The ACT programme included outpatient and inpatient trials, each with a 2x2 factorial design, which assessed the efficacy of anti-inflammatory therapy with colchicine (both trials) and the efficacy of antithrombotic therapy – aspirin alone in the ACT Outpatient Trial and aspirin plus rivaroxaban in the ACT Inpatient Trial – across the spectrum of mild, moderate and severe COVID-19.
As presented at a Hot Line session today, Doctor John Eikelboom (McMaster University - Hamilton, Canada) described results from the ACT Outpatient Trial where 3,917 community-based patients with laboratory-diagnosed COVID-19 were randomised to 28 days of treatment with: (1) colchicine 0.6 mg twice daily for 3 days, followed by 0.6 mg once daily for an additional 25 days versus control and (2) aspirin 100 mg once daily versus control.
Regarding the main outcomes, colchicine did not significantly reduce hospitalisation or death compared with control (3.4% versus 3.3% events; hazard ratio [HR] 1.02; 95% CI 0.72 to 1.43, p=0.926) and there was no significant reduction in major thrombosis, hospitalisation or death with aspirin versus control (3.0% versus 3.8% events; HR 0.80; 95% CI 0.57 to 1.13, p=0.211). There was no evidence of benefit of either treatment in any of the subgroups examined or in an updated meta-analysis of randomised trials of colchicine in outpatients (n=8,369) and inpatients (n=15,335) with COVID-19, performed by the authors.
Event rates in the control group fell progressively during the course of the study from around 7–8% at the beginning to less than 2% towards the end, and the number of patients who experienced an outcome was substantially lower than expected. Dr. Eikelboom notes, “Several factors may have contributed to the falling event rates over time, including changing virulence of different strains of the SARS-CoV-2 virus, increasing population immunity conferred by a combination of herd immunity and immunisation, increasing use of effective cointerventions in more vulnerable populations, or changing patterns of disease management.”
He concludes, “Taken together with the results of our updated meta-analysis, the evidence from the ACT Outpatient Trial does not support the use of either colchicine or aspirin for the treatment of outpatients with COVID-19. Patients with COVID-19 who are currently infected and at risk of disease progression might consider the use of proven effective antiviral therapies, if accessible, to prevent disease progression.”
The ACT Inpatient Trial, presented by Doctor Sanjit Jolly (Population Health Research Institute - Hamilton, Canada), involved the randomisation of more than 2,000 patients with symptomatic and laboratory-diagnosed COVID-19 within 72 hours of admission or worsening clinically. Patients received (1) colchicine (loading dose 1.2 mg, followed by 0.6 mg 2 hours later, then 0.6 mg twice daily for 28 days) or control and (2) rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily) or control for 28 days.
Regarding the main outcomes, colchicine compared with control did not significantly reduce high-flow oxygen, mechanical ventilation or death (28.2% versus 27.2% events; HR 1.04, 95% CI 0.90 to 1.28, p=0.578). Furthermore, the combination of aspirin and rivaroxaban versus control did not significantly reduce major thrombosis, the need for high-flow oxygen, mechanical ventilation or death (26.4% versus 28.4% events; HR 0.92, 95% CI 0.78 to 1.09, p=0.324). There was no evidence of benefit of either treatment in any of the major subgroups examined.
The investigators also performed an updated meta-analysis of randomised 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 comments, “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 hospitalised COVID-19 patients.” He concludes, “Inpatients with COVID-19 should continue to be managed with antiviral drugs and anti-inflammatory therapies demonstrated to be effective in randomised trials and recommended by guidelines.”