Two Old Meds and a DOAC a Bust Across Range of COVID Severity: The ACT Trials

August 31, 2022

A discovery that some of the best drugs for treating patients with COVID-19 are also inexpensive, fairly safe, and easily available would be remarkable good fortune. But if such drugs are out there, they're unlikely to include colchicine or aspirin, suggests a pair of randomized trials that enrolled COVID patients who were either hospitalized or treated as outpatients.

Colchicine made no difference to outcomes such as hospitalization, mechanical ventilation, or death over 6 weeks in either the inpatient or outpatient studies that make up the Anti-Coronavirus Therapy (ACT) trial program. Aspirin's effect on major thrombosis, hospitalization, or mortality in the outpatient trial was similarly neutral.

In hospitalized COVID patients, moreover, aspirin paired with low-dose rivaroxaban (Xarelto), a direct oral anticoagulant (DOAC), didn't improve the composite risk for serious events like venous thromboembolism (VTE), need for ventilatory support, or death. The combo treatment did appear to elevate the risk of bleeding overall but had no effect on clinically serious bleeds.

The upshot of the two studies, especially given earlier trials on the same issues, is that aspirin with low-dose rivaroxaban should not be used in COVID inpatients, daily aspirin by itself doesn't benefit outpatients with COVID, and colchicine has no effect on clinically important outcomes in either setting, researchers report.

There are other therapies available, including anti-inflammatories, "certainly vaccination, and to some degree antivirals," that are "probably much more effective" in COVID-19 than those tested in the ACT trials, observed Sanjit Jolly, MD, MSc, McMaster University and Population Health Research Institute, Hamilton, Ontario, Canada.

Colchicine, in particular, has shown "no benefit in outpatients, no benefit in inpatients for mortality" across a range of trials covering inpatients and outpatients with COVID. Together they suggest that "colchicine does not have a role to play in the treatment of COVID-19, irrespective of the severity," Jolly said during a press conference on the two trials. Rather, "we probably need to focus on effective therapies that, on balance, will reduce significant complications."

The briefing was held prior to Jolly's August 29 presentation of the ACT Inpatient Trial at the European Society of Cardiology Congress 2022 sessions, held in Barcelona, Spain. It accompanied a report on the ACT Outpatient Trial delivered by John Eikelboom, MBBS MSc, from the same centers, who is an ACT clinical trial program principal investigator.

Separate comparisons of colchicine, aspirin, and the aspirin-DOAC combo in the ACT trials were made possible by double randomizations of their outpatient and inpatient populations; the former with mild COVID and the latter with moderate or severe disease.

The trials tested the anti-inflammatory colchicine for its ability to modulate the immune response to SARS-CoV-2 infection, as well as antiplatelet and anticoagulant therapy "with the specific goal of targeting microvascular thrombosis, thought to be critically important in organ failure and in death," explained Eikelboom during his presentation.

The objective, he said, was to determine whether anti-inflammatory and antithrombotic therapies "can prevent disease progression across the spectrum of disease severity."

End of Story?

Jolly also unveiled the results of two meta-analyses looking at colchicine and antithrombotic therapy — intensified anticoagulation, not low-dose anticoagulation — in the two COVID clinical settings.

In the colchicine meta-analysis, which covered about 8,400 outpatients and more than 15,000 inpatients, colchicine showed no effects on mortality or the major clinical events that composed the trials' primary endpoints.

The analysis was intended to help clear up confusion from the variable results of a number of COVID-colchicine studies, Jolly said. Several of those that predated the ACT presentations, including ColCORONA in outpatients and COLCOVID in inpatients, had shown or at least hinted at benefits from colchicine. And there was RECOVERY, "which was wholly neutral."

The RECOVERY trial, which is exploring a slew of potential COVID inpatient drug therapies for the primary endpoint of mortality in separate randomizations, last year halted its colchicine group early for lack of efficacy, as previously reported. The COLCOVID primary outcomes were mortality and, separately, death or new need for mechanical ventilation; ColCORONA primarily looked at death or 30-day COVID hospitalization.

As invited discussant for Jolly's presentation, Jurriën M. ten Berg, MD, PhD, Maastricht University, the Netherlands, reminded his audience that powerfully anti-inflammatory corticosteroids are known to improve outcomes in patients with COVID-19. Colchicine, he said, is probably too weak an anti-inflammatory to make a difference in such cases when given on top of steroids, which occurred frequently in the inpatient ACT study.

Given the multiple COVID studies in hospitalized patients that have failed to show benefits from the drug, ten Berg proposed, the ACT Inpatient Trial "is the end of the story for colchicine in COVID-19."

How Big a Concern Is VTE?

But there may potentially be such a role for intensified anticoagulation. In the meta-analysis of inpatient COVID trials, Jolly said, intensified anticoagulation in more than 7500 patients had zero effect on mortality but led to a precipitous drop in risk for VTE, with a hazard ratio (HR) of 0.57 (95% CI, 0.44 - 0.73).

That suggests VTE, which struck fewer than 2% of patients in the ACT Inpatient Trial, whether in the antithrombotic active-therapy or control group, doesn't have much impact on mortality in hospitalized COVID patients, Jolly said.

He and Eikelboom questioned whether the risk of clinically important bleeding from intensive anticoagulation, even if it prevents deep vein thrombosis (DVT), is acceptable if there's no effect on survival.

"If you don't reduce mortality, from a patient perspective," Jolly said, "is it better to have a major bleed or is it better to have DVT on ultrasound if, at the end of the day, it's not going to impact whether I get on a ventilator or whether I died?"

At the same forum, Eikelboom said, "I think we should abandon intensified anticoagulation, or the thought that intensified anticoagulation should be routine, in COVID-19. Because it doesn't overall make people emerge from the hospital alive."

It may be useful against venous thrombosis, he said, but "there are about a dozen guidelines right now on anticoagulation in COVID-19 with conflicting recommendations, and to me it's become a big distraction. Let's focus on things that really matter for COVID-19."

Still, "there are a lot of other clinically relevant consequences of thrombosis that are not just mortality," offered press-conference panelist David Berg, MD, Brigham and Women's Hospital, Boston. "It has to do with how people feel, it has to do with post-thrombotic complications, in terms of functional status down the road, postvenous thrombotic syndromes."

It is therefore important to know that intensive anticoagulation can reduce the risk for thrombotic events, said Berg, who presented the Prevention of Arteriovenous Thrombotic Events in Critically Ill COVID-19 Patients Trial (COVID-PACT) during the same congress session.

By the Numbers

The ACT Outpatient Trial, conducted in 12 countries, assigned 3917 patients in the community with laboratory-confirmed COVID-19 to a 28-day course of either colchicine, starting at 0.6 mg twice daily for 3 days and thereafter 0.6 mg once daily, or usual care. The treatment groups consisted of 1956 and 1961 patients, respectively.

The colchicine comparison's primary outcome was hospitalization or death at 45 days, for which the colchicine-vs-control HR was 1.02 (95% CI, 0.72 - 1.43; P = .93).

In a separate randomization of the same cohort, 1964 patients were assigned to receive aspirin at 100 mg/d and 1953 to usual care for 28 days. The HR for the primary endpoint of major thrombosis, hospitalization, or death at 45 days was 0.80 (95% CI, 0.57 - 1.13; P = .21).

In the 11-country ACT Inpatient Trial of patients who had been admitted with laboratory-confirmed COVID-19, 1304 were assigned to colchicine at an initial dose of 12 mg, followed 0.6 mg 2 hours later and 0.6 mg twice daily, and 1307 went to a usual-care group, both for 28 days. The HR for their primary endpoint of need for high-flow oxygen, mechanical ventilation, or death at 45 days was 1.04 (95% CI, 0.90 - 1.21; = .58).

In addition, 1063 patients were assigned to rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/d, and 1056 to usual care for 28 days, and were followed for major thrombosis, need for high-flow oxygen, mechanical ventilation, or death at 45 days. The HR was 0.92 (95% CI, 0.78 - 1.08; = .32).

Safety Endpoints in the ACT Inpatient Trial Anticoagulation Group
Endpoints Rivaroxaban + Aspirin (%) Usual Care (%) Value
Any bleeding 1.6 0.66 .04
Serious bleeding 0.19 0.57 .18

In both the outpatient and inpatient trials, there were no significant differences for individual components of the primary endpoints in either randomization.

In the outpatient trial, no significant primary endpoint differences were seen between either colchicine or aspirin, compared with usual care, in any patient subgroup, including by SARS-CoV-2 vaccination status, time from symptom onset to randomization, or comorbidities such as diabetes or cardiovascular disease.

The findings were similar for both inpatient randomizations. "In all the prespecified subgroups, we have observed consistently no benefit," Jolly said, "irrespective of whether you're on oxygen at baseline, whether you had been previously vaccinated, or whether you had a shorter or longer duration of symptoms."

The ACT trials were funded by the Canadian Institutes for Health Research, the Thistledown Foundation, and Bayer AG. Jolly discloses holding research contracts with Bayer and Boston Scientific. Eikelboom discloses receiving honoraria and research support from Bayer. Ten Berg discloses receiving fees for speaking or consulting from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, Accu-Metrics, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Ferrer, and CeleCor Therapeutics; and receiving research grants from ZonMw and AstraZeneca. Berg discloses receiving consulting fees from AstraZeneca, Mobility Bio, and Youngene Therapeutics; honoraria from the Medical Education Speakers Network; participating in committees for studies sponsored by Kowa Pharmaceuticals; and being a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from many companies.

European Society of Cardiology (ESC) Congress 2022: Hot Line Session 10. Presented August 29, 2022.

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