ACT trials: long-term outcomes

The anti-coronavirus therapies (ACT) outpatient and inpatient trials in patients with COVID-19 found no evidence of a benefit of 28 days of anti-inflammatory or antithrombotic therapy during the first 45 days of follow-up.1, 2 A report published in 2022 suggests that after recovering from the acute illness, patients are at increased risk of cardiovascular events during the next 6–12 months.³ In the ACT trials we followed up participants for 180 days to record clinical outcomes and assess possible long-term effects of study interventions.

The ACT inpatient trial randomly assigned 2611 patients to receive colchicine or control and 2119 patients in a second randomisation to receive the combination of rivaroxaban and aspirin or control. The ACT outpatient trial randomly assigned 3917 patients to receive colchicine or control and in a second randomisation to receive aspirin or control. Study interventions were administered for 28 days and follow-up at day 180 was completed by 6583 (98·9%) of 6659 patients.

Long-term primary outcomes are shown in the table . In the inpatient trial, between day 45 and day 180, an additional nine patients in the colchicine versus control comparison had ventilation, high-flow oxygen, or death and seven patients in the rivaroxaban plus aspirin versus control comparison had major thrombosis, ventilation, high-flow oxygen, or death. In the outpatient trial, between day 45 and day 180, an additional 14 patients in the colchicine versus control comparison were hospitalised or died and 14 patients in the rivaroxaban plus aspirin versus control comparison had major thrombosis, were hospitalised, or died. For all randomised comparisons, estimates of treatment effects at day 180 were similar to those previously reported at day 45.

Table.

Day 45 and day 180 outcomes for the anti-coronavirus therapy trials

		Inpatient trial (n=2749)†		Outpatient trial (n=3917)
		Colchicine vs control	Rivaroxaban plus aspirin vs control	Colchicine vs control	Aspirin vs control
Primary outcome		Ventilation, high-flow oxygen, or death	Major thrombosis, ventilation, high-flow oxygen, or death	Hospitalisation or death	Major thrombosis, hospitalisation, or death
Day 45
	Patients with events	725 (27·8%)	582 (27·5%)	131 (3·4%)	132 (3·4%)
	HR	1·04 (0·90–1·21)	0·92 (0·78–1·09)	1·02 (0·72–1·43)	0·80 (0·57–1·13)
Day 180*
	Patients with events	734 (28·1%)	589 (27·8%)	145 (3·7%)	146 (3·8%)
	HR	1·06 (0·92–1·23)	0·93 (0·79–1·10)	1·10 (0·80–1·53)	0·84 (0·61–1·17)
Patients with first events between day 45 and day 180*		3 per 1000	3 per 1000	3 per 1000	4 per 1000

Data are n (%) or HR (95% CI). HR=hazard ratio.

^*A total of 78 patients were lost to follow-up or withdrew consent prior to the final visit.

^†1981 patients participated in both randomisations, 630 participated only in the colchicine vs control randomisation and 130 participated only in the rivaroxaban plus aspirin vs control randomisation.

Our results in both the inpatient and outpatient trials show that only three to four patients per 1000 with COVID-19 had a primary outcome between day 45 and 180, suggesting that their long-term cardiovascular risk is lower than previously reported. The explanation for this lower-than-expected event rate during long-term follow-up remains uncertain, but it might reflect lower virulence of COVID-19 variants among patients enrolled during the latter half of 2021 and early 2022, or increasing immunity conferred by a combination of infection and the use of vaccination.⁴ The absence of long-term benefit of either colchicine or aspirin with or without rivaroxaban provides no support for their use in patients with COVID-19.

JWE reports grant or in-kind support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Janssen, and Sanofi-Aventis and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Merck, Pfizer, Janssen, Sanofi-Aventis, and Servier. EB-C reports grant support from Bayer, Roche, and Bristol Myers Squibb-Pfizer. RPW reports grant support from Bayer, Roche, and BMS-Pfizer; grant support and honorarium from Boehringer Ingelheim; and consultancy fees from Atricure and Phasebio. SSJ reports grant support from Boston Scientific and honoraria from Medtronic and Penumbra. SW reports honoraria from Pfizer; and safety monitoring committee membership of an AIDS Clinical Trial Group. SY reports institutional grant support, honoraria, and travel costs for lectures from Bayer.