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Giving the P2Y12 inhibitor antiplatelet drugs ticagrelor or clopidogrel to noncritically ill, hospitalized patients with COVID-19 did not result in a greater number of days alive and free of cardiovascular or respiratory organ support in the ACTIV-4a trial.  

“While safe for most patients, P2Y12 inhibitors, when combined with anticoagulation with heparin, neither increased patients’ chances for survival or the number of days they were free of cardiovascular or respiratory organ support,” lead investigator Jeffrey Berger, MD, said.

The trial, which had a Bayesian design, showed a 96% likelihood of no benefit, and an 81% likelihood of a worse outcome with P2Y12 inhibitors in noncritically ill, hospitalized COVID-19 patients.

These results only relate to noncritically ill patients, and the part of the study including critically ill patients is still ongoing.

Berger, director of the Center for the Prevention of Cardiovascular Disease at NYU Grossman School of Medicine, New York, presented the ACTIV-4a results at the American Heart Association (AHA) Scientific Sessions on November 15.

The trial is part of the National Institutes of Health-sponsored ACTIV-4 trial looking at different antithrombotic strategies in the treatment of COVID-19.

Berger explained that patients with COVID-19 are at significant risk for morbidity and all-cause mortality, and that thrombosis and inflammation contribute to the risk for death and complications.

Previous data from the ACTIV-4 trial and other studies have shown that therapeutic-dose heparin increased days alive and free of organ support in noncritically ill patients with COVID-19. Nonetheless, nearly one out of four patients receiving therapeutic-dose heparin still died or received intensive care-level support, highlighting the need for additional therapies.

The current ACTIV-4a study included noncritically ill, hospitalized patients with confirmed COVID-19 deemed to be at increased risk for complications with one of the following criteria: D-dimer ≥ 2-fold upper limit of normal; age 60 – 84 years, or if less than 60 years of age, one of the following risk factors: use of oxygen, hypertension, diabetes, kidney disease, cardiovascular disease, or obesity.

Patients were randomized to treatment with a P2Y12 inhibitor (ticagrelor 60 mg twice daily or clopidogrel 300-mg load followed by 75 mg daily) or no P2Y12 inhibitor (usual care). Duration of P2Y12 inhibitor treatment was 14 days or until hospital discharge, whichever came first.

Enrollment was discontinued in the noncritically ill group in June 2021, after a planned analysis demonstrated that the statistical criterion for futility was met. At that time, 562 participants had been randomized.

Of those in the active treatment group, 63% were taking ticagrelor and 37% clopidogrel. The median duration of study drug treatment was 6 days, and the median duration of length of stay postrandomization was 6 days.

The vast majority of patients in both active treatment and usual-care groups (87% to 88%) were also receiving therapeutic-dose heparin.

Results showed that patients taking a P2Y12 inhibitor had fewer days without organ support than those in the usual-care group, with an adjusted odds ratio of 0.83 (95% credible intervals, 0.55 – 1.25).

There was a 96% probability that futility was met, and an 81% probability that a P2Y12 inhibitor strategy was associated with inferiority, Berger reported.

In prespecified subgroup analyses, the treatment effect did not vary meaningfully by age, sex, race, amount of supplemental oxygen support at enrollment, site preference for ticagrelor or clopidogrel, or heparin dose used.

The effect of P2Y12 Inhibitor on the composite endpoint of death or organ support showed that there were numerically more events in the P2Y12 inhibitor arm at 26% versus 22% in the usual-care group, giving an adjusted hazard ratio of 1.19 (95% confidence interval [CI], 0.84 – 1.68; P = .34).

The key secondary endpoint of major thromboembolic event or in-hospital death occurred in 6.1% of the antiplatelet group and 4.5% of the usual-care group; adjusted odds ratio 1.42 (95% CI, 0.64 – 3.13).

The key safety endpoint of major bleeding occurred in 2% of the antiplatelet group vs 0.7% in the usual-care group; adjusted odds ratio 3.31 (95% CI, 0.64 – 17.2).

Moving forward, the ongoing ACTIV-4a trial continues to evaluate P2Y12 inhibitors in critically ill COVID-19 patients.

Further, two other arms of the trial will begin this month testing other strategies including the use of P-selectin inhibitors and SGLT2 inhibitors in COVID-19, Berger said.

Low-Risk Population

Discussing the study at the late-breaking science session, Erin Bohula, MD, Brigham and Women’s Hospital, Boston, Massachusetts, pointed out that the rates of in-hospital death were low in this study, and the duration of hospitalization was quite short, with a median of 6 days, highlighting that this population was generally fairly low risk.

“The rate of thrombotic complications was low, as was the rate of major bleeding considering these patients were also on full dose anticoagulation,” she said.

“When we think about the neutral result that we’ve seen, we have to remember that this is on top of full dose anticoagulation so maybe there’s no added benefit of antiplatelet therapy in this population,” Bohula commented.

She concluded: “These data do not support the use of these P2Y12 inhibitor agents in this context, but it is still important to address the similar question in a higher risk population, in studies that are underway.”

She also questioned whether the endpoint used in this study is modifiable. “We know COVID can lead to multiple complications including respiratory failure, hemodynamic instability, thrombotic events and other end organ dysfunction and that can translate to death. But the question is what is the major mechanisms for these complications and are they modifiable?”

She added; “We know that COVID patients are hypercoagulable, and it is reasonable to hypothesize that antithrombotic therapy would alter that, but the question is which of these complications might it modify.”

Also commenting on the study was Manesh Patel, MD, chief of the Division of Cardiology and codirector of the Heart Center at Duke University, Durham, North Carolina, and chair of the Scientific Sessions program.

“What is really interesting is the biology here,” Patel said. “We’ve seen that unfractionated heparin is beneficial so there is a pro-thrombotic inflammatory vasculitis going on with COVID, but these results suggest the platelet pathway is not involved as much.”

American Heart Association Scientific Sessions 2021. Presented November 15, 2021. Abstract.

The ACTIV-4a trial is f unded by the National Heart, Lung, and Blood Institute. Berger reports research support from the National Institutes of Health, the American Heart Association, Astra Zeneca, and Janssen, and honoraria from Amgen. 

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