VESALIUS-CV: Evolocumab and Mortality in High-Risk Adults
Key Takeaways
- Among patients with qualifying atherosclerosis or high-risk diabetes and no prior myocardial infarction or stroke, observed all-cause mortality was lower with evolocumab than with placebo.
- Cardiovascular mortality was lower with evolocumab, while the individual noncardiovascular mortality comparison was inconclusive.
- A model estimated that prevention of earlier nonfatal cardiovascular events accounted for much of the noncardiovascular mortality difference, without establishing causation.
Investigators randomized 12,257 participants in a double-blind comparison of evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, with placebo. Participants had qualifying atherosclerosis or high-risk diabetes, no previous myocardial infarction or stroke, and elevated atherogenic lipoproteins; median follow-up was 4.6 years. The prespecified VESALIUS-CV mortality analysis in Circulation assessed all-cause death and deaths from cardiovascular, noncardiovascular, or undetermined causes. Investigators also used multistate modeling to estimate whether preventing intervening nonfatal cardiovascular events might account for differences in later noncardiovascular death.
All-cause deaths numbered 434 with evolocumab versus 539 with placebo. Estimated five-year Kaplan–Meier mortality was 7.9% versus 9.7%, respectively, a calculated absolute difference of 1.8 percentage points.
The all-cause mortality hazard ratio was 0.80, with a 95% confidence interval of 0.70–0.91 and a reported P=0.0005. These results describe an observed survival difference over follow-up, not confirmation from a trial powered for mortality.
Cardiovascular deaths were fewer with evolocumab than with placebo. Noncardiovascular deaths were also fewer, but that individual comparison was inconclusive; deaths of undetermined cause were fewer as well. Noncardiovascular causes accounted for the largest share of deaths overall. Multistate modeling attributed an estimated 78% of the observed noncardiovascular mortality difference to prevention of preceding nonfatal cardiovascular events.
Although mortality was a prespecified outcome of interest, the trial was not powered for mortality. The noncardiovascular mortality confidence interval encompassed no difference between groups, and the modeled contribution of intervening events cannot establish a causal pathway. Participants without a previous myocardial infarction or stroke were not an unselected, low-risk population: eligibility included qualifying atherosclerosis, while some participants qualified through high-risk diabetes without qualifying atherosclerosis.
The investigators interpreted the mortality pattern as supporting a possible survival benefit with evolocumab among these high-risk patients, including those with high-risk diabetes but without qualifying atherosclerosis. That interpretation is not a definitive mortality finding.
Clinician Questions
What lipid thresholds qualified adults for the VESALIUS-CV evolocumab mortality analysis?
Participants without prior myocardial infarction or stroke had qualifying atherosclerosis or high-risk diabetes and met at least one alternative threshold: low-density lipoprotein cholesterol ≥90 mg/dL, non–high-density lipoprotein cholesterol ≥120 mg/dL, or apolipoprotein B ≥80 mg/dL. These were research eligibility criteria, not treatment thresholds.
Which nonfatal cardiovascular events preceded later noncardiovascular deaths in VESALIUS-CV?
Among high-risk participants without prior myocardial infarction or stroke, a nonfatal myocardial infarction, ischemic stroke, or ischemia-driven arterial revascularization after randomization was associated with greater subsequent noncardiovascular death within the next four years. Most such deaths occurred in the first year after the event; the association does not establish causation.
Recommended Reading
- For more on evolocumab and cardiovascular outcomes: Pre-PCI Evolocumab Improves LDL-C After Acute MI