Anticoagulation in COVID-19: reaction to the ACTION trial

Early in the COVID-19 pandemic, it became clear that coagulopathy leading to macrovascular and microvascular thrombotic events was a considerable potential complication for patients with COVID-19.¹ Increased inflammation and coagulopathy were independently associated with critical illness and all-cause mortality and had a synergistic role in the pathogenesis of COVID-19.² Early observations of a benefit from heparin³ in a selected cohort of severely ill patients with COVID-19 in China, followed by reports of increased thromboembolic events in patients with COVID-19 (both in and outside of intensive care units [ICUs]) despite the use of standard-dose venous thromboembolism prophylaxis,4, 5 led many physicians to use increased anticoagulant doses, even without robust data available.⁶ Autopsy findings, showing widespread pulmonary microvascular thrombosis, suggested that the hypoxaemia and respiratory failure in COVID-19 resulted from microvascular thrombosis.7, 8 A need to further understand these findings and the potential role of anticoagulation in this context prompted new research.

Among these studies, three platforms—ACTIV-4a, ATTACC, and REMAP-CAP—joined forces to evaluate therapeutic-dose versus prophylactic-dose heparin in hospitalised patients with COVID-19. In December, 2020, this multiplatform randomised clinical trial paused enrolment into the severe COVID-19 stratum (ie, patients receiving ICU level of care) because of futility,⁹ and a month later terminated enrolment into the moderate COVID-19 stratum (ie, hospitalised patients not receiving ICU level of care) for superiority. In patients with moderate disease, regardless of D-dimer concentration, therapeutic anticoagulation decreased the number of days on organ support.¹⁰ These seemingly discrepant results suggested that therapeutic heparin worked best when started early in the disease course, before patients became critically ill.

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In The Lancet, Renato Lopes and colleagues¹¹ report the results of the ACTION trial of therapeutic versus prophylactic anticoagulation for patients hospitalised with COVID-19. 615 patients (mean age 56·6 years [SD 14·3]; 368 [60%] men and 247 [40%] women) admitted to hospitals in Brazil with confirmed COVID-19 and elevated D-dimer concentration were randomly assigned to either a therapeutic or a prophylactic anticoagulation strategy. The therapeutic strategy (311 patients) was either therapeutic-dose rivaroxaban (20 mg or 15 mg daily) with extended post-discharge rivaroxaban (20 mg daily) up to 30 days, if clinically stable; or enoxaparin (1 mg/kg twice per day) or unfractionated heparin in hospital, if clinically unstable. 280 (90%) patients in the therapeutic group were given rivaroxaban. The prophylactic anticoagulation strategy (304 patients) consisted of standard-of-care inpatient enoxaparin or unfractionated heparin at a prophylactic dose, and 38 (13%) also received heparin for 30 days post discharge at the treating physician's discretion. The median time from symptom onset to hospital admission was 8·0 days (IQR 6·0–10·0) and from hospital admission to randomisation was 2·0 days (1·0–3·0). 460 (75%) patients required oxygen support and 510 (83%) were receiving systemic corticosteroids at baseline.

The primary outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen use through 30 days, conducted with the win ratio method. This method, a novel approach to the analysis of composite endpoints in clinical trials based on clinical priorities,¹² compares treatment assignment between every patient in both groups to identify a “winner” on the basis of prespecified criteria. This method accounts for relative priorities of the composite endpoint by prioritising fatal outcomes, allowing for enhanced statistical power. The therapeutic anticoagulation group had 34·8% wins, versus 41·3% wins in the prophylactic group (win ratio 0·86 [95% CI 0·59–1·22], p=0·40). Risk of a secondary composite outcome of thromboembolic events was not significantly different in the therapeutic group versus the prophylactic group (relative risk 0·75 [95% CI 0·45–1·26], p=0·32), nor was all-cause death (1·49 [0·90–2·46], p=0·13). However, risk of the primary safety outcome, major or clinically relevant non-major bleeding, was significantly higher (3·64 [1·61–8·27], p=0·0010) in the therapeutic group (26 [8%] of 310 patients) than in the prophylactic group (seven [2%] of 304).

The Brazilian investigators from the ACTION trial deserve recognition for conducting this important trial that contributes new information for the management of patients with COVID-19. A strategy of inpatient and post-discharge therapeutic rivaroxaban is not superior to inpatient-only use of prophylactic heparin, highlighting that the choice of drug, dose, and timing of anticoagulant are important. Whether improvements in care, with systemic corticosteroids and antivirals, have mitigated thromboinflammation is also unclear. Similarly, criteria for admission to the hospital might vary from region to region and during different stages of the pandemic, affecting risk of both thrombotic and fatal outcomes. Although the previous multiplatform trial used therapeutic heparin, ACTION used rivaroxaban in 92% of patients in the therapeutic group. Heparin, unlike other anticoagulants, has anti-inflammatory and possibly direct antiviral effects.¹³ It is also possible that the 20 mg dose of rivaroxaban is suboptimal in patients hospitalised with the highly coagulopathic thromboinflammation of SARS-CoV-2 infection driving microvascular thrombosis, as 15 mg twice per day is used for acute treatment of venous thromboembolism; however, bleeding was already markedly increased. The additional 30 days of anticoagulation post discharge might be of no benefit and only cause harm in patients with COVID-19 who have cleared the virus and survived to hospital discharge. A dedicated randomised trial is ongoing in the post-discharge population (NCT04650087).

The results of ACTION add important information on how best to treat patients with COVID-19. In these primarily stable hospitalised patients, therapeutic dose rivaroxaban in hospital with post-discharge treatment up to 30 days conferred no additional benefit when compared with in-hospital prophylactic-dose heparin. Although COVID-19 outcomes have improved over time, 15% of patients in ACTION still had either a thrombotic event or died. Continued investigation with randomised controlled trials assessing the use of anticoagulants and antiplatelets and the timing of administration during the course of COVID-19 are much needed.