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      Simvastatin with or without ezetimibe in familial hypercholesterolemia.

      The New England journal of medicine

      pathology, Adult, Tunica Media, ultrasonography, Tunica Intima, blood, Triglycerides, Treatment Outcome, therapeutic use, adverse effects, Simvastatin, Middle Aged, Male, drug therapy, Hyperlipoproteinemia Type II, Humans, Femoral Artery, Female, Drug Therapy, Combination, Double-Blind Method, Cholesterol, LDL, Cholesterol, Carotid Arteries, Azetidines, Anticholesteremic Agents

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          Abstract

          Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].). Copyright 2008 Massachusetts Medical Society.

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          Most cited references 26

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          Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study.

          Noninvasive assessment of intima-media thickness (IMT) is widely used in observational studies and trials as an intermediate or proxy end point for cardiovascular disease. However, data showing that IMT predicts cardiovascular disease are limited. We studied whether common carotid IMT is related to future stroke and myocardial infarction. We used a nested case-control approach among 7983 subjects aged > or =55 years participating in the Rotterdam Study. At baseline (March 1990 through July 1993), ultrasound images of the common carotid artery were stored on videotape. Determination of incident myocardial infarction and stroke was predominantly based on hospital discharge records. Analysis (logistic regression) was based on 98 myocardial infarctions and 95 strokes that were registered before December 31, 1994. IMT was measured from videotape for all case subjects and a sample of 1373 subjects who remained free from myocardial infarction and stroke during follow-up. The mean duration of follow-up was 2.7 years. Results were adjusted for age and sex. Stroke risk increased gradually with increasing IMT. The odds ratio for stroke per standard deviation increase (0.163 mm) was 1.41 (95% CI, 1.25 to 1.82). For myocardial infarction, an odds ratio of 1.43 (95% CI, 1.16 to 1.78) was found. When subjects with a previous myocardial infarction or stroke were excluded, odds ratios were 1.57 (95% CI, 1.27 to 1.94) for stroke and 1.51 (95% CI, 1.18 to 1.92) for myocardial infarction. Additional adjustment for several cardiovascular risk factors attenuated these associations: 1.34 (95% CI, 1.08 to 1.67) and 1.25 (95% CI, 0.98 to 1.58), respectively. The present study, based on a short follow-up period, provides evidence that an increased common carotid IMT is associated with future cerebrovascular and cardiovascular events.
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            High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.

            Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol (LDL-C) than is commonly applied clinically will provide further benefit in stable coronary artery disease. To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI). The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at 190 ambulatory cardiology care and specialist practices in northern Europe between March 1999 and March 2005 with a median follow-up of 4.8 years, which enrolled 8888 patients aged 80 years or younger with a history of acute MI. Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d; n = 4439), or usual-dose simvastatin (20 mg/d; n = 4449). Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07). Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71-0.98; P = .02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% CI, 0.76-0.91; P<.001). Noncardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% CI, 0.73-1.15; P = .47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85-1.13; P = .81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P<.001). Serious myopathy and rhabdomyolysis were rare in both groups. In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.Trial Registration ClinicalTrials.gov Identifier: NCT00159835.
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              The safety of statins in clinical practice.

               Jane Armitage (2007)
              Statins are effective cholesterol-lowering drugs that reduce the risk of cardiovascular disease events (heart attacks, strokes, and the need for arterial revascularisation). Adverse effects from some statins on muscle, such as myopathy and rhabdomyolysis, are rare at standard doses, and on the liver, in increasing levels of transaminases, are unusual. Myopathy--muscle pain or weakness with blood creatine kinase levels more than ten times the upper limit of the normal range--typically occurs in fewer than one in 10,000 patients on standard statin doses. However, this risk varies between statins, and increases with use of higher doses and interacting drugs. Rhabdomyolysis is a rarer and more severe form of myopathy, with myoglobin release into the circulation and risk of renal failure. Stopping statin use reverses these side-effects, usually leading to a full recovery. Asymptomatic increases in concentrations of liver transaminases are recorded with all statins, but are not clearly associated with an increased risk of liver disease. For most people, statins are safe and well-tolerated, and their widespread use has the potential to have a major effect on the global burden of cardiovascular disease.
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                Author and article information

                Journal
                10.1056/NEJMoa0800742
                18376000

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