Muscle-related events, including less severe muscle complaints without a clear pharmacological relationship to the treatment, may hamper compliance with lipid-lowering therapy and increase the risk of drug discontinuation ([1][1]). In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy

BACKGROUND An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. OBJECTIVES The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). METHODS Within IMPROVE-IT, 17,708 patients post-acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took $1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy. RESULTS In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68). CONCLUSIONS Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Statin therapy is associated with a slightly increased risk of developing diabetes mellitus and insulin resistance in patients without diabetes. Ezetimibe combined with statins may be considered for high-risk patients who do not achieve optimal low-density lipoprotein cholesterol lowering on statin monotherapy or who are statin intolerant. Changes in fasting serum glucose (FSG) levels during ezetimibe, ezetimibe/statin, and statin treatments were assessed using data pooled from clinical trials in hypercholesterolemic and heterozygous familial hypercholesterolemic patients, who were or were not receiving statin therapy. Study types included first-line trials in statin-naive/wash-out patients and second-line add-on and uptitration studies in patients on stable statin therapy. Similar analyses of FSG changes were performed separately for each study type in patients who were nondiabetic at baseline. Across all study types and treatments, mean FSG increases from baseline were small (0.5 to 3.7 mg/dl with ezetimibe/statin; 0.2 to 4.6 mg/dl with statins) and decreased over time; between-treatment differences (0.3 to 1.4 mg/dl) were nonsignificant for all comparisons. Proportions of patients with elevated FSG ≥126 mg/dl during therapy were low and similar for all treatments in the overall cohort (1.2% to 4.3%). Elevations were highest (3.3% to 25.7%) among patients with baseline factors characteristic of metabolic syndrome and prediabetes, including higher FSG, body mass index, and triglyceride levels, and numerically lower baseline high-density lipoprotein cholesterol; however, these factors were not related to FSG increases. Changes in low-density lipoprotein cholesterol, body mass index, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were not significantly correlated with FSG increases. In conclusion, statin therapy was associated with small FSG increases, and the addition of ezetimibe did not further increase FSG levels beyond those of statins when given to patients who are statin naive or those on statin therapy.

Background We aimed to determine the efficacy and safety of adding ezetimibe (Ez) to simvastatin (S) in a post-acute coronary syndrome (ACS) population in a prespecified on-treatment analysis.Methods We evaluated 17,706 post-ACS patients from the IMPROVE-IT trial who had low-density lipoprotein cholesterol values between 50 and 125mg/dL andwho received Ez 10mg/d with S 40mg/d (Ez/S) or placebo with simvastatin 40mg/d (P/ S). The primary composite end point was cardiovascular death, myocardial infarction, unstable angina, coronary revascularization >= 30 days postrandomization, or stroke. The on-treatment analysis included patients who received study drug for the duration of the trial or experienced a primary end point or noncardiovascular death within 30 days of drug discontinuation.Results Mean low-density lipoprotein cholesterol values at 1 year were 71 mg/dL for P/S and 54 mg/dL for Ez/S (absolute difference -17 mg/dL = -24%; P < .001). The 7-year Kaplan-Meier estimate of the primary end point occurred in 32.4% in the P/S arm and 29.8% in the Ez/S arm (absolute difference 2.6%; HRadj 0.92 [ 95% CI 0.87-0.98]; P = .01). The absolute treatment effect favoring Ez/S was 30% greater than in the intention-to-treat analysis of IMPROVE-IT.Conclusions This analysis provides additional support for the efficacy and safety of adding Ez to S in this high-risk, post-ACS population.

BACKGROUND:Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.METHODS:We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years.RESULTS:The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups.CONCLUSIONS:When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).

The relationship between LDL-C measured at the time of an ACS event and subsequent treatment benefit from LDL-C lowering is poorly understood. The IMPROVE IT trial randomized 18,144 patients post-ACS to either ezetimibe or placebo, on a background of simvastatin 40-80 mg. We compared clinical

IMPROVE-IT is a randomized, double-blind trial evaluating whether the addition of ezetimibe (EZE) to simvastatin (simva) improves CV outcomes over statin monotherapy in post-ACS patients. The REACH score predicts secondary CV events in outpatients with known CV disease (Am J Med 2012;125). We

Background: Statin therapy is established in primary and secondary prevention guidelines both for men and women, although some people have questioned the benefits in women, where data are more limited. Adding the non-statin ezetimibe to statin therapy further reduced future CV events post ACS in IMPROVE-IT, but detailed analyses by sex have not been reported. Methods: In the IMPROVE-IT trial, patients hospitalized with ACS and LDL-C ≤125 mg/dL were randomized to ezetimibe/simvastatin 40mg (E/S) or placebo/simvastatin 40mg (P/S) and were followed up for a median of 6 yrs. The primary composite endpoint was CVD, MI, hospitalization for UA, coronary revascularization >30 days, and stroke. Efficacy and safety outcomes in women vs men were compared, one of 23 pre-specified subgroups. Results: Among 18144 patients from IMPROVE-IT, 4416 (24%) were women. Compared with men, women were more likely to be older, diabetic, and hypertensive, but less likely to have prior revascularization or multiple vessel disease. At 12 months, the median difference in LDL-C in both women and men was 16 mg/dl between E/S and P/S. Women receiving E/S had a 12% RRR of the primary endpoint (HR vs P/S, 0.88; 95% CI, 0.79 to 0.99), compared with a 5% reduction for men (HR vs P/S; 0.95, 95% CI, 0.90 to 1.01; p interaction p=0.26). There were no differences between E/S and P/S in this or safety events (E/S vs. P/S; AST and/or ALT>3ULN, 2.5% vs. 2.6%, 2.5% vs. 2.2%, cholecystectomy, 1.8% vs. 1.6%, 1.4% vs. 1.4%, myopathy, 0.2% vs. 0.2%, 0.1% vs. 0.1%, gallbladder-related AEs, 3.9% vs. 4.3%, 2.9% vs. 3.3%, in women and in men, respectively, p=all NS). Conclusion: IMPROVE-IT demonstrated that adding ezetimibe to statin reduces LDL-C and CV events in both women and men. A safety profile of ezetimibe supports the use of intensive, combination lipid lowering therapy to optimize CV outcomes in women as well as men.

Introduction: While lipid lowering reduces cardiovascular (CV) events, evidence supporting high-intensity lipid lowering among elderly pts is more limited, and recent guidelines recommend moderate rather than high-intensity therapy for pts >75 yrs. We explored age subgroups within the IMPROVE-IT trial to evaluate whether age modified the benefit of adding ezetimibe (EZ) to statin therapy. Methods and Results: The IMPROVE-IT trial demonstrated the combination of EZ and simvastatin (EZ/S) significantly reduced major CV events vs. simvastatin (S) alone in pts with acute coronary syndrome (ACS) and LDL-C between 50 and 125 mg/dL. The primary composite endpoint was CV death, myocardial infarction, stroke, unstable angina requiring hospitalization, and coronary revascularization >30 days. Outcomes according to age were compared in pre-specified subgroups using Kaplan-Meier (KM) analysis and Cox proportional hazards models using age as a continuous variable. Of the 18,144 pts enrolled, 7971 (44%) were 65 yrs or older and 2798 (15%) were 75 yrs or older at randomization. As age increased, event rate increased with KM rates at 7 yrs in the S arm of 30.8% for pts <65 yrs, 39.9% for pts ≥65 yrs, and 47.6% for pts ≥75 yrs. Treatment with EZ/S compared with S resulted in lower event rates in all age groups with an absolute reduction for pts <65 yrs of 0.85% (HR 0.98 CI 0.90-1.05), for pts ≥65 yrs of 3.6% (HR 0.89 CI 0.82-0.96), and for pts ≥75 yrs of 8.7% (HR 0.80 CI 0.70-0.90), with interaction P values of 0.09 and 0.005, respectively. Using age as a continuous variable found event rates for EZ/S vs. S were always lower, but the test for interaction between age and treatment effect for the primary endpoint was non-significant (P=0.15). The rate of gallbladder, liver, and muscle-related adverse events was not increased with EZ/S vs. S among older pts or younger pts. Conclusions: In the IMPROVE-IT trial, pts 65 yrs or older and especially pts 75 yrs or older after ACS derived substantial benefit from higher-intensity lipid lowering therapy with EZ/S compared with S alone, with no increase in safety issues among older age subgroups. These results may have implications for guideline recommendations regarding more intensive lipid lowering in the elderly.

Background: Statins have been demonstrated to reduce ischemic stroke. Intensive therapy with ezetimibe/simvastatin (E/S) in IMPROVE-IT significantly reduced the occurrence of cardiovascular events in patients post ACS compared to placebo/simvastatin (S). We evaluated the effect of E/S vs S on stroke outcomes. Methods: We determined the KM-rate of stroke, by type,during the median 6 year follow-up in 18,144 patients treated with E/S vs S in the IMPROVE-IT trial. Stroke was adjudicated and divided into non-hemorrhagic (NH), hemorrhagic (H), or unknown (U) by a blinded clinical event committee. Stroke reductions were adjusted to absolute change in LDL-C for comparison to prior studies. Results: There were 641 (3.5%) subjects with stroke during follow up, including 533 non-hemorrhagic, 102 hemorrhagic, and 14 unknown strokes. Overall, stroke tended to be reduced with E/S (4.2 vs 4.8%; HR 0.86, CI 0.73-1.00, p=0.052), with a significant reduction of NH stroke (3.4 vs 4.1%; HR 0.79, CI 0.67-0.94, p=0.008, Figure), but a numerical increase in H stroke (0.8 vs 0.6%; HR 1.38, CI 0.93-2.04, p=0.11, Figure). Results were similar when NH/U strokes were combined. When adjusted for LDL reduction, the NH stroke reduction appears to be similar to greater than the extent previously reported with statin therapy alone (figure). Reductions in NH strokes were consistent across major demographic and lipid subgroups. Of note, in 1071 patients with prior stroke or TIA, a known high-risk group, the absolute benefit of E/S was particularly marked for NH strokes; 9.9vs 14.7% (HR 0.61 (0.41-0.91, NNT 21), though benefit remained in those without prior stroke 3.1 vs 3.5% (HR 0.84, CI 0.70-1.01, NNT 250, Pint=0.16). No difference in hemorrhagic stroke was noted in either group. Conclusions: Lipid lowering therapy with E/S was superior to S in the incidence of non-hemorrhagic stroke through a median of 6 years; there was a large absolute benefit in patients with prior stroke or TIA.

Dr. Toth has served on the speakers bureau for Abbvie, Amarin, AstraZeneca, Merck, Kowa, and is a consultant to Amgen, AstraZeneca, Genzyme, Kowa, and Merck. None

Background The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is evaluating the potential benefit for reduction in major cardiovascular (CV) events from the addition of ezetimibe versus placebo to 40 mg/d of simvastatin therapy in patients who present with acute coronary syndromes and have low-density lipoprotein cholesterol (LDL-C) <= 125 mg/dL.Methods The primary composite end point is CV death, nonfatal myocardial infarction (MI), nonfatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization (>= 30 days postrandomization). The simvastatin monotherapy arm's LDL-C target is <70 mg/dL. Ezetimibe was assumed to further lower LDL-C by 15 mg/dL and produce an estimated similar to 8% to 9% treatment effect. The targeted number of events is 5,250.Results We enrolled 18,144 patients with either ST-segment elevation MI (STEMI, n = 5,192) or UA/non-ST-segment elevation MI (UA/NSTEMI, n = 12,952) from October 2005 to July 2010. Western Europe (40%) and North America (38%) were the leading enrolling regions. The STEMI cohort was younger and had a higher percentage of patients naive to lipid-lowering treatment compared with the UA/NSTEMI cohort. The UA/NSTEMI group had a higher prevalence of diabetes, hypertension, and prior MI. Median LDL-C at entry was 100 mg/dL for STEMI and 93 mg/dL for UA/NSTEMI patients.Conclusions This trial is evaluating LDL-C lowering beyond previously targeted LDL-C levels. The results depend on achieving the desired separation of LDL-C with ezetimibe and on the assumption that ezetimibe's lowering of LDL-C will have similar event reduction efficacy as the LDL-C lowering from a statin. The results could affect future therapies and guidelines.

Dr. Toth has served on the speaker's bureau for Abbvie, Amarin Corp., AstraZeneca, Genzyme, Kowa Pharmaceuticals America, and Merck & Co. Dr. Toth has been a consultant to Amgen, Atherotech, Kowa Pharmaceuticals America, LipoScience Inc., and Merck & Co.

The risk of death due to heart disease and stroke is up to four times higher in individuals with diabetes compared to individuals without diabetes. Most guidelines that address treatment of dyslipidemia in patients with diabetes consider diabetes a cardiovascular disease (CVD) "risk equivalent" and recommend intensive treatment of dyslipidemia for the purpose of CVD prevention. Statins (3-hydroxy 3-methylglutaryl coenzyme A reductase [HMG-CoA reductase] inhibitors) are first-line agents in achieving lipid goals as an adjunct to diet and exercise and should be used in most patients. In addition to lipid management and blood pressure control, glycemic control is a basic component in the management of diabetes. Glycemic control is achieved by combining diabetes self-management education, diet and exercise, and, where required, antihyperglycemic agents (OHAs). Persistence and adherence to therapy are critical in achieving recommended treatment goals. However, overall compliance with concomitantly prescribed OHAs and statins is low in patients with type 2 diabetes. Fixed-dose combination (FDC) therapies have been shown to improve adherence by reducing pill burden, the complexity of treatment regimen, and, potentially, cost. Based on the available evidence regarding the pharmacokinetics and the efficacy and safety profiles of each component drug, the sitagliptin/simvastatin FDC may provide a rational and well-tolerated approach to achieving better adherence to multiple-drug therapy and improved lipid lowering and glycemic control, with consequent reduction in cardiovascular risk, diabetic microvascular disease, and mortality in diabetic patients for whom treatment with both compounds is appropriate.

Objective: Reverse cholesterol transport (RCT) can be defined as a pathway of flux of cholesterol from peripheral tissues to the liver for potential excretion into feces. This prospective, placebo-controlled, double-blind crossover study assessed the effect of ezetimibe on several RCT parameters in hyperlipidemic patients.Methods: Following 7 weeks of treatment (ezetimibe 10 mg/day or placebo), 26 patients received 24-h continuous IV infusions of [3,4-C-13(2)]-cholesterol, then took heavy water ((H2O)-H-2) by mouth. Cholesterol excretion was measured by quantification of neutral/acid sterols in stool and blood samples during 7 days post-infusion with continued treatment. Plasma de novo cholesterol synthesis was assessed by H-2-labeling from (H2O)-H-2.Results: Ezetimibe significantly reduced levels of low-density lipoprotein cholesterol (22%, P < 0.001) without significant changes in triglycerides and high-density lipoprotein cholesterol and significantly increased the flux of plasma-derived cholesterol into fecal neutral sterols by 52% (P = 0.04) without change in flux into fecal bile acids. Total fecal neutral sterol output increased by 23% (P = 0.02). Plasma de novo cholesterol synthesis increased by 57% (P < 0.001). The fractional clearance rate (FCR) of plasma cholesteryl-ester trended higher (7%; P = 0.055) with a reduction in absolute cholesteryl-ester production rate (9%, P < 0.01). Whole-body free cholesterol efflux rate from extra-hepatic tissues into plasma was not measurably changed by ezetimibe.Conclusion: Ezetimibe treatment approximately doubled the flux of plasma-derived cholesterol into fecal neutral sterols, in association with increases in total fecal neutral sterol excretion, FCR of plasma cholesterol ester, and plasma de novo cholesterol synthesis. These effects are consistent with increased cholesterol transport through the plasma compartment and excretion from the body, in response to ezetimibe treatment in hyperlipidemic humans.Clintrials.gov: NCT00701727. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Objectives To evaluate the lipid-altering efficacy and safety of ezetimibe monotherapy in young children with heterozygous familial hypercholesterolemia (HeFH) or nonfamilial hypercholesterolemia (nonFH).Study design One hundred thirty-eight children 6-10 years of age with diagnosed HeFH or clinically important nonFH (low-density lipoprotein cholesterol [LDL-C] >= 160 mg/dL [4.1 mmol/L]) were enrolled into a multicenter, 12-week, randomized, double-blind, placebo-controlled study. Following screening/drug washout and a 5-week single-blind placebo-run-in with diet stabilization, subjects were randomized 2: 1 to daily ezetimibe 10 mg (n = 93) or placebo (n = 45) for 12 weeks. Lipid-altering efficacy and safety were assessed in all treated patients.Results Overall, mean age was 8.3 years, 57% were girls, 80% were white, mean baseline LDL-C was 228 mg/dL (5.9 mmol/L), and 91% had HeFH. After 12 weeks, ezetimibe significantly reduced LDL-C by 27% after adjustment for placebo (P < .001) and produced significant reductions in total cholesterol (21%), nonhigh-density lipoprotein cholesterol (26%), and apolipoprotein B (20%) (P < .001 for all). LDL-C lowering response in sex, race, baseline lipids, and HeFH/nonFH subgroups was generally consistent with overall study results. Ezetimibe was well tolerated, with a safety profile similar to studies in older children, adolescents, and adults.Conclusions Ezetimibe monotherapy produced clinically relevant reductions in LDL-C and other key lipid variables in young children with primary HeFH or clinically important nonFH, with a favorable safety/tolerability profile.

Purpose of review Statin therapy is the mainstay of lipid-lowering therapy; however, many patients, particularly those at high risk, do not achieve sufficient LDL-cholesterol (LDL-C) lowering. Thus, there remains an unmet medical need for more effective and well tolerated lipid-lowering agents. Guidelines recommend combining additional lipid-lowering agents with a complementary mode of action for these patients. One approach to complementing statin therapy is combination with inhibitors that block the intestinal absorption of dietary and biliary cholesterol. This review summarizes what is currently known about intestinal sterol transporters and cholesterol absorption inhibitors (CAIs). Recent findings The only lipid-lowering agent currently available that specifically targets an intestinal sterol transporter ( Niemann-Pick C1-like 1) is the CAI, ezetimibe. It is effective in lowering LDL-C, both when given alone and when combined with a statin. Clinical outcome data with ezetimibe combined with simvastatin have recently become available, and definitive evidence that the incremental LDL-C lowering attributable to the ezetimibe component reduces cardiovascular events beyond simvastatin alone is currently under study. Other novel CAIs have been evaluated based upon the structure and properties of ezetimibe, but none remain in development. Summary Additional lipid-lowering agents are needed to fulfill an unmet medical need for those patients who do not achieve optimal LDL-C goals on statin monotherapy. The inhibition of cholesterol absorption is an important therapeutic strategy to reduce cholesterol levels. Based upon the demonstrated lipid-altering efficacy and safety of ezetimibe, several CAIs have been identified; all to date have been discontinued due to limited efficacy.

Purpose of review Statin therapy is the mainstay of lipid-lowering therapy; however, many patients, particularly those at high risk, do not achieve sufficient LDL-cholesterol (LDL-C) lowering. Thus, there remains an unmet medical need for more effective and well tolerated lipid-lowering agents. Guidelines recommend combining additional lipid-lowering agents with a complementary mode of action for these patients. One approach to complementing statin therapy is combination with inhibitors that block the intestinal absorption of dietary and biliary cholesterol. This review summarizes what is currently known about intestinal sterol transporters and cholesterol absorption inhibitors (CAIs). Recent findings The only lipid-lowering agent currently available that specifically targets an intestinal sterol transporter (Niemann-Pick C1-like 1) is the CAI, ezetimibe. It is effective in lowering LDL-C, both when given alone and when combined with a statin. Clinical outcome data with ezetimibe combined with simvastatin have recently become available, and definitive evidence that the incremental LDL-C lowering attributable to the ezetimibe component reduces cardiovascular events beyond simvastatin alone is currently under study. Other novel CAIs have been evaluated based upon the structure and properties of ezetimibe, but none remain in development. Summary Additional lipid-lowering agents are needed to fulfill an unmet medical need for those patients who do not achieve optimal LDL-C goals on statin monotherapy. The inhibition of cholesterol absorption is an important therapeutic strategy to reduce cholesterol levels. Based upon the demonstrated lipid-altering efficacy and safety of ezetimibe, several CAIs have been identified; all to date have been discontinued due to limited efficacy.

Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin.This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy.All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis.Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005).Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878)