An extended analysis of the ODYSSEY OUTCOMES trial has confirmed alirocumab, a PCSK9 inhibitor that hit the medical market in 2015, reduces a patient’s total risk of nonfatal and fatal cardiovascular events after an acute coronary syndrome (ACS).
Though ODYSSEY results were published in the New England Journal of Medicine last year, Michael Szarek, PhD, and co-authors said those findings might not be entirely comprehensive. Results were reported after just 2.8 years of follow-up, and the researchers focused on a short-term primary endpoint composed of death from coronary heart disease, nonfatal MI, stroke or unstable angina.
“An analysis involving only the first event may not capture the totality of the clinical impact of an intervention,” Szarek, of the State University of New York, and colleagues wrote in the Journal of the American College of Cardiology. “Furthermore, the burden of a disease process may be best assessed by all of the events experienced by a patient, as those occurring after the first add to morbidity, mortality and healthcare expenditures.”
Szarek et al. developed a model of total nonfatal cardiovascular and fatal events in an attempt to determine the extent to which alirocumab (Praluent) reduced both first and subsequent CV events and all-cause deaths in the ODYSSEY cohort, tweaking their algorithm to allow for the possibility that patients may experience more than one nonfatal event. The base study randomized 18,924 ACS patients to treatment with a high-intensity or maximum-tolerated statin and either alirocumab or a placebo.
The authors said there were 3,064 first and 5,425 total events in the study group, and 190 fewer first and 385 fewer total nonfatal CV events or death were observed in alirocumab patients compared to their counterparts taking a placebo. Alirocumab reduced total nonfatal CV events and death in its users by 13 percent and 17 percent, respectively.
When Szarek and colleagues normalized their results for duration of follow-up, they found 7.2 first events and 14.6 total events were avoided with alirocumab per 1,000 patient-years of assigned treatment, suggesting an analysis of only first events reflects just half of the total event reductions associated with alirocumab treatment.
“To analyze recurrent events in a clinical trial is atypical but, in the present case, very informative,” Jacques Genest, MD, and Dong-Vu Nguyen, MD, both of McGill University Health Center in Quebec, wrote in a related JACC editorial. “The authors argue that this helps us measure the total clinical impact to the patient. As an adjunct to the primary study based on first events only, which was positive, this pre-specified analysis does indeed provide us with data that further guides us in assessing the clinical impact alirocumab may have on our patients’ outcomes.”
Genest and Nguyen said they thought Szarek et al.’s study should be included in an economic analysis, since such a dramatic reduction in nonfatal events could have big implications for healthcare costs. PCSK9 inhibitors have a reputation as pricey drugs, and a recent Annals of Internal Medicine study found that even with recent price cuts, alirocumab still isn’t cost-effective.
“While the efficacy of alirocumab treatment after ACS was established on analysis of time to first primary endpoint event, the efficiency of the intervention to reduce morbidity and mortality after ACS, and its benefit to reduce the total burden of disease and healthcare costs, are best reflected by an analysis of total events,” Szarek and co-authors wrote. “Further studies are needed to quantify the broader socioeconomic implications of interventions that reduce the total burden of fatal and nonfatal cardiovascular and noncardiovascular events in high-risk patient populations that accumulate frailty over time.”