, age, lymphocyte count, and cardiovascular disease may represent important risk factors that could help identify at-risk patients who require long-term hospitalization with therapeutic dose AC treatment.

IntroductionAlthough patients with severe COVID-19 are known to be at high risk of developing thrombotic events, the effects of anticoagulation (AC) dose and duration on in-hospital mortality in critically ill patients remain poorly understood and controversial. The goal of this study was to investigate survival of critically ill COVID-19 patients who received prophylactic or therapeutic dose AC and analyze the mortality rate with respect to detailed demographic and clinical characteristics.Materials and methodsWe conducted a retrospective, observational study of critically ill COVID-19 patients admitted to the ICU at Stony Brook University Hospital in New York who received either prophylactic (n = 158) or therapeutic dose AC (n = 153). Primary outcome was in-hospital death assessed by survival analysis and covariate-adjusted Cox proportional hazard model.ResultsFor the first 3 weeks of ICU stay, we observed similar survival curves for prophylactic and therapeutic AC groups. However, after 3 or more weeks of ICU stay, the therapeutic AC group, characterized by high incidence of acute kidney injury (AKI), had markedly higher death incidence rates with 8.6 deaths (95% CI = 6.2–11.9 deaths) per 1,000 person-days and about 5 times higher risk of death (adj. HR = 4.89, 95% CI = 1.71–14.0, p = 0.003) than the prophylactic group (2.4 deaths [95% CI = 0.9–6.3 deaths] per 1,000 person-days). Among therapeutic AC users with prolonged ICU admission, non-survivors were characterized by older males with depressed lymphocyte counts and cardiovascular disease.ConclusionsOur findings raise the possibility that prolonged use of high dose AC, independent of thrombotic events or clinical background, might be associated with higher risk of in-hospital mortality. Moreover, AKI, age, lymphocyte count, and cardiovascular disease may represent important risk factors that could help identify at-risk patients who require long-term hospitalization with therapeutic dose AC treatment.

EFFICACY AND SAFETY OF THERAPEUTIC VERSUS PROPHYLACTIC ANTICOAGULATION IN PATIENTS WITH COVID-19 INFECTION: A SYSTEMATIC REVIEW OF RANDOMIZED CONTROLLED TRIALS

IntroductionThe efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic isolated distal deep vein thrombosis (IDDVT). In real-world clinical practice, both therapeutic and prophylactic anticoagulation...

Effect of therapeutic anticoagulation on gas exchange in mechanically ventilated COVID-19 patients: A secondary analysis of the COVID-HEP trial

Age-adjusted D-dimer cutoffs to guide anticoagulation in COVID-19

Abdominal paracentesis is a frequently performed procedure in hospitalised patients with ascites. Concurrently, most hospitalised adult patients receive pharmacologic anticoagulation, either for therapeutic purposes or prophylactically to prevent venous thromboembolism. Despite this, minimal evidence exists to guide management of anticoagulant therapy pre- and post-paracentesis. The authors aimed to investigate the safety of abdominal paracentesis in hospitalised patients receiving therapeutic or prophylactic anticoagulation, including in patients for whom these medications were withheld periprocedurally. TriNetX, an electronic health record data set, was queried to identify patients between the ages of 18 and 80 years who received an abdominal paracentesis while hospitalised at the authors' institution between September 2017 and June 2022. Patients receiving prophylactic anticoagulation (137), therapeutic anticoagulation (74) and no anticoagulation because of coagulopathy or thrombocytopenia (15) were compared. Rates of withholding anticoagulation, performing service, pre- and post-paracentesis haemoglobin, bleeding complications, thrombotic complications and need for red blood cell transfusion were analysed. Procedure-related bleeding complications occurred in two (1.4%) patients in the prophylactic group and 0 (0%) patients in the therapeutic group (P = 0.54). No thrombotic complications occurred. Rates of red blood cell transfusions post-paracentesis were similar between groups. Analysis of secondary end-points identified significant differences in rates of withholding anticoagulation and mean change in haemoglobin between performing services. Performance of abdominal paracentesis in patients receiving therapeutic or prophylactic anticoagulation appears to be safe regardless of whether anticoagulation was interrupted periprocedurally, with low rates of bleeding complications, thrombotic complications or need for red blood cell transfusions post-paracentesis.

Pre-admission anticoagulant therapy and mortality in hospitalized COVID-19 patients: A retrospective cohort study

Background: COVID-19 is associated with a hypercoagulable state leading to an increased risk of thrombotic events. Although anticoagulation therapy is widely used, the optimal dosing strategy remains uncertain. Objective: The aim of this study was to evaluate the impact of therapeutic versus prophylactic anticoagulation on outcomes in critically ill COVID-19 patients. Methods: A retrospective cohort study was conducted on 315 critically ill COVID-19 patients. Patients were divided into two groups based on their anticoagulation regimen: therapeutic dose and prophylactic dose. The primary outcome was in-hospital mortality, while secondary outcomes included major bleeding events, thromboembolic events, and mechanical ventilation requirements. Results: No significant difference in mortality was observed between the therapeutic and prophylactic anticoagulation groups. Additionally, there were no significant differences in secondary outcomes. Conclusion: Our findings suggest that therapeutic anticoagulation may not provide a significant survival benefit compared to prophylactic anticoagulation in critically ill COVID-19 patients. To optimize patient outcomes, a more tailored approach to anticoagulation may be necessary, taking into account individual patient factors and risk assessment. Further prospective studies are needed to definitively establish the optimal anticoagulation strategy, especially in the context of evolving treatment modalities and vaccinations.