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

Abstract

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.

Randomized trials of therapeutic heparin for COVID‐19: A meta‐analysis

“… 9 , 10 , 21 , 22 Three trials included moderately ill ward patients with COVID‐19: a multiplatform trial integrating the Antithrombotic Therapy to Ameliorate Complications of COVID‐19 (ATTACC), Accelerating COVID‐19 Therapeutic Interventions and Vaccines‐4 Antithrombotics Inpatient Platform Trial (ACTIV‐4a) and the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community‐Acquired Pneumonia (REMAP‐CAP) 9 the Coagulopathy of COVID‐19, A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to the COVID‐19 Pandemic (RAPID), 21 and the Systemic Anticoagulation With Full Dose Low Molecular Weight Heparin (LMWH) Versus Prophylactic or Intermediate Dose LMWH in High Risk COVID‐19 Patients (HEP‐COVID) trial). 22 Three trials included severely ill patients with COVID‐19: a separate multiplatform trial conducted by the same investigators evaluated therapeutic heparin in severely ill ICU patients, 23 a small phase II randomized trial of mechanically ventilated patients (Therapeutic Versus Prophylactic Anticoagulation for Severe COVID‐19: A Randomized Phase II Clinical Trial [HESACOVID]), 24 and the HEP‐COVID trial, which also included severely ill patients, with randomization stratified according to disease severity. 22 We excluded the Therapeutic versus Prophylactic Anticoagulation for Patients Admitted to Hospital with COVID‐19 and Elevated D‐dimer Concentration (ACTION) trial, as it combined therapeutic anticoagulation with rivaroxaban in moderately ill patients and therapeutic enoxaparin in severely ill patients, without reporting any of our prespecified outcomes by illness severity.…”

“…Major thrombotic events were defined as the composite of myocardial infarction, pulmonary embolism, ischemic stroke, or systemic arterial embolism; any thrombotic events were defined as a major thrombotic event or deep vein thrombosis; major bleeding defined by the ISTH Scientific and Standardization Committee. 15 The observation time for the outcomes in the trials were 28 days for the multiplatform trials (with the exception of organ support free days which was calculated for an observation time of 21 days), 28 days for the RAPID trial and 30 days for the HEP‐COVID trial 16 , 17 , 23 …”

Thrombosis and Haemostasis 2021 Editors' Choice Papers

“…Such high-risk hospitalized COVID-19 patients may indeed benefit from treatment-dose instead of prophylactic-or intermediate-dose low-molecular-weight heparin (LMWH) as demonstrated by the results from the recent multicenter HEP-COVID randomized trial. 17,18 The multicenter observational GeroCovid study, presented convincing data on the role of direct oral anticoagulants (DOACs) in reducing the risk of death in COVID-19 older patients. 19 While the beneficial anticoagulation effects of heparin on the thrombotic arm of COVID-19 is easily explicable, intriguing data from Mycroft-West et al suggested that heparin may also prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from infecting cells, 20 opening options for repurposing heparin and its derivatives as antiviral agents.…”

Tinzaparin—a review of its molecular profile, pharmacology, special properties, and clinical uses

“…Based on the latest evidence, in moderately ill hospitalized COVID-19 patients on low flow oxygen, full dose anticoagulant prophylaxis with LMWH can be considered in patients with low bleeding risk, for 14 days or until discharge (whichever happens first), as this may improve patient survival until hospital discharge without the need for ICU-level organ support. Also, in critically ill hospitalized COVID-19 patients with no contra-indications to anticoagulation, prophylactic dose of anticoagulant is suggested over full treatment dose [ 91 , 92 ].…”