A randomized trial in hospitalized COVID-19 patients has found no benefit of treatment with colchicine or the combination of aspirin and rivaroxaban, according to research presented at ESC Congress 2022.1

Study author Dr. Sanjit Jolly of the Population Health Research Institute, Hamilton, Canada said: “Disease progression in patients hospitalised with COVID-19 can result in respiratory failure and death. Interventions that target the virus (e.g. remdesivir) and those that suppress inflammation (e.g. glucocorticoids, tocilizumab) can prevent adverse outcomes but are incompletely effective, often not affordable, and may be associated with life-threatening toxicity. Additional treatments are needed to prevent serious adverse outcomes. Unfortunately the treatments tested in this trial were not beneficial and more work needs to be done to find effective therapies.”

Worsening disease in hospitalised COVID-19 patients is characterised by an inflammatory response and hypercoagulability which are thought to contribute to organ dysfunction and thromboembolic complications. Colchicine targets the NLRP3 inflammasome which is activated by the SARS-CoV-2 virus, thereby suppressing inflammation. The combination of antiplatelet and anticoagulant therapy targets platelets and coagulation, with the potential to reduce vascular thrombosis. The Anti-Coronavirus Therapies (ACT) Inpatient Trial tested two treatments: colchicine to target inflammation and the combination of aspirin and rivaroxaban to target haemostatic activation with the goal of preventing the need for increased respiratory support and death in hospitalised patients with COVID-19. The study was conducted at 62 sites in 11 countries.

The trial randomised COVID-19 inpatients to receive 28 days of treatment with: (1) colchicine (loading dose 1.2 mg, followed by 0.6 mg two hours later, then 0.6 mg twice daily for 28 days) versus control and (2) rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) versus control, using a factorial design.2 The design enabled simultaneous evaluation of the independent effects of colchicine and the combined strategy and possible additive effects. A total of 492 patients did not participate in the second randomisation, therefore 2,611 were randomised to colchicine versus control, and 2,119 were randomised to rivaroxaban plus aspirin versus control.

The main outcome for the comparison between colchicine and control was the need for high flow oxygen, mechanical ventilation or death and for the comparison between aspirin plus rivaroxaban versus control was major thrombosis, need for high flow oxygen, mechanical ventilation or death.

Colchicine compared with control did not significantly reduce high flow oxygen, mechanical ventilation or death (368 [28.2%] vs. 356 [27.2%] events, hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.90–1.28, p=0.578). The combination of aspirin and rivaroxaban versus control did not significantly reduce major thrombosis, the need for high flow oxygen, mechanical ventilation or death (281 [26.4%] vs. 300 [28.4%] events, HR 0.92, 95% CI 0.78–1.09, p=0.324). There was no evidence of benefit of either treatment in any of the major subgroups examined including the need for oxygen at baseline, admission to the intensive care unit at randomization, COVID-19 vaccination status or time from COVID-19 symptom onset to randomization. 

The investigators also performed an updated meta-analysis of randomized trials of intensified anticoagulation versus control. Among 7,503 patients, intensified anticoagulation compared with control reduced venous thromboembolism by about one-half, whereas among 7,640 patients intensified anticoagulation compared with control did not reduce mortality. There was statistical evidence of heterogeneity for the outcome of mortality which was driven by two smaller trials that suggested implausibly large reductions in mortality (46–77% relative risk reductions).

Dr. Jolly said: “The ineffectiveness of colchicine contrasts with a clear benefit of glucocorticoids, and raises several possibilities: concomitant use glucocorticoids negated any benefit of colchicine, colchicine is not sufficiently potent to suppress inflammation, or activation of the NLRP3 inflammasome does not play a major causal role in COVID-19 disease progression. The low rate of major thrombosis in the control group (<2%) suggests thrombosis is less of a problem than originally thought. Although trials of intensified anticoagulation have consistently demonstrated a reduction in venous thrombosis, the lack of mortality benefit suggests that venous thromboembolism does not substantially contribute to mortality in hospitalized COVID-19 patients.”

He concluded: “Taken together with the results of our updated meta-analysis, the evidence from the ACT Inpatient Trial does not support the use of either colchicine or intensified anticoagulant therapy for the treatment of inpatients with COVID-19. Inpatients with COVID-19 should continue to be managed with antiviral drugs and anti-inflammatory therapies demonstrated to be effective in randomized trials and recommended by guidelines.”

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References / notes

1ACT Inpatient Trial will be discussed during Hot Line Session 10 on Monday 29 August at 16:30 to 17:30 CEST in the Barcelona auditorium.

2Eikelboom J, Rangarajan S, Jolly SS, et al. The Anti-Coronavirus Therapies (ACT) trials: design, baseline characteristics, and challenges. CJC Open. 2022;4:568–576.

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