Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID‐19: A multi‐center, open‐label, randomized controlled trial

Perepu, Usha; Chambers, Isaac; Wahab, Abdul; Eyck, Patrick Ten; Wu, Chaorong; Dayal, Sanjana; Sutamtewagul, Grerk; Bailey, Steven R.; Rosenstein, Lori J.; Lentz, Steven R.

doi:10.1111/jth.15450

Cited by 107 publications

(149 citation statements)

References 37 publications

(105 reference statements)

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“…In patients admitted to the intensive care unit (ICU), intermediate‐dose or full‐dose prophylactic anticoagulation did not lead to improvement in clinical outcomes. 5 , 6 , 7 , 8 Among patients hospitalized in medical wards, the results for heparin‐based regimens are promising, although some details are yet to be clarified. Escalated‐dose prophylaxis with rivaroxaban was not associated with improvement in outcomes.…”

Section: Introductionmentioning

confidence: 99%

Use of novel antithrombotic agents for COVID‐19: Systematic summary of ongoing randomized controlled trials

Talasaz

Sadeghipour

Aghakouchakzadeh

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Coronavirus disease 2019 (COVID‐19) is associated with macro‐ and micro‐thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID‐19, with preliminary results not demonstrating benefit in several studies. Objectives Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID‐19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. Methods We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID‐19. Results Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. Conclusion Some novel antithrombotic agents have pleiotropic anti‐inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID‐19.

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Section: Introductionmentioning

confidence: 99%

Use of novel antithrombotic agents for COVID‐19: Systematic summary of ongoing randomized controlled trials

Talasaz

Sadeghipour

Aghakouchakzadeh

et al. 2021

Journal of Thrombosis and Haemostasis

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“…Regarding the use of intermediate doses, a recent RCT compared the use of standard-doses thromboprophylaxis with intermediate doses of enoxaparin in patients with COVID-19 admitted to ICU and/or had laboratory evidence of coagulopathy, defined by a modified International Society on Thrombosis and Haemostasis (ISTH) with an overt disseminated intravascular coagulation (DIC) score ≥3. This RCT also found no significant differences in the primary endpoint of 30-day overall mortality (21% vs. 15%) [29]. Preliminary results of the HEP-COVID RCT in ICU patients showed no benefit in the primary composite endpoint (VTE, arterial thromboembolic events and all-cause mortality at 30 days) for those randomized to therapeutic LMWH doses (n = 45) compared to intermediate/standard-doses thromboprophylaxis of LMWH (n = 38) (51.1% vs. 55.3%) and higher risk of bleeding (8.9% vs. 0%) [27].…”

Section: Consensus: 13/13mentioning

confidence: 73%

“…However, how to control the hypercoagulable state generated by this endothelial dysfunction remains controversial. Regarding the use of anticoagulation with heparin at therapeutic doses, all the RCTs carried out in critically ill patients have obtained similar results, with no evidence of clinical benefit [23,[27][28][29]. Therapeutic anticoagulation may be unable to influence the inflammatory cascade and extensive pulmonary microthrombosis secondary to severe endothelial damage, which is characteristic of these critically ill patients [2,3].…”

Section: Discussionmentioning

confidence: 99%

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19

Riera‐Mestre

Jara‐Palomares

Trujillo‐Santos

et al. 2021

Viruses

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Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19.

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“…Among the 8318 articles initially retrieved through our literature search, 21 fulfilled the inclusion criteria and were included in our analysis [ 11 , 12 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. The PRISMA 2020 flow diagram for systematic reviews and meta-analyses study selection is presented in Supplementary File, Figure S1 .…”

Section: Resultsmentioning

confidence: 99%

“…The PRISMA 2020 flow diagram for systematic reviews and meta-analyses study selection is presented in Supplementary File, Figure S1 . A total of 7 studies reported data for intermediate versus prophylactic dose [ 11 , 27 , 28 , 29 , 30 , 34 , 35 ], while 17 studies reported data for therapeutic versus prophylactic dose of thromboprophylaxis [ 12 , 23 , 24 , 25 , 26 , 29 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Three studies contributed data for both intermediate versus prophylactic and therapeutic versus prophylactic dose analyses [ 29 , 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

Kyriakoulis

Trontzas

Rapti

et al. 2021

JCM

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Thromboprophylaxis in hospitalized patients with COVID-19 has been associated with a survival benefit and is strongly recommended. However, the optimal dose of thromboprophylaxis remains unclear. A systematic review and meta-analysis (PubMed/EMBASE) of studies comparing high (intermediate or therapeutic dose) versus standard (prophylactic dose) intensity of thrombo-prophylaxis with regard to outcome of hospitalized patients with COVID-19 was performed. Randomized and non-randomized studies that provided adjusted effect size estimates were included. Meta-analysis of 7 studies comparing intermediate versus prophylactic dose of thromboprophylaxis (2 randomized and 5 observational, n = 2009, weighted age 61 years, males 61%, ICU 53%) revealed a pooled adjusted relative risk (RR) for death at 0.56 (95% confidence intervals (CI) 0.34, 0.92) in favor of the intermediate dose. For the same comparison arms, the pooled RR for venous thromboembolism was 0.84 (95% CI 0.54, 1.31), and for major bleeding events was 1.63 (95% CI 0.79, 3.37). Meta-analysis of 17 studies comparing therapeutic versus prophylactic dose of thromboprophylaxis (2 randomized and 15 observational, n = 7776, weighted age 64 years, males 54%, ICU 21%) revealed a pooled adjusted RR for death at 0.73 (95% CI 0.47, 1.14) for the therapeutic dose. An opposite trend was observed in the unadjusted analysis of 15 observational studies (RR 1.24 (95% CI 0.88, 1.74)). For the same comparison arms, the pooled RR for venous thromboembolism was 1.13 (95% CI 0.52, 2.48), and for major bleeding events 3.32 (95% CI 2.51, 4.40). In conclusion, intermediate compared with standard prophylactic dose of thromboprophylaxis appears to be rather safe and is associated with additional survival benefit, although most data are derived from observational retrospective analyses. Randomized studies are needed to define the optimal thromboprophylaxis in hospitalized patients with COVID-19.

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Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID‐19: A multi‐center, open‐label, randomized controlled trial

Cited by 107 publications

References 37 publications

Use of novel antithrombotic agents for COVID‐19: Systematic summary of ongoing randomized controlled trials

Use of novel antithrombotic agents for COVID‐19: Systematic summary of ongoing randomized controlled trials

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19

High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

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