Coronavirus disease-2019 (COVID-19) has important manifestations outside the pulmonary parenchyma, including thromboembolic events. It is unclear whether the use, type, and dosage of anticoagulant treatment may improve survival and reduce the burden of thrombosis. Three key questions remain to be answered: (i) is early thromboprophylaxis in symptomatic outpatients able to reduce the progression of the disease and the occurrence of thromboembolic events; (ii) is a higher dosage of anticoagulant treatment able to reduce fatality in hospitalized COVID-19 patients? (iii) Is thromboprophylaxis needed in the post-acute phase after hospital discharge?
A number of consensus documents and guidances have been published in the early phase of the pandemic with the aim of guiding global actions concerning the use of anticoagulant agents. In light of the substantial thrombotic burden posed by this novel virus, as emerged by early observational studies among hospitalized COVID-19 patients, the vast majority of them suggested higher-than-standard anticoagulant regimens over standard-dose thromboprophylaxis. These recommendations were supported by the initial evidence from retrospective studies. In parallel, a number of randomized controlled trials had been planned to answer this question.
The Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19 (INSPIRATION) trial represents the first published large randomized controlled trial answering the second of these questions, namely whether a higher-than-standard thromboprophylaxis is beneficial in COVID-19 patients admitted to the ICU.
A total of 600 patients were at 10 enrolling centers in Tehran and Tabriz (Iran) between July 29, 2020, and November 19, 2020. This trial was designed as a multicenter randomized trial with a 2 × 2 factorial design comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis). The primary efficacy outcome was a composite of adjudicated acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality within 30 days of enrollment.
The results of this trial concerning the first hypothesis, the only ones that have been published thus far, are as disappointing as clinically useful. In fact, the study showed that the use of intermediate-dose vs standard-dose prophylactic anticoagulation did not improve the outcome of these patients: the primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, −6.6% to 9.8%]). The rate of adjudicated VTE was 3.3% and 3.5% in the two groups, respectively. Indeed, the rate of bleeding was overall low, but higher among patients receiving the intermediate dose (2.5% vs. 1.4% in the standard-dose prophylaxis group, a result that did not met the noninferiority criteria. These results were confirmed in the 90-day follow-up analysis.
What this study also tells us is that the severity of the baseline disease, COVID-19, in this high-risk population may be too pronounced to be affected by the administration of a higher dosage of anticoagulant treatment. Heparins may not be able to exert a postulated antiviral and anti-inflammatory effect in the presence of a systemic, multiorgan involvement. At the same time, thrombosis may simply be a marker of the severity of disease, but not modify per se the prognosis of COVID-19 patients. Therefore, a more potent prevention of thromboembolic events may not impact the course of COVID-19 and reduce fatality in an advanced phase of the disease.
Can we consider the chapter as closed? Not at all. The results of at least two other large randomized controlled trials on different dosages of anticoagulant treatment in hospitalized patients focusing on important clinical outcomes may soon appear in the peer-reviewed scientific literature and further broaden our knowledge on this topic.
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