Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention

Study Questions:

Is atherothrombotic risk stratification useful for identifying post-acute coronary syndrome (ACS) patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy?


The TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2°P) was developed in a large population with atherothrombosis to predict cardiovascular (CV) death, MI, and ischemic stroke. The authors used the TRS 2°P at baseline in 17,717 post-ACS patients randomized to ezetimibe/simvastatin or placebo/simvastatin in the IMPROVE-IT trial. Treatment efficacy was assessed by baseline risk for the IMPROVE-IT composite endpoints (CEs), and individual component endpoints at 7 years.


The median age of patients was 63 years, and 24% were women. The median follow-up was 6.0 years (quartiles: 4.3, 7.1 years). The median achieved low-density lipoprotein cholesterol (LDL-C) values at 1 year were similar across risk categories by treatment (~68 mg/dl for placebo/simvastatin and ~51 mg/dl for ezetimibe/simvastatin). The most prevalent of the nine atherothrombotic risk indicators were hypertension, active smoking, diabetes, and renal dysfunction. The rate of CV death, MI, or ischemic stroke at 7 years in the placebo/simvastatin group ranged from 8.6% for patients with 0 risk indicators, to 68.4% with ≥5 risk indicators (p-trend < 0.0001). All nine clinical variables in the TRS 2°P were independent risk indicators for CEs (p < 0.001). The integer-based scheme showed a strong graded relationship with the rate of CEs, the trial endpoints, and the individual components (p-trend < 0.0001 for each). High-risk patients (n = 4,393; 25%), defined by ≥3 risk indicators, had a 6.3% (95% confidence interval, 2.9-9.7%) absolute risk reduction (ARR) in CE at 7 years with ezetimibe/simvastatin, translating to a number needed to treat of 16. Intermediate-risk patients (2 risk indicators; n = 5,292; 30%) had a 2.2% (-0.3 to 4.6%) ARR. Low-risk patients (0-1 risk indicator; n = 8,032; 45%) did not appear to derive benefit from the addition of ezetimibe (p-interaction = 0.010). Similar findings were observed for the IMPROVE-IT primary CE.


Atherothrombotic risk stratification using the TRS 2°P identifies high-risk patients who derive the greatest benefit from the addition of ezetimibe to statin therapy for secondary prevention after ACS.


Considering that ezetimibe is now generic, it would be reasonable to prescribe it in addition to statins when the LDL-C is >70 mg/dl post-ACS in the high- and intermediate-risk groups, as defined with the TRS 2°P. This type of analysis is a welcome model to assess the cost-effectiveness of treatment paradigms based on placebo-controlled studies. Of course it is not in the best interest of the pharmaceutical industry to reduce the market for a drug that has been shown to be effective and thus requires the investigators to have access to the data (usually not the case). A similar analysis of the number needed to treat to prevent one event and CV mortality will be extremely valuable for deciding who should be prescribed the very expensive PCSK9 antibody drugs that lower the LDL-C several-fold more than ezetimibe.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension, Smoking

Keywords: Acute Coronary Syndrome, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Myocardial Infarction, Renal Insufficiency, Risk Factors, Secondary Prevention, Simvastatin, Smoking, Stroke, Thrombosis, Treatment Outcome

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