Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID)

Abstract

Introduction: Coronavirus disease 2019 (COVID-19) causes a hypercoagulable state. Several autopsy studies have found microthrombi in pulmonary circulation. Methods: In this randomized, open-label, phase II study, we randomized COVID-19 patients requiring mechanical ventilation to receive either therapeutic enoxaparin or the standard anticoagulant thromboprophylaxis. We evaluated the gas exchange over time through the ratio of partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) at baseline, 7, and 14 days after randomization, the time until successful liberation from mechanical ventilation, and the ventilator-free days. Results: Ten patients were assigned to the therapeutic enoxaparin and ten patients to prophylactic anticoagulation. There was a statistically significant increase in the PaO2/FiO2 ratio over time in the therapeutic group (163 [95% confidence interval-CI 133-193] at baseline, 209 [95% CI 171-247] after 7 days, and 261 [95% CI 230-293] after 14 days), p = 0.0004. In contrast, we did not observe this improvement over time in the prophylactic group (184 [95% CI 146-222] at baseline, 168 [95% CI 142-195] after 7 days, and 195 [95% CI 128-262] after 14 days), p = 0.487. Patients of the therapeutic group had a higher ratio of successful liberation from mechanical ventilation (hazard ratio: 4.0 [95% CI 1.035-15.053]), p = 0.031 and more ventilator-free days (15 days [interquartile range IQR 6-16] versus 0 days [IQR 0-11]), p = 0.028 when compared to the prophylactic group. Conclusion: Therapeutic enoxaparin improves gas exchange and decreases the need for mechanical ventilation in severe COVID-19. Trial registration: REBEC RBR-949z6v.

Clinical Characteristics, Diagnosis, and Treatment of Major Coronavirus Outbreaks

“…No difference was found in all-cause mortality and in-hospital mortality between the two groups. Although this study shows that therapeutic enoxaparin improves gas exchange and ventilatorfree day in severe COVID-19 patients, further large randomized clinical trials are needed as it was a single-center study with a small sample (191).…”

RETRACTED: Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19

“…The first RCT comparing therapeutic AC to standard thromboprophylaxis in COVID-19 ICU patients on mechanical ventilation (HESACOVID) was recently published, and although small, reported statistically significant improvements in oxygenation, liberation from mechanical ventilation (hazard ratio: 4.0 [95% CI 1.035–15.053], p = 0.031), and ventilator-free days (15 days [IQR 6–16] versus 0 days [IQR 0–11], p = 0.028) in patients treated with therapeutic doses of AC. 101…”

Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19): a systematic review of in vitro, in vivo, and clinical trials

“…A greater proportion of participants in the therapeutic anticoagulant group were able to be weaned from MV successfully compared to the prophylactic anticoagulant group (8 out of 10 [80%] vs . 3 out of 10 [30%]; HR 4.0, 95% CI 1.04 to 15.05; P = 0.031) 75 ( Table 3 ). In two meta-analyses including non-RCTs on COVID-19, anticoagulant therapy did not show a therapeutic effect 76 , 77 ( Table 4 ).…”

“…It has been reported that coagulopathy was associated with the prognosis of COVID-19 115 - 117 and these results are consistent with what has been known in ARDS and sepsis. In a small-scale RCT of severe COVID-19, therapeutic anticoagulant therapy with enoxaparin showed a better outcome than prophylactic anticoagulant therapy 75 . More studies investigating the efficacy of augmenting these anticoagulation or thrombolytic treatments, while weighing the risk of hemorrhage, and narrowing the indications are required.…”