AHA 2021: P2Y12 Inhibitors Fail to Improve Outcomes in Non-Critically Ill Patients Hospitalized With COVID-19
Analysis in critically ill patients is ongoing
November 15, 2021—P2Y12 inhibition did not result in more days alive and free of cardiovascular or respiratory organ support among non-critically ill patients hospitalized with COVID-19, according to results of the ACTIV-4a trial, presented at the American Heart Association’s Scientific Sessions, which took place virtually from November 13 to 15.
“It is well-known that patients infected with SARS-CoV-2 are at significant risk for morbidity and all-cause mortality,” said lead author Jeffrey S. Berger, MD, of the New York University School of Medicine in New York City, during his presentation of the data. “Both thrombosis and inflammation contribute to the risk of death and complications among patients with COVID-19, and data from mpRCT demonstrated that therapeutic-dose heparin increased days alive and free of organ support in non-critically ill, or moderate, patients with COVID-19. Nonetheless, nearly 1 out of 4 patients receiving therapeutic-dose heparin still died or received intensive care level support, highlighting the need for additional therapies in this cohort.”
For the international, open-label, adaptive, controlled ACTIV-4a trial, patients who were hospitalized for COVID-19 were randomized to receive a P2Y12 inhibitor or usual care, without a P2Y12 inhibitor. This treatment was given in combination with recommended therapeutic doses of heparin for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor and was used in 63% of patients on a P2Y12 inhibitor. The remaining 37% of patients in this group received clopidogrel.
Patients were stratified by severity of disease, with severe disease defined as critically ill and receiving organ support and/or intensive care unit (ICU) level care. Moderate severity of illness was defined as hospitalization without an initial requirement for ICU therapies or level of care. Enrollment in the trial was discontinued in the moderate severity group on June 19, 2021, after a planned adaptive analysis demonstrated that the statistical criterion for futility was met. At this time, 562 patients with moderate severity illness had been randomized, 293 in the P2Y12 group and 269 in the usual care group. Dr. Berger presented results only for this moderate severity group.
Patients who did and did not receive P2Y12 inhibition were similar in terms of baseline characteristics, with a mean age of about 52 years, and about 41% being female. Just over 60% of patients were white, and the remainder were Hispanic. Nearly 60% were obese, and about one-quarter had diabetes. Almost 90% of patients required some form of oxygen support, and about 40% had a D-dimer greater than 2 times the upper limit of normal. The proportion of patients with cardiovascular disease was 43.7% for those on a P2Y12 inhibitor and 55.8% for those receiving usual care. The median duration of study drug treatment was 6 days, and the median duration of hospitalization after randomization was also 6 days. Overall, 87% of participants on a P2Y12 inhibitor and 88% on usual care received therapeutic-dose heparin by the end of day 1 of the study.
The primary endpoint of the trial was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for those who survived to hospital discharge, the number of index hospitalization days free of cardiovascular or respiratory organ support up to day 21. After adjusting for age, sex, enrollment epoch, cardiovascular disease, and baseline respiratory support, the adjusted odds ratio for this outcome with active therapy versus placebo was -0.83 (95% confidence interval 0.55–1.25). The probability that futility was met was 96.2%. “In fact,” said Dr. Berger, “we have 81% probability that a P2Y12 inhibitor strategy was associated with inferiority, or an odds ratio < 1.0.” In prespecified analyses, these findings did not vary meaningfully by age, sex, race, amount of supplemental oxygen support at enrollment, site preference for ticagrelor or clopidogrel, or heparin dose.
Similarly, there was no significant effect of P2Y12 inhibition on the composite of death or organ support, with a hazard ratio of 1.19 (95% confidence interval 0.84–1.68). Other key secondary endpoints that were not improved with P2Y12 inhibition included the composite of major thrombotic events (defined as the composite of myocardial infarction, pulmonary embolism, ischemic stroke, and systemic arterial embolism) or in-hospital death or either of these outcomes alone.
Key safety endpoints were major bleeding as well as the composite of major bleeding or in-hospital death. Both of these occurred in more patients on P2Y12 inhibition, but the odds ratios were not significant between the two groups.
“In non-critically ill hospitalized patients with COVID-19, use of P2Y12 inhibitors did not result in a greater number of days alive and free of cardiovascular or respiratory organ support,” concluded Dr. Berger. “There was a low rate of major bleeding, with an approximate 1% absolute risk increase, and testing of P2Y12 inhibitors in critically ill patients is still ongoing.”
In an independent comment, Erin Bohula, MD, DPhil, of Brigham & Women’s Hospital and Harvard Medical School in Boston, said that “in non-critically ill patients with COVID-19 who are mostly treated with therapeutic anticoagulation, the addition of a P2Y12 inhibitor provided no benefit for the endpoint of organ support-free days. Keep in mind, [the study] was not powered to detect differences in key secondary efficacy or safety outcomes, but the rates of these events, generally speaking, were quite low, and so I think the data [here] do not support the use of these agents in this context. It definitely will be important to address the similar question in higher-risk populations.”
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