乌鸦传媒

BARCELONA -- Full-dose anticoagulation prevented thromboembolic events in critically ill COVID-19 patients in the COVID-PACT trial. However, modest antithrombotic doses and colchicine didn't pan out in or out of the hospital for COVID-19 progression and mortality in the ACT trial.

Both trials were reported here at the European Society of Cardiology (ESC) Congress.

In Critical Illness

In the randomized controlled COVID-PACT trial, full-dose heparin had a 95% greater likelihood of benefit for a composite of fatal and nonfatal thrombotic endpoints compared with standard prophylactic anticoagulation in critically ill COVID patients, reported David Berg, MD, MPH, of Brigham and Women's Hospital in Boston. The findings were also published in .

The win ratio came out to 1.95 for the hierarchical composite of venous or arterial thrombosis death, pulmonary embolism, clinically evident deep venous thrombosis (DVT), type 1 myocardial infarction, ischemic stroke, systemic embolic events and acute limb ischemia, or clinically-silent DVT through hospital discharge or 28 days (12.3% vs 6.4% wins, P=0.028).

Stronger anticoagulation (low-molecular-weight heparin in 82%, unfractionated in 18%) didn't improve mortality, though the trial was underpowered to determine this, Berg noted at the hotline session. But as expected, it did increase bleeding -- numerically for the primary safety endpoint of GUSTO (Global Use of Strategies to Open Occluded Arteries) severe or fatal bleeding (2.1% vs 0.5%, P=0.19) and significantly for the secondary safety endpoint of GUSTO moderate to severe bleeding (7.9% vs 0.5%, P=0.002).

The trial also included randomization to clopidogrel or no antiplatelet agent, but no benefits were seen in those groups.

Among the 390 patients requiring ICU-level care for acute COVID-19 at the 34 U.S. centers included in the trial, 99% required advanced respiratory therapy at randomization, including 15% on invasive mechanical ventilation, which rose to 40% during hospitalization. Treatment was administered open label with blinded event adjudication. The trial was terminated early at about 50% of planned enrollment.

In the Wards

The randomized ACT trial focused more on microvascular risk, using a combination of colchicine as an anti-inflammatory together with aspirin and low-dose rivaroxaban (Xarelto) to tackle the clotting cascade.

It was split into an inpatient (largely moderate disease) and an outpatient portion, both presented at the same session as COVID-PACT and announced to be in the press in Lancet Respiratory Medicine.

For the inpatient portion of the trial, colchicine had no impact on need for high flow oxygen or mechanical ventilation, or death (HR 1.04, 95% CI 0.90-1.21), reported Sanjit Jolly, MD, MSc, of the Population Health Research Institute in Hamilton, Ontario.

The antithrombotic comparison likewise proved no better than control for the primary endpoint in that analysis, which added major thrombosis to the composite outcome (HR 0.92, 95% CI 0.78-1.08). As anticipated, there was more bleeding with the antiplatelet/anticoagulant combination (1.60% vs 0.66%, P=0.042), although not more serious bleeds.

Other individual outcomes, including mortality and any thrombosis, were similar between groups for both treatments and across patient subgroups.

The ACT Inpatient trial included 2,500 adults with symptomatic, laboratory-confirmed COVID-19 enrolled within 72 hours of admission or clinical worsening. They could not yet have been on ventilation for more than 72 hours, nor be pregnant or have advanced kidney or liver disease. Patients were enrolled from Aug. 27, 2020, through Feb. 10, 2022, in 11 countries, with a predominance from South America.

They were randomized to colchicine plus rivaroxaban and aspirin, colchicine and control, the antithrombotics plus control, or neither active medication for 28 days. Colchicine was given as a 1.2-mg loading dose, followed by a 0.6-mg dose 2 hours later and 0.6 mg twice daily thereafter. Rivaroxaban was given at the 2.5-mg twice daily dose proven effective in prevention in the COMPASS trial, while aspirin was 100 mg once daily.

Notably, while more than 80% of patients were on oxygen at baseline, only about 2% were on invasive ventilation and 11% to 13% were in the ICU.

In the Community

For the outpatient portion of the ACT trial, colchicine had no impact on hospitalization or death (HR 1.02, 95% CI 0.72-1.43), reported John William Eikelboom, MBBS, of McMaster University in Hamilton, Ontario.

Nor did the factorial randomization to aspirin impact the primary endpoint for this portion of the trial -- a composite of major thrombosis, hospitalization, and death (HR 0.80, 95% CI 0.57-1.13).

Subgroup analyses suggested no population in which benefit was greater for either treatment.

The ACT Outpatient trial included 3,500 high-risk adults ages 30 and older with symptomatic, laboratory-confirmed COVID-19 from August 2020 through February 2022. They were randomized to colchicine (a loading dose of 0.6 mg twice daily for 3 days then once daily for 25 days) or no colchicine, with factorial randomization to aspirin (100 mg per day for 28 days) or no aspirin.

Enrollment had to be within 7 days of diagnosis or clinical worsening at centers around the world, with the top-enrolling countries being Egypt, Russia, and Canada.

Limitations to both the inpatient and outpatient portions of the trial included use of a control group without placebo and lower-than-anticipated event rates.

COVID-PACT was also limited by exclusion of patients with high bleeding risk and by early termination and use of prespecified on-treatment analysis instead of intent-to-treat analysis.

Implications

Jolly presented a meta-analysis of the ACT results in context with other trials presented or published prior to the ESC meeting. For colchicine, the outpatient findings together with the trial and the inpatient findings pooled with RECOVERY, COLCOVID, and ORECO suggested no significant benefit for either disease progression and mortality or mortality alone.

"It's the end of the story for colchicine," argued Jurrien ten Berg, MD, PhD, of St. Antonius Hospital in Nieuwegein, the Netherlands, who was the ESC study discussant for the ACT Inpatient trial. "Colchicine is probably a too weak inhibitor and difficult to have effect on top of steroids," which 85% to 90% of the inpatient ACT trial patients were on.

Low-dose rivaroxaban and aspirin might have just been too little to overcome the activated coagulation and inflammation of severe COVID, ten Berg suggested, pointing to no impact of even full-dose rivaroxaban in the ACTION trial. Heparin's benefits in the same setting could be due to its additional impacts outside of just anticoagulation, such as reducing endothelial leakage and viral cellular entry, he speculated.

But it's also reassuring that there was no evidence of harm from taking aspirin for milder disease at home, if patients take it for fever reduction, for example, Eikelboom said.

Even so, the story isn't over for direct oral anticoagulants in COVID, ten Berg noted, as the FREEDOM COVID trial is comparing therapeutic-dose apixaban (Eliquis) to full-dose and prophylactic-dose enoxaparin. Other studies are also underway with stronger platelet inhibitors, such as glycoprotein IIb/IIIa inhibitors and P-selectin inhibitors.

Even as COVID hospitalization rates fall, some proportion of patients will still get seriously ill, Eikelboom noted. "The world still today, in August of 2022, needs additional inexpensive, widely applicable treatments to prevent disease progression in outpatients with COVID-19."

Further research on the pathogenic mechanisms with current virus variants are warranted, agreed Alida Caforio, MD, PhD, of the University of Padua, Italy, who was the ESC study discussant for the ACT Outpatient trial. But the findings also highlight the need for more complete vaccination coverage worldwide, she added.

Changing ICU Practice?

For venous thromboembolism prevention with intensified anticoagulation, on the other hand, the numerous trials available, from ACTION to REMAP CAP, together provided a pooled estimate of a 43% relative reduction in risk (95% CI 0.44-0.73). For mortality, intensified anticoagulation still had no significant benefit across the trials (RR 0.94, 95% CI 0.80-1.10).

The International Society on Thrombosis and Haemostasis in COVID-19 support no direct oral anticoagulant use or antiplatelet agents for prophylaxis and preference for standard-dose prophylactic-dose heparin in the ICU and therapeutic-dose heparin in the general wards.

These recommendations were guided in large part by the large platform trials with endpoints focused on COVID survival and disease progression.

"There are about a dozen guidelines right now on anticoagulation in COVID-19 with conflicting recommendations," Eikelboom said. "It's become, to me, a big distraction from things that really matter in COVID-19."

Berg agreed that there has been a lot of confusion. "We start full-dose anticoagulation when patients are in the hospital and then as soon as they go to the ICU, do we stop? What about that patient who is on high flow nasal cannula and is making that transition toward more severe illness, what do we do?"

He said his results should give confidence that "full-dose anticoagulation in a critically ill population is highly effective for reducing thrombotic complications. And so I think there's a consistency of approach of using full-dose anticoagulation across the spectrum of acuity."

"Now I don't think that means we use this in every patient who comes into the hospital with COVID-19. I think it's important to consider who's not included in this [COVID-PACT] trial: patients who were severely coagulopathic, patients who had severe thrombocytopenia, low platelet counts, patients already on dual antiplatelet therapy. That's a group I would have some hesitations about using full-dose anticoagulation," he noted.

Furthermore, older patients were more likely to have bleeds on that regimen, he added.

The reasons for use might be different between the wards, Berg acknowledged, but he argued that stronger anticoagulation is still worthwhile in the ICU, even without a mortality benefit. The reason prophylactic anticoagulation is used routinely in the ICU for non-COVID cases is not on the basis of mortality or organ failure, but because of a reduction in thromboembolic complications, he said.

"There's clinical significance to a reduction in thrombotic events beyond just a reduction in mortality," he said. "It has to do with how people feel. It has to do with post-thrombotic complications in terms of functional status down the road, post-venous thrombotic syndromes."

However, the bleeding risk shouldn't be forgotten, Jolly argued. A recent meta-analysis suggested a 70% increase in bleeding risk with full-dose anticoagulation. "So there may be this interplay, and that may be why we don't see a reduction in mortality. I think my practice would be to ... use prophylaxis as a default, balancing that risk of thrombosis versus bleeding. But I think there will be a fair amount of practice variation as there is now."

Either way, "probably we will have to revisit guidelines," said Eduardo Ramacciotti, MD, PhD, of the Science Valley Research Institute in Santo André, Brazil, who was the ESC study discussant for the COVID-PACT trial. "We will have hard discussions."