ezetimibe--simvastatin-drug-combination and Myocardial-Infarction

Background Unlike patients with low ejection fraction after an acute coronary syndrome (ACS), little is known about the long-term incidence and influence of cardiovascular events before sudden death among stabilized patients after ACS. Methods and Results A total of 18 144 patients stabilized within 10 days after ACS in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) were studied. Cumulative incidence rates (IRs) and IRs per 100 patient-years of sudden death were calculated. Using Cox proportional hazards, the association of ≥1 additional postrandomization cardiovascular events (myocardial infarction, stroke, and hospitalization for unstable angina or heart failure) with sudden death was examined. Early (≤1 year after ACS) and late sudden deaths (>1 year) were compared. Of 2446 total deaths, 402 (16%) were sudden. The median time to sudden death was 2.7 years, with 109 early and 293 late sudden deaths. The cumulative IR was 2.47% (95% CI, 2.23%-2.73%) at 7 years of follow-up. The risk of sudden death following a postrandomization cardiovascular event (150/402 [37%] sudden deaths; median 1.4 years) was greater (IR/100 patient-years, 1.45 [95% CI, 1.23-1.69]) than the risk with no postrandomization cardiovascular event (IR/100 patient-years, 0.27 [95% CI, 0.24-0.30]). Postrandomization myocardial infarction (hazard ratio [HR], 3.64 [95% CI, 2.85-4.66]) and heart failure (HR, 4.55 [95% CI, 3.33-6.22]) significantly increased future risk of sudden death. Conclusions Patients stabilized within 10 days of an ACS remain at long-term risk of sudden death with the greatest risk in those with an additional cardiovascular event. These results refine the long-term risk and risk effectors of sudden death, which may help clinicians identify opportunities to improve care. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878.

Topics: Acute Coronary Syndrome; Death, Sudden, Cardiac; Ezetimibe, Simvastatin Drug Combination; Heart Failure; Humans; Myocardial Infarction; Risk Factors; Treatment Outcome

IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex.. In IMPROVE-IT, patients with acute coronary syndrome and low-density lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization ≥30 days, and stroke. Among 18 144 patients in IMPROVE-IT, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced low-density lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79-0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90-1.01;. IMPROVE-IT demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid-lowering therapy to optimize cardiovascular outcomes.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878.

Topics: Acute Coronary Syndrome; Aged; Anticholesteremic Agents; Dose-Response Relationship, Drug; Double-Blind Method; Ezetimibe, Simvastatin Drug Combination; Female; Global Health; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Secondary Prevention; Sex Factors; Survival Rate; Treatment Outcome

In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)-reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown.. To assess the safety and clinical efficacy of achieving a very low (<30 mg/dL) level of LDL-C at 1 month using data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.. This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years' median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017.. Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial.. Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30 mg/dL, 30 to 49 mg/dL, 50 to 69 mg/dL, and 70 mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30 mg/dL (median, 25 mg/dL; interquartile range, 21-27 mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a first myocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30 mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P = .001) compared with 70 mg/dL or greater.. Patients achieving an LDL-C level less than 30 mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels.. clinicaltrials.gov Identifier: NCT00202878.

Topics: Acute Coronary Syndrome; Aged; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Double-Blind Method; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Liver Diseases; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Muscular Diseases; Myocardial Infarction; Neoplasms; Patient Care Planning; Practice Guidelines as Topic; Proportional Hazards Models; Rhabdomyolysis; Stroke; Treatment Outcome

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.. Randomized double blind clinical trial in patients with acute coronary syndrome and low cholesterol level. The simvastatin monotherapy arms LDL-C target was < 70 mg/dl, the comparison arm was simvastatin + ezetimibe. Ezetimibe was assumed to further lower LDL-C by 15 mg/dl and produce an estimated ~ 8 % to 9 % treatment effect. The primary composite end point was CV death, nonfatal myocardial infarction (MI), nonfatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization ( 30 days postrandomization). The targeted number of events was 5,250.. 18,144 patients were enroled 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. Primary endpoint occured in 2 742 patients (34.7 %) treated with simvastatin in monotherapy and in 2 572 patients (32.7 %) (p = 0.016) treated with combination. Compared to patients with coronary heart disease given the drug simvastatin plus a placebo, those given both simvastatin and the non-statin drug, ezetimibe, had a 6.4 % lower combined risk of subsequent heart attack, stroke, cardiovascular death, rehospitalization for unstable angina and procedures to restore blood flow to the heart. Heart attacks alone were reduced by 13 %, and non-fatal stroke by 20 %. Deaths from cardiovascular disease were statistically the same in both groups. Patients were followed an average of approximately six years, and some as long as 8.5 years. Approximately 2 patients out of every 100 patients treated for 7 years avoided a heart attack or stroke [Number Needed to Treat (NNT) = 50/7 years].. The study has shown a claer benefit from combination treatment with simvastatin and ezetimibe in patients with acute coronary syndrome and low LDL-C.

Topics: Acute Coronary Syndrome; Aged; Anticholesteremic Agents; Azetidines; Cholesterol, LDL; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Ezetimibe; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Male; Middle Aged; Myocardial Infarction; Simvastatin

The aim of our study was to evaluate the effects of two different statins and a statin/ezetimibe combination on high sensitive C-reactive protein (hsCRP) values, which were given at high doses in the early period of acute coronary syndromes.. A total of 150 patients with non-ST elevation myocardial infarction and unstable angina pectoris were enrolled to our prospective, randomized, single-blind study. Patients were divided into three groups by block randomization method. One group received 20 mg/day atorvastatin, one group received 10 mg/day rosuvastatin and the other group received 10 mg/day ezetimibe/simvastatin combination therapy, which was initiated within the first 24 hours of admission. Follow-up duration was 2 months . Biochemical investigations and hsCRP levels (by nephelometric method) were performed with 138 patients evaluated at baseline, 10th and 60th days of therapy. Decreases of hsCRP levels were analyzed with one-way MANOVA and repeated measures of ANOVA methods. Post-hoc Tukey HSD test was performed for finding the different group, when the difference was detected between the groups.. Tenth day hsCRP levels in ezetimibe/simvastatin group was significantly lower than the other groups (p<0.001). Further, after 60 days of follow-up a significant reduction was seen in hsCRP levels in ezetimib/simvastatin group (in ezetimibe/simvastatin group the mean hsCRP was reduced from 38.4±15.0 mg/L to 2.4±1.3 mg/L, in atorvastatin group the mean hsCRP was reduced from 27.3±11.7 mg/L to 4.1±2.4 mg/L and in rosuvastatin group the mean hsCRP was reduced from 22.0±6.9 mg/L to 3.6±1.7 mg/L (F (1.1, 148.2) = 746.9, p<0.01 and the difference between drugs; F (2.2, 148.2) = 32.1, p<0.01). No side effects related to drugs were seen during follow-up in all three treatment groups.. This study showed that ezetimibe/simvastatin 10 mg/day combination treatment was superior to atorvastatin 20 mg/day and rosuvastatin 10 mg/day treatment in reducing the inflammatory markers when high dose statins was started in the early period of unstable angina and non ST elevation myocardial infarction.

Topics: Angina, Unstable; Atorvastatin; Azetidines; C-Reactive Protein; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Female; Fluorobenzenes; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Simvastatin; Single-Blind Method; Sulfonamides; Treatment Outcome

Patients with heterozygous familial hypercholesterolemia (FH) have an increased risk of premature myocardial infarction, stroke, and surgical revascularization, and an increased rate of progression of carotid intima-media thickness (IMT). The most commonly used drugs for cholesterol lowering, statins, have a limited action in these patients. Ezetimibe, a novel compound, selectively inhibits cholesterol uptake and when associated with statins has an additional low-density lipoprotein cholesterol (LDL-C) reducing effect. The aim of this study is to evaluate the effects of long-term combined Ezetimibe/Simvastatin (EZE/SIMVA) therapy (30 months) on the lipidic pattern, inflammatory markers, and carotid IMT in patients with FH subdivided into two groups: one with a history of acute myocardial infarction (IMA) and the other with carotid atherosclerotic plaques but no history of cardiovascular events.. All patients enrolled in this study (group A: patients with a history of IMA; group B, patients with carotid lesions but no history of cardiovascular events) were submitted to a 6-week period of isocaloric diet and to a 4-week lipid-lowering wash-out period before study entry. After the wash-out period at baseline (time 0) and then every two months total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B and A1 were determined. LDL-C levels were calculated. Fibrinogen and hs-CRP at baseline and at 6, 18, and 30 months were determined. All patients were submitted to an ultrasonographic evaluation of the carotid intima-media thickness at baseline, 18 and 30 months. The scheduled duration time of the study was 30 months. At the beginning of the study all patients were assigned to receive the combined EZE/SIMVA treatment 10/20 mg per day. After two months, patients who had not reached the respective LDL-C targets proposed by NCEP ATPIII (<70 mg/dL for patients with a history of IMA and <100 mg/dL for patients with carotid lesions) were assigned to receive EZE/SIMVA 10/40 mg per day and, after four months, patients who had not reached the respective LDL-C targets were assigned to receive EZE/SIMVA 10/80 mg per day.. At the end-point, significant reductions (P<0.001) of about 70% in LDL-C, of 57% in total cholesterol (TC), of 46% in Apo-B, and of 46% in hs-C-reactive protein (hs-CRP) were observed in both groups compared to baseline. Also, triglyceride and fibrinogen levels were significantly (P<0.01) reduced, respectively by 26% and 15% compared to baseline. The EZE/SIMVA association resulted in significant increases in HDL-C (P<0.01) of 11% and in Apo-A1 (P<0.05) by 9% and in significant (P<0.001) reductions of the mean of the carotid IMT in both groups. The EZE/SIMVA treatment was generally well-tolerated, with a safety profile on laboratory parameters. During the 30-month scheduled period of the study, no patient in either group presented any further cardiovascular events.. In patients with FH, combined EZE/SIMVA treatment resulted in a significant LDL-C lowering, achieving the goals proposed by NCEP ATP III, in a significant improvement of all the lipidic and inflammatory patterns, and above all in a progressive decrease of the carotid IMT. Although the results of ongoing randomized controlled trials are required before making any definitive conclusions, our results support the hypothesis of stabilizing effect of EZE/SIMVA on the atherosclerotic disease both in primary and in secondary prevention.

Topics: Aged; Analysis of Variance; Anticholesteremic Agents; Apolipoprotein A-I; Apolipoproteins B; Azetidines; Biomarkers; C-Reactive Protein; Carotid Artery Diseases; Cholesterol; Cholesterol, HDL; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Female; Fibrinogen; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Inflammation Mediators; Italy; Male; Middle Aged; Myocardial Infarction; Primary Prevention; Secondary Prevention; Simvastatin; Time Factors; Treatment Outcome; Triglycerides; Ultrasonography

To determine all-cause mortality in patients with a first myocardial infarct who were treated with simvastatin compared with high-potency statin and simvastatin/ezetimibe combination.. Despite statin use, residual cardiovascular risk remains. Therapeutic options include more potent statins or addition of ezetimibe. There is no clinical outcome data on the use of ezetimibe in such patients.. Retrospective longitudinal study using the United Kingdom General Practice Research Database. Patients who had survived 30 days after their first acute myocardial infarct (AMI), had not received prior statin or ezetimibe therapy and were started on a statin within 30 days of AMI were included. Three groups were identified according to their follow-up: (i) simvastatin monotherapy; (ii) high-potency statin group (patients who started on simvastatin and switched to atorvastatin or rosuvastatin); and (iii) ezetimibe/statin combination group (patients who received ezetimibe in addition to statin).. 9597 patients (57% male, mean age of 65 ± 13 years) matched study criteria: simvastatin (n=6990 (72.8%)); high-potency statin (n=1883, (19.6%)); and ezetimibe/statin combination (n=724 (7.5%)). During a mean follow-up of 3.2 years, there were 1134 (12%) deaths. In the multivariate proportional hazards model, the adjusted HR for high-potency statin and ezetimibe group were 0.72 (95% CI 0.59 to 0.88, p<0.001) and 0.96 (95% CI 0.64 to 1.43, p=0.85), respectively. A similar result was also obtained in the propensity score analysis that took into account covariates that predicted drug treatment groups.. Patients switched to a high-potency statin had a significantly reduced mortality compared with simvastatin monotherapy. There was no observed mortality benefit in the ezetimibe group.

Topics: Aged; Azetidines; Drug Combinations; Drug Therapy, Combination; Ezetimibe, Simvastatin Drug Combination; Female; Follow-Up Studies; Humans; Lipids; Male; Middle Aged; Myocardial Infarction; Population Surveillance; Retrospective Studies; Simvastatin; Survival Rate; Survivors; Time Factors; Treatment Outcome; United Kingdom

Topics: Azetidines; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Lipids; Male; Myocardial Infarction; Population Surveillance; Simvastatin; Survivors

Topics: Anticholesteremic Agents; Atorvastatin; Azetidines; Cholesterol, LDL; Cost-Benefit Analysis; Drug Combinations; Drug Costs; Ezetimibe; Ezetimibe, Simvastatin Drug Combination; Financing, Personal; Fluorobenzenes; Germany; Heptanoic Acids; Humans; Hydroxymethylglutaryl CoA Reductases; Myocardial Infarction; National Health Programs; Pyrimidines; Pyrroles; Rosuvastatin Calcium; Secondary Prevention; Simvastatin; Sulfonamides