Clinical Outcomes With the Use of Prophylactic Versus Therapeutic Anticoagulation in COVID-19

Motta, Jishu Kaul; Ogunnaike, Rahila; Shah, Rutvik; Stroever, Stephanie; Cedeño, Harold V; Thapa, Shyam K; Chronakos, John; Jiménez, Eric J Carro; Petrini, Joann; Hegde, Abhijith

doi:10.1101/2020.07.20.20147769

Cited by 6 publications

(5 citation statements)

References 29 publications

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“…While reduced VTE events and mortality has been noted with full-dose anticoagulation compared to low-dose, 3,7 more recent studies have found either no benefit between prophylactic and therapeutic anticoagulation or have found that in-hospital mortality was 2.3 times greater with preemptive treatment-dose anticoagulation from the time of hospital admission. 8,9 With limited data in large populations of hospitalized COVID-19 patients to date, as well as conflicting data on predictors of VTE or mortality, we assessed the prevalence and predictors of VTE or mortality in hospitalized COVID-19 patients.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Prevalence and Predictors of Venous Thromboembolism or Mortality in Hospitalized COVID-19 Patients

et al. 2021

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Objectives: To identify the prevalence and predictors of VTE or mortality in hospitalized COVID-19 patients. Methods: A retrospective cohort study of adult COVID-19 patients admitted to an integrated health care network in the New York metropolitan region between March 1, 2020 and April 27, 2020. The final analysis included 9407 patients with an overall VTE rate of 2.9% (2.4% in the medical ward and 4.9% in the ICU) and a VTE or mortality rate of 26.1%. Most patients received prophylactic-dose thromboprophylaxis. Multivariable analysis showed significantly reduced VTE or mortality with Black race, history of hypertension, angiotensin converting enzyme/angiotensin receptor blockers use, and initial prophylactic anticoagulation. It also showed significantly increased VTE or mortality with age 60 years or greater, Charlson Comorbidity Index (CCI) of 3 or greater, patients on Medicare, history of heart failure, history of cerebrovascular disease, body mass index greater than 35, steroid use, anti-rheumatologic medication use, hydroxychloroquine use, maximum D-dimer 4 times or greater than the upper limit of normal (ULN), ICU level of care, increasing creatinine, and decreasing platelet counts. Conclusion: In our large cohort of hospitalized COVID-19 patients, the overall in-hospital VTE rate was 2.9% (4.9% in the ICU) and a VTE or mortality rate of 26.1%. Key predictors of VTE or mortality included advanced age, increasing CCI, history of cardiovascular disease, ICU level of care, and elevated maximum D-dimer with a cutoff at least 4 times the ULN. Use of prophylactic-dose anticoagulation but not treatment-dose anticoagulation was associated with reduced VTE or mortality.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Prevalence and Predictors of Venous Thromboembolism or Mortality in Hospitalized COVID-19 Patients

et al. 2021

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“…Since elevated D-dimer levels are often found in patients with clotting problems, severe COVID-19 patients with elevated D-dimer levels are treated with unfractionated heparin or LMWH as an anticoagulation to reduce mortality ( Table 1 ) [ 82 , 83 , 84 , 85 , 86 , 87 ]. However, the current anticoagulation options have limited effect on thrombosis in general COVID-19 patients, and some of the observed effects were not significant [ 88 , 89 , 90 , 91 ]. In a Dutch study of COVID-19 patients, all 184 ICU patients received at least standard doses thromboprophylaxis, but thrombosis still occured in 31% patients, including 27% venous thromboembolism (VTE) and 3.7% arterial thrombotic events [ 92 ].…”

Section: Coagulation Dysfnction In Covid-19 and The Risk Of Hitmentioning

confidence: 99%

Structural Features and PF4 Functions that Occur in Heparin-Induced Thrombocytopenia (HIT) Complicated by COVID-19

et al. 2020

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Platelet factor 4 (PF4, CXCL4) is a small chemokine protein released by activated platelets. Although a major physiological function of PF4 is to promote blood coagulation, this cytokine is involved in innate and adaptive immunity in events when platelets are activated in response to infections. Coronavirus disease 2019 (COVID-19) patients have abnormal coagulation activities, and severe patients develop higher D-dimer levels. D-dimers are small protein products present in the blood after blood clots are degraded by fibrinolysis. To prevent clotting, heparin is often clinically used in COVID-19 patients. Some clinical procedures for the management of COVID-19 patients may include extracorporeal membrane oxygenation (ECMO) and renal replacement therapy (CRRT), which also require the use of heparin. Anti-PF4 antibodies are frequently detected in severe patients and heparin-induced thrombocytopenia (HIT) can also be observed. PF4 and its role in HIT as well as in pathologies seen in COVID-19 patients define a potential therapeutic option of using blocking antibodies in the treatment of COVID-19.

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“…30 However, more recent studies have found either no benefit between prophylactic and therapeutic anticoagulation or have found that in-hospital mortality was 2.3 times greater with preemptive treatment-dose anticoagulation from the time of hospital admission. 15,31 Lastly, whether the mechanisms of thrombosis in COVID-19 are due primarily to in situ immunothrombosis or classic thromboembolic macrovessel disease continues to be a matter of debate, with the former theoretically less susceptible and more resistant to heparin-based strategies for management, even with escalating or treatment doses. 32 In short, there continues to remain true clinical equipoise for both the efficacy and safety of using treatment-dose anticoagulation for primary thromboprophylaxis in this high-risk hospitalized COVID-19 population.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a recent small randomized trial of therapeutic versus prophylactic anticoagulation in patients with severe COVID-19 revealed that therapeutic anticoagulation improved ventilator-free days (30). However, more recent studies have found either no benefit between prophylactic and therapeutic anticoagulation or have found that in-hospital mortality was 2.3 times greater with preemptive treatment-dose anticoagulation from the time of hospital admission (15,31). Lastly, whether the mechanisms of thrombosis in COVID-19 are due primarily to in situ immunothrombosis or classic thromboembolic macrovessel disease continues to be a matter of debate, with the former theoretically less susceptible and more resistant to heparin-based strategies…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Treatment-Dose LMWH versus Prophylactic/Intermediate Dose Heparins in High-Risk COVID-19 Inpatients: Rationale and Design of the HEP-COVID Trial

et al. 2021

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Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a Phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low molecular weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality (ACM) 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4x upper limit of normal (ULN) or sepsis-induced coagulopathy (SIC) score ≥4. Subjects are randomized to enoxaparin 1 mg/kg SQ/BID (CrCl ≥ 30 ml/min) or 0.5 mg/kg (CrCl 15-30 ml/min) vs local institutional prophylactic regimens including: a) UFH up to 22,500 IU daily (divided BID or TID), b) enoxaparin 30mg and 40mg SQ QD or BID, or c) dalteparin 2500IU or 5000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction (RRR) with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4x ULN, stratification by ICU vs non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge.

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Clinical Outcomes With the Use of Prophylactic Versus Therapeutic Anticoagulation in COVID-19

Cited by 6 publications

References 29 publications

Prevalence and Predictors of Venous Thromboembolism or Mortality in Hospitalized COVID-19 Patients

Prevalence and Predictors of Venous Thromboembolism or Mortality in Hospitalized COVID-19 Patients

Structural Features and PF4 Functions that Occur in Heparin-Induced Thrombocytopenia (HIT) Complicated by COVID-19

Treatment-Dose LMWH versus Prophylactic/Intermediate Dose Heparins in High-Risk COVID-19 Inpatients: Rationale and Design of the HEP-COVID Trial

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