The results of a follow-up analysis of data from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial suggest that the addition of the PCSK9 inhibitor evolocumab to statin therapy not only reduces the risk of first major vascular events in patients with stable atherosclerotic disease, but also reduces the risk of recurrent cardiovascular events. Findings from the analysis were presented by Sabina A. Murphy, MPH, at Scientific Sessions on Monday.
“Looking at total vascular events during the 2.2-year median follow-up in the FOURIER trial, our analysis revealed more than double the number of events prevented — driven by decreases in MI, stroke and coronary revascularization — as compared with an analysis of just first events,” said Murphy, director of biostatistics for the TIMI Study Group at Brigham and Women’s Hospital in Boston.
In the FOURIER trial, patients with atherosclerotic cardiovascular disease who were receiving background statin therapy were randomized in a double-blind manner to continued statin therapy plus treatment with either evolocumab or placebo.
“The primary analysis of long-term cardiovascular trials often use survival analysis methods to evaluate efficacy on the first event that a patient experiences during the trial, as was done in FOURIER,” Murphy said. “This is most commonly done using a standard Cox proportional hazards model, which censors patients after that first event has occurred.”
To evaluate the effect of evolocumab on total events that occurred throughout the trial, the investigators used a negative binomial regression model to evaluate the total count of events that occurred in a subject. They also performed a sensitivity analysis using the Wei, Lin and Weissfeld model, which is an extension of survival models based on the Cox proportional hazard. The primary endpoint was a composite of CV death, MI, stroke, unstable angina or coronary revascularization.
There were 4,906 primary endpoint events that occurred during the course of the trial, Murphy said. Of those events, 2,907 were first primary endpoint events, which were included in the primary analysis, but there were an additional 1,999 primary endpoint events that patients experienced during the course of follow-up that were not included in the primary analysis, she said.
Among the findings of the follow-up analysis, Murphy reported that evolocumab reduced total primary endpoint events by 18 percent (incidence-rate ratio [RR] 0.82, 95 percent CI 0.75-0.90, p<0.001), including both first events (HR 0.85 [0.79-0.92], p<0.001) and subsequent events (RR 0.74 [0.65-0.85], p<0.001). Reductions in total events were driven by fewer total MIs (RR 0.74, p<0.001), fewer total strokes (RR 0.77, p=0.007) and fewer total coronary revascularizations (RR 0.78, p<0.001).
“Overall, our data showed that evolocumab prevented 22 primary endpoint events per 1,000 patients treated for three years when considering first events only, and 52 such events when taking into account total vascular events,” Murphy said. “We believe these data support long-term use of evolocumab in conjunction with statin therapy to reduce the risk of recurrent cardiovascular events. With continued research, we hope to more clearly define the magnitude of benefit of LDL-C lowering with evolocumab in various patient subgroups, taking into account the effect on total events.”