Patient Phenotypes, Cardiovascular Risk, and Ezetimibe Treatment in Patients After Acute Coronary Syndromes (from IMPROVE-IT)

Am J Cardiol. 2019 Apr 15;123(8):1193-1201. doi: 10.1016/j.amjcard.2019.01.034. Epub 2019 Jan 25.

Abstract

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p <0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.

Trial registration: ClinicalTrials.gov NCT00202878.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Coronary Syndrome / diagnosis
  • Acute Coronary Syndrome / mortality
  • Acute Coronary Syndrome / therapy*
  • Aged
  • Anticholesteremic Agents / therapeutic use
  • Cause of Death / trends
  • Coronary Artery Bypass / methods*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Ezetimibe / therapeutic use*
  • Ezetimibe, Simvastatin Drug Combination / therapeutic use*
  • Female
  • Follow-Up Studies
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Male
  • Middle Aged
  • North America / epidemiology
  • Phenotype
  • Risk Assessment / methods*
  • Risk Factors
  • Simvastatin / therapeutic use*
  • Survival Rate / trends
  • Treatment Outcome

Substances

  • Anticholesteremic Agents
  • Ezetimibe, Simvastatin Drug Combination
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Simvastatin
  • Ezetimibe

Associated data

  • ClinicalTrials.gov/NCT00202878