Author + information
- Gregory G. Schwartz, MD, PhD∗ ()
- Cardiology Section, Veterans Affairs Medical Center, Denver, Colorado, and the University of Colorado School of Medicine, Denver, Colorado
- ↵∗Address for correspondence:
Dr. Gregory G. Schwartz, VA Medical Center, Cardiology Section (111B), 1055 Clermont Street, Denver, Colorado 80220.
- acute coronary syndrome
- low-density lipoprotein cholesterol
- risk stratification
- secondary prevention
For 28 years after the first approval of a statin in 1987, no lipid-modifying therapy was shown to improve cardiovascular outcomes when added to background statin therapy. That changed in 2015 when IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) (1) provided landmark proof of concept by demonstrating that ezetimibe, compared with placebo, reduced cardiovascular events in patients with an initial acute coronary syndrome (ACS) who received background therapy with simvastatin. The clinical benefit of ezetimibe was associated with lower low-density lipoprotein cholesterol (LDL-C) levels compared with placebo (median 1.4 mmol/l vs. 1.8 mmol/l), as expected from ezetimibe’s action as an inhibitor of cholesterol absorption.
Despite the scientific importance of the findings from IMPROVE-IT, practical application of the trial has been problematic; the clinical benefit of ezetimibe was modest. It took more than 18,000 high-risk patients with ACS, who were followed-up for a median of 6 years, to demonstrate a 6% relative reduction in the primary endpoint event (first occurrence of cardiovascular death or nonfatal myocardial infarction, stroke, unstable angina requiring hospital admission, or coronary revascularization at least 30 days after randomization). This finding corresponded to a need for 350 patient-years of treatment with ezetimibe to prevent 1 primary endpoint event. Moreover, ezetimibe did not reduce mortality rates. Thus, IMPROVE-IT did not provide a clear answer to the question, “Who should receive ezetimibe?”
In this issue of the Journal, Bohula et al. (2) attempt to address that question by defining subgroups of IMPROVE-IT participants who benefited most from ezetimibe. These investigators tested a simple risk score that had been derived from another trial of patients with chronic atherosclerotic cardiovascular disease. The score assigns 1 point for the presence of each of 9 standard and routinely measured clinical characteristics (age of at least 75 years; estimated glomerular filtration rate <60 ml/min/1.73 m2; active smoking; and history of diabetes, hypertension, peripheral arterial disease, stroke, coronary artery bypass surgery, or heart failure). When applied to the IMPROVE-IT cohort, the score performed well to provide a graded prediction of the risk of “hard” cardiovascular events: cardiovascular death; myocardial infarction; or ischemic stroke. For example, patients with 0 risk factors had a 7-year risk of 8.6%, whereas patients with 5 or more risk factors had a 7-year risk of 68%. Next, Bohula et al. (2) divided participants into 3 groups according to risk scores of 0 or 1, 2, or 3 or more points, thereby comprising 45%, 30%, and 25% of the cohort, respectively. Reduction in the risk of cardiovascular death, myocardial infarction, or ischemic stroke with ezetimibe was found to be associated with risk score category. Among participants with a risk score of 0 or 1, there was no risk reduction with ezetimibe. In contrast, among participants with a risk score of 3 or more, ezetimibe reduced 7-year relative risk by 19% and absolute risk by 6.3% compared with placebo. Both relative risk reduction and absolute risk reduction with ezetimibe increased monotonically with categories of the risk score, an observation that differs from findings within and among statin trials, which have generally shown fairly uniform relative risk reduction across strata of absolute risk (3,4). In the highest of the 3 risk categories in the present analysis of IMPROVE-IT, approximately 111 patient-years of treatment with ezetimibe were required to avoid 1 cardiovascular death, myocardial infarction, or ischemic stroke—a moderate, clinically relevant therapeutic benefit. To place this finding in context with placebo-controlled statin trials, 36 patient-years of treatment with simvastatin were required to prevent 1 major coronary event (death resulting from coronary heart disease, nonfatal myocardial infarction, or resuscitated cardiac arrest) among patients in the highest tertile of risk in the Scandinavian Simvastatin Survival Trial (3).
LDL-C levels did not differ among the 3 risk score categories, either at baseline or during assigned treatment. At face value, this finding could suggest that risk reduction with ezetimibe is determined more by the level of global cardiovascular risk than by the degree of dyslipidemia. However, it is also possible that the identification of patients who benefit from ezetimibe would have been improved had the risk score incorporated baseline LDL-C levels or perhaps plasma markers of cholesterol absorption (5).
In the IMPROVE-IT trial, all patients were initially treated with 40 mg of simvastatin daily, and a majority remained on that dose throughout the trial. An important caveat in interpreting the findings from the analysis by Bohula et al. (2) and from the IMPROVE-IT trial more broadly is that background moderate intensity statin therapy with 40 mg of simvastatin daily is arguably suboptimal treatment after ACS. For example, in the A to Z (Aggrastat to Zocor) trial, 40 mg of simvastatin daily for the first 4 months following ACS did not improve cardiovascular outcomes compared with placebo (6). In contrast, the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial demonstrated a reduction of cardiovascular events during the same time interval after ACS with 80 mg of atorvastatin daily compared with placebo (7). A meta-analysis of 5 randomized trials that compared high-intensity with moderate-intensity statin treatment confirmed a significant long-term benefit of the former approach (4). Therefore, irrespective of the current findings from the IMPROVE-IT trial, it remains an open question whether ezetimibe, or any other lipid-modifying therapy, improves outcomes after ACS if added to a background of high-intensity statin treatment.
In the near future, this question may be answered with more certainty. Large outcome trials will report whether treatment with monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9), expected to lower LDL-C to a much greater degree than ezetimibe, reduces cardiovascular events (8,9). One of these trials is studying this approach in patients with recent ACS who are receiving optimal, high-intensity statin treatment (9). Risk scores such as that presented by Bohula et al. (2) may prove useful to determine which patients derive the greatest benefit from new lipid-modifying therapies.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the author and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Schwartz, through his institution, has received research support from Cerenis, The Medicines Company, Resverlogix, Roche, and Sanofi.
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