Lower Really Is Better for Secondary Prevention Cholesterol Targets

NEW ORLEANS — The more intensive LDL cholesterol target guidelines recommended for secondary prevention in high-risk patients with atherosclerotic cardiovascular (CV) disease improved outcomes in a randomized trial from South Korea.

Compared with the LDL cholesterol target of less than 70 mg/dL typical for lower risk and primary prevention patients, targeting less than 55 mg/dL cut risk of major CV adverse events (AEs) by 33%, with a Kaplan-Meier estimate of cumulative incidence over 3 years of 6.6% versus 9.7% (P=0.002), reported Byeong-Keuk Kim, MD, PhD, of Severance Hospital and Yonsei University College of Medicine in Seoul, at the American College of Cardiology annual meeting.

The number needed to treat was 32 to prevent one event in that primary endpoint composite of death from CV causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina at 3 years. The findings were simultaneously published in the New England Journal of Medicine.

European guidelines call for a target under 55 mg/dL for all patients with atherosclerotic CV disease, while the newly released U.S. guidelines give a strong recommendation for that target only in patients considered at very high risk for CV events, defined by multiple prior major atherosclerotic CV events or multiple high-risk factors — >65 years of age, coronary artery revascularization, current smoker, diabetes, history of heart failure, hypertension, LDL >100 mg/dL despite maximally tolerated statin and ezetimibe (Zetia) — along with one prior event.

“The data lend firm support to current international lipid guidelines and further advance the idea that a lower LDL cholesterol level is better for secondary prevention of atherosclerotic cardiovascular disease,” said Jeffrey Probstfield, MD, and Kelley Branch, MD, both of the University of Washington School of Medicine in Seattle, in an accompanying editorial.

The lipid guidelines’ targets had been largely based on extrapolation from achieved LDL cholesterol levels rather than data from the few trials that aimed for specific LDL cholesterol levels, they noted.

With foundations firmed up in this patient population, Ez-PAVE trial also “potentially paves the way for more definitive trials to evaluate targeted LDL cholesterol levels in other populations, with other treatment combinations, and with other LDL cholesterol goals for primary prevention,” Probstfield and Branch wrote.

The impact on outcomes was unexpectedly large for a difference of 10 mg/dL in the median LDL cholesterol level between the two treatment groups, they noted.

That “could be due to differential benefit within a South Asian population, selection bias from enrollment of an adherent patient population (9 of 10 patients were taking a statin at baseline), benefits of combination therapy with ezetimibe, or other factors,” Probstfield and Branch wrote.

And it’s not entirely certain whether the findings can be extrapolated to populations outside of South Asia, they said. “These data also do not fully answer the question of whether the target LDL cholesterol level should be 70 mg per deciliter or less in a primary-prevention population. This question remains a topic for further investigation.”

The trial included 3,048 patients ages 19 to 80 (mean 64, 20.9% women) at 17 sites in South Korea who had atherosclerotic CV disease (prior acute coronary syndrome, stable angina with imaging or functional studies, coronary revascularization or other arterial revascularization, stroke or transient ischemic attack, or peripheral artery disease) and an LDL over 70 mg/dL. They were randomly assigned to a target LDL cholesterol level of less than 55 mg/dL or less than 70 mg/dL.

That goal was to be achieved by increasing statin dose and adding ezetimibe and then considering PCSK9 inhibitors, with treatment decisions left to the treating physicians’ discretion. They ended up with higher use of ezetimibe in the trial (66.6% in the intensive-targeting group and 56.7% in the conventional-targeting group at 3 years) than the typical 6% in the U. S. population, but low PCSK9 inhibitor use (2.3% and 0.9%, respectively, at 3 years).

Median LDL cholesterol dropped from 76 mg/dL at baseline to 56 mg/dL in the intensive-target arm and 66 mm/dL in the conventional-target arm, with a consistent between-group difference throughout follow-up.

AEs were similar between groups for most safety events of concern, except for lower incidence of elevated creatinine level in the intensive-target group (1.2% vs 2.7%, P=0.004).