In an early-release, retrospective, peer-reviewed article, the 28-day mortality of 449 Chinese patients with severe COVID-19 was compared among heparin users and nonusers. These patients met the Third International Consensus Definitions for Sepsis. Patients were also stratified for the risk of coagulopathy based on the presence of sepsis-induced coagulopathy (SIC) scores and D-dimer levels. SIC is an early phase of sepsis-associated disseminated intravascular coagulation coined by the International Society of Thrombosis and Haemostasis.
This study analyzed data from 449 patients who were hospitalized between January 1, 2020 and February 13, 2020. Patients were excluded if they had a bleeding diathesis; were hospitalized for fewer than 7 days; had missing information on coagulation parameters and medication use; or were younger than age 18 years. Criteria for the presence of severe COVID-19 included respiratory rate greater than or equal to 30 breaths/min, arterial oxygen saturation less than or equal to 93% at rest, or a PaO2/FiO2 less than or equal to 300 mmHg.
Study population characteristics included a mean age of 65.1 years and a majority being male (60%) with 60.6% having at least one chronic disease (39.4% hypertension, 20.7% diabetes, and 9.1% heart disease). Of these patients, 22% received heparin therapy in the form of enoxaparin 40 to 60 mg/day or unfractionated heparin in dosages of 10,000 to 15,000 units/day for at least 1 week.
In addition to anticoagulation, all patients received an unspecified antiviral therapy and supportive care. Over one-fifth of patients had a SIC score of equal to or greater than 4, indicating severe disease. There was no difference in the overall mortality rate, which was 30%, at 28 days in heparin users compared with nonusers (30.3% vs. 29.7%, respectively). However, a stratification of these patients by SIC scores showed that heparin therapy was significantly associated with reduced mortality only in those with scores of greater than or equal to 4 (40.0% vs. 64.2%, P = .029).
There was a positive correlation between D-dimer and prothrombin time values with 28-day mortality; the converse was true for platelet count. For patients with D-dimer levels of greater than 3.0 mcg/mL, which is six times the upper limit of normal, heparin therapy was associated with a 20% reduction in mortality compared with nonuse (32.8% vs. 52.4%, respectively). However, for patients with D-dimer levels equal to or less than 1, there was a numerically higher, but statistically nonsignificant, difference in mortality between those who received heparin versus those who were not anticoagulated. It is thought that the coagulation process may help compartmentalize pathogens, preventing further spread.
The study had a number of limitations including the risk of selection bias, insufficient medical resources resulting in misrepresentation of disease severity and mortality, and confounding by other therapies, including both pharmacological and nonpharmacological interventions.
The American Society of Hematology has advised that all hospitalized COVID-19 patients receive thromboprophylaxis with either low molecular weight heparins (LMWH) or fondaparinux (especially for those with heparin-induced thrombocytopenia) rather than heparin. An exception would be if the risk of bleeding outweighs potential benefit. If anticoagulation is not possible, the use of mechanical thromboprophylaxis is recommended. However, using both pharmacological and nonpharmacological thromboprophylaxis is not advised.
Intermediate-intensity LWMH (i.e., twice-daily dosing) or therapeutic LWMH doses have been utilized for thromboprophylaxis. Risk of venous thromboembolism (VTE) may remain elevated for 90 days post discharge, and continued thromboprophylaxis should be considered on an individualized basis. In low-risk patients, aspirin use may be considered.
These recommendations also stress that it is important to recognize the potential for drug-drug interactions with direct-acting oral anticoagulants and drugs such as sarilumab, an Interleukin-6 receptor antagonist and cytochrome P450 enzyme inducer. The University of Liverpool has developed a website (http://covid19-druginteractions.org) to check for potential COVID-19 drug-drug interactions.
The British Thoracic Society recommends standard thrombophylaxis with a LMWH in patients with standard risk of a VTE. For high-risk patients, the use of intermediate dosing of LWMH may be warranted.
Given the varied recommendations surrounding the use of anticoagulation in COVID-19 patients, more research is needed. The optimal anticoagulation dosing strategy for COVID-19 patients is under active clinical investigation.
The clinical pharmacist, therefore, should be familiar with the evolving literature on the management of COVID-19-induced coagulopathy.
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