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Biomarkers and Clinical Benefit of Ezetimibe
Study Questions:
Can biomarkers be used to identify subsets of post-acute coronary syndrome (ACS) patients who would benefit best from adjunctive ezetimibe treatment?
Methods:
The authors measured four biomarkers (high-sensitivity troponin T [hsTnT], N-terminal pro-B-type natriuretic peptide [NT-proBNP], growth-differentiation factor-15 [GDF-15], and high sensitivity C-reactive protein [hsCRP]) in 7,195 patients 1 month post-ACS who had been enrolled in the IMPROVE-IT trial and were randomized to ezetimibe/simvastatin versus placebo/simvastatin. The primary prespecified endpoint for this substudy was a composite of cardiovascular death, myocardial infarction, or stroke. The following cut-points above which 1 point per biomarker was assigned for each patient to create a multimarker risk score that ranges from 0 to 4: hsTnT >14 ng/L, NT-proBNP >450 pg/ml, GDF-15 >1,800 pg/ml, and hsCRP >2 mg/L. The impact of ezetimibe/simvastatin on outcomes was examined across the multimarker risk score.
Results:
The baseline characteristics of the participants of this substudy were similar to the overall trial participants. Patients in the highest quartile of each biomarker were at an approximately fivefold higher risk of cardiovascular death or heart failure. Among patients in the high-risk category (biomarker score of 4), the addition of ezetimibe to simvastatin resulted in a 7.3% (95% confidence interval [CI], -13.8% to -0.8%) absolute risk reduction in the composite outcome, with a number needed to treat of 14. Patients in the low-risk category (biomarker score of 0) had no apparent risk reduction (3%, 95% CI, -1.6%-7.7%). The heterogeneity in the relative effect of ezetimibe, however, was not statistically significant (p = 0.11).
Conclusions:
A biomarker-based strategy could potentially identify high-risk patients that would correspondingly derive higher absolute benefit from ezetimibe to statin therapy.
Perspective:
This well-conducted study is one of the few that explores the potential of prognostic blood-based biomarkers in personalizing the management of cardiovascular disease. A multimarker risk score that accounts for the various pathogenic processes that drive outcomes in cardiovascular disease represents the approach with the maximum potential yield in risk discrimination. A major caveat of the study was that subgroup analyses and comparisons were performed despite the absence of statistical significance for the heterogeneity test. The findings may also not apply to the current era of post-ACS management in which high-intensity statins are mainly used. Nevertheless, this study sets an example for future trials as we move away from trying to find the elusive silver bullet and look to incorporate biomarker testing as a method to identify subgroups with maximal or minimal benefit from therapy.
Keywords: Acute Coronary Syndrome, Biomarkers, C-Reactive Protein, Growth Differentiation Factor 15, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Myocardial Infarction, Myocardial Ischemia, Natriuretic Peptide, Brain, Peptide Fragments, Risk Reduction Behavior, Secondary Prevention, Simvastatin, Stroke, Troponin T
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