Add-on alirocumab confers favourable benefits for patient-centred outcomes in ACS

Use of the PCSK9* inhibitor alirocumab in acute coronary syndrome (ACS) patients on a background of high-intensity statin treatment delivers reductions in total hospitalizations and death with corresponding gains in days alive and out of hospital (DAOH), according to the results of prespecified and posthoc analyses of the ODYSSEY OUTCOMES** trial presented at the American Heart Association (AHA) 2019 Scientific Sessions.

“These outcomes provide alternative patient-centred metrics of the totality of alirocumab’s effects, capturing benefits beyond first and total adjudicated events avoided,” namely the first occurrence of major adverse cardiovascular events, as well as total nonfatal cardiovascular events and death, the investigators said.

“Analyses that account for total adjudicated nonfatal and fatal events measure the effect of an intervention on the total burden of a disease process,” they explained. “[However], central adjudication may not consider events other than particular study endpoints that nonetheless lead to hospitalization, and therefore have meaningful negative consequences to patients and contribute to their total disease burden.”

ODYSSEY OUTCOMES evaluated the effect of alirocumab vs placebo when added to high-intensity or maximum tolerated statin treatment after ACS in 18,924 patients. Over a median follow-up of 2.8 years, 16,629 total hospitalizations and 726 deaths occurred.

Compared with placebo, treatment with alirocumab led to fewer hospitalizations and deaths (difference in incidence, 331 and 58, respectively). This translated to 15.6 total hospitalizations or deaths prevented with the PCSK9 inhibitor per 1,000 patient-years of assigned treatment. [Circ Cardiovasc Qual Outcomes 2019;doi:10.1161/CIRCOUTCOMES.119.005858]

Alirocumab was associated with significant reductions in total hospitalizations (hazard ratio [HR], 0.96, 95 percent confidence interval [CI], 0.92–1.00; p=0.04) in a model using hospitalizations for any reason, and this effect further increased in a model using hospitalizations attributed to a protocol efficacy endpoint (HR, 0.89, 95 percent CI, 0.84–0.95; p=0.0005). The estimate for death was similar in the two models (HR, 0.83, 95 percent CI, 0.71–0.97; p=0.02).

“Thus, the exclusion of hospitalizations not attributed to a protocol efficacy endpoint strengthened the relative effect of alirocumab,” according to the investigators.

“Furthermore, the parameters describing the estimated association between death and hospitalization were considerably >1, indicating that death is informative for the hospitalization rate. Specifically, conditional on treatment assignment, patients at the highest risk of death were also at elevated risk for hospitalization, so that death removed those patients at highest risk for hospitalizations from the risk set,” they continued.

Finally, the PCSK9 inhibitor yielded an increase in DAOH relative to placebo (rate ratio, 1.003, 95 percent CI, 1.000–1.007; p=0.05), driven mainly by a reduction in days dead (rate ratio, 0.847, 95 percent CI, 0.728–0.986; p=0.03). Alirocumab-treated patients were also at much greater odds of surviving to the end of the study without hospitalization (odds ratio, 1.06, 95 percent CI, 1.00–1.13; p=0.03).

“A possible limitation of total hospitalizations and DAOH is that the analyses relied on investigator reports of hospitalizations on a dedicated case report form. While this had the benefit of allowing investigators to provide a primary reason for a given hospitalization, there may have been additional hospitalizations that either was not recorded on this form or were unknown to the investigators, resulting in an underreporting of hospitalizations,” the investigators acknowledged.

*Proprotein convertase subtilisin−kexin type 9

**Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab