key: cord-0747730-3q5ai4kr authors: Giannis, Dimitrios; Douketis, James D.; Spyropoulos, Alex C. title: Anticoagulant therapy for COVID-19: What we have learned and what are the unanswered questions? date: 2021-11-11 journal: Eur J Intern Med DOI: 10.1016/j.ejim.2021.11.003 sha: f6700e7b6cad3ca221379799dc39d1b8f1aacd7f doc_id: 747730 cord_uid: 3q5ai4kr nan Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), and arterial thromboembolism (ATE), which includes myocardial infarction, ischemic stroke, systemic embolism, and peripheral arterial events, are common among hospitalized patients with coronavirus disease-2019 and are major causes of morbidity and mortality. [1, 2] The incidence of VTE in this population has been estimated between 5.5% to 14.1%, and such patients have a more than two-fold higher risk for developing VTE than matched controls. [2, 3] This increased VTE risk has been attributed to microvascular thrombosis and systemic coagulopathy [4] , while autopsy studies have identified unsuspected VTE or in situ pulmonary arterial thrombosis in more than 60% of patients with COVID-19 [5, 6] Lastly, despite the administration of prophylactic-dose anticoagulation with a low-molecularweight heparin (LMWH) or unfractionated heparin (UFH), in accordance with initial (i.e., published in 2020) international guidance statements for hospitalized COVID-19 patients, such patients continued to develop VTE and ATE at high incidence rates (i.e., 20-30%), a phenomenon referred to as "breakthrough thrombosis". [7, 8] Given the apparent inadequacy of low-dose heparin to prevent thrombosis and other adverse outcomes in COVID-19, several randomized trials were launched to address the pivotal question of whether escalating the intensity of anticoagulation to therapeutic-dose (or full-dose) anticoagulant intensity could decrease the incidence of thrombosis and prevent overall clinical deterioration risk in hospitalized patients with COVID-19, without materially increasing their risk for major bleeding. [7, 9] Globally, over 20 randomized trials (including the large multiplatform ATTACC, REMAP-CAP, and ACTIVE-IV trials) have compared (within some trials ongoing) a strategy of therapeuticdose anticoagulation compared with a prophylactic-dose (or low-dose) approach, in hospitalized COVID-19 patients. Most of these trials have distinguished patients according to disease severity, with separate analyses done in patients who are critically ill and require intensive care unit (ICU) level care and those with moderate-severity COVID-19 who require medical-ward level care. The primary outcomes assessed have varied across trials but most trials have included as primary or secondary outcomes VTE, ATE, all-cause mortality, survival without ventilation, ICU admission, organ support-free days, need for vasopressor treatment, and duration of hospitalization. [9] In a broader clinical context, these trials assess the use of anticoagulant therapy as an add-on treatment approach aimed at reducing the overall severity and morbidity related to COVID-19 pneumonia, while a minority have used a traditional anticoagulant trial design that focuses on reducing macrovascular thromboembolic events and related mortality. The past year has witnessed the emergence of several high-quality randomized trials in which, over time, there has been convergence of findings to support therapeutic-dose anticoagulation for hospitalized COVID-19 patients; however, this benefit appears limited to those patients with moderate disease severity and not requiring ICU level care. [10] [11] [12] [13] First, the multiplatform trials (ATTACC, ACTIV-4a, and REMAP-CAP) demonstrated a reduction in organ support-free days with therapeuticdose LMWH or UFH in non-critically ill patients (adjusted odds ratio [OR] = 1.27; 95% confidence interval [CI]: 1.03-1.58), with an absolute treatment benefit more apparent in patients with high D-dimer (≥2 times the upper limit of the local laboratory normal [ULN]). [10] Secondly, the ACTION trial included hospitalized COVID-19 patients with elevated D-dimer (greater than the local laboratory ULN) and showed that therapeuticdose rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes (time to death, duration of hospitalization, or duration of supplemental oxygen to day 30) (win ratio = 0.86; 95% CI: 0.59-1.22), while it increased major or clinically relevant non-major bleeding compared with prophylactic anticoagulation. [12] Thirdly, the INSPIRATION trial assessed ICU patients with COVID-19 and showed no difference between an intermediate-dose anticoagulant regimen (approximately 50% of therapeutic-dose) and a prophylactic-dose LMWH or UFH for the outcomes of VTE, ATE, need for extracorporeal membrane oxygenation (ECMO), or 30-day mortality. [13] Finally, the recently published HEP-COVID trial was the first randomized trial using a classic antithrombotic clinical trial design to show that in hospitalized COVID-19 patients with a D-dimer level ≥4 times the ULN therapeutic-dose LMWH reduced a composite of VTE, ATE, and death, as compared with prophylactic-dose LMWH or UFH (relative risk The optimal anticoagulant management in patients who progress from moderate to severe COVID-19 (or vice-versa) and in patients requiring ICU level care is uncertain. The benefit of therapeutic-dose heparins may indicate their multimodal effects (anticoagulant, anti-inflammatory, immunomodulatory, and antiviral) early in the course of COVID-19 to prevent both micro-and macrovascular thrombosis and the selfpropagating positive feedback loop between coagulation and inflammation (thromboinflammation), before the development of an irreversible, overwhelming hyperinflammatory state and cytokine storm that may occur by the time a patient requires ICU level care. [17] Novel antithrombotic and other approaches in reducing the thrombotic burden in critically ill COVID-19 patients are needed, including the potential use of fibrinolytic agents, contact pathway activators, TF/VIIa complex inhibitors, and multimodal approaches. The type of anticoagulant and the associated pleiotropic effects may be important and may explain why molecules potentially lacking these properties, such as direct oral anticoagulants (DOACs), are not equally effective. [12, 17] There are currently no clinical data supporting the use of DOACs in COVID-19 inpatients. Based on the current evidence from the ACTION trial and the potential for multiple drug-drug interactions between DOACs and immunosuppressive/antiviral medications, hospitalized patients with moderate disease and previously on DOACs should be switched to treatment dose LMWH or UFH. [18] The optimal post-hospital thromboprophylaxis strategy, comprising the anticoagulant type, duration of treatment, and risks-benefit assessment is uncertain but is being actively investigated. The risk of VTE, ATE, and all-cause mortality remains high at up to 90-days after discharge and prophylactic-dose anticoagulants have been associated with a 46% decrease in the composite endpoint of major thromboembolism or all-cause mortality in a recent prospective registry of hospitalized COVID-19 patients. [19] The MICHELLE trial identified a high risk group of post-discharge COVID-19 patients using the IMPROVE VTE score ≥4 or elevated (≥2 times the ULN) D-dimer and found a 6% absolute risk reduction (67% relative risk reduction) for the composite primary outcome of major thromboembolism and cardiovascular death favoring rivaroxaban 10 mg daily for 30 days versus no anticoagulation (3.14% vs 9.43%, RR = 0.33; 95% CI: 0.13-0.90). [20] Extended thromboprophylaxis with a DOAC may be considered for up to six weeks post-discharge in high-risk hospitalized COVID-19 patients (IMPROVE VTE score ≥4, increased D-dimer >2 times the ULN, >60 years and without bleeding risk factors, or recent ICU stay). [21] In summary, current data suggest the use of therapeutic-dose LMWH or UFH over standard heparin thromboprophylaxis to reduce VTE, ATE, organ support, and The authors declare the following conflicts of interest: Thrombosis in hospitalized patients with COVID-19 in a New York City health system Risk of venous thromboembolism in patients with COVID-19: A systematic review and meta-analysis Pulmonary embolism in patients with COVID-19: Awareness of an increased prevalence Anticoagulation in COVID-19: reaction to the ACTION trial Pulmonary arterial thrombosis in COVID-19 with fatal outcome: Results from a prospective, single-center, clinicopathologic case series Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up Scientific and Standardization Committee Communication: Clinical Guidance on the Diagnosis, Prevention and Treatment of Venous Thromboembolism in Hospitalized Patients with COVID-19 Anticoagulant interventions in hospitalized patients with COVID-19: A scoping review of randomized controlled trials and call for international collaboration Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19 Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19 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 Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate-intensity anticoagulation in critically ill patients The Potential Role of Heparin in Patients With COVID-19: Beyond the Anticoagulant Effect. A Review DOAC in COVID-19: Yes or No? Post-Discharge Thromboembolic Outcomes and Mortality of Hospitalized COVID-19 Patients: The CORE-19 Registry Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised controlled trial Emergence of institutional antithrombotic protocols for coronavirus 2019 Research Grants -Boerhringer Ingelheim, Janssen, Agency for Healthcare Research and Quality; Research Grants -Boerhringer Ingelheim, Janssen, Agency for This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.