Philippe Brudi

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

BACKGROUND Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. METHODS We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. RESULTS During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). CONCLUSIONS Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.)

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction The Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Lipid‐altering efficacy of ezetimibe/simvastatin 10/20 mg compared with rosuvastatin 10 mg in high‐risk hypercholesterolaemic patients inadequately controlled with prior statin monotherapy – The IN‐CROSS study

Aims:  To evaluate the efficacy of switching from a previous statin monotherapy to ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg vs. rosuvastatin (ROSUVA) 10 mg.

Lipid-altering efficacy and safety profile of combination therapy with ezetimibe/statin vs. statin monotherapy in patients with and without diabetes: an analysis of pooled data from 27 clinical trials

Aim: This post hoc analysis compared the lipid‐altering efficacy and safety of ezetimibe 10 mg plus statin (EZE/statin) vs. statin monotherapy in hypercholesterolaemic patients with and without diabetes.

Impact of Baseline Severity of Aortic Valve Stenosis on Effect of Intensive Lipid Lowering Therapy (from the SEAS Study)

Retrospective studies have suggested a beneficial effect of lipid-lowering treatment on the progression of aortic stenosis (AS) in milder stages of the disease. In the randomized, placebo-controlled Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, 4.3 years of combined treatment with simvastatin 40 mg and ezetimibe 10 mg did not reduce aortic valve events (AVEs), while ischemic cardiovascular events (ICEs) were significantly reduced in the overall study population. However, the impact of baseline AS severity on treatment effect has not been reported. Baseline and outcomes data in 1,763 SEAS patients (mean age 67 years, 39% women) were used. The study population was divided into tertiles of baseline peak aortic jet velocity (tertile 1: ≤ 2.8 m/s; tertile 2: > 2.8 to 3.3 m/s; tertile 3: > 3.3 m/s). Treatment effect and interaction were tested in Cox regression analyses. The rates of AVEs and ICEs increased with increasing baseline severity of AS. In Cox regression analyses, higher baseline peak aortic jet velocity predicted higher rates of AVEs and ICEs in all tertiles (all p values < 0.05) and in the total study population (p < 0.001). Simvastatin-ezetimibe treatment was not associated with a statistically significant reduction in AVEs in any individual tertile. A significant quantitative interaction between the severity of AS and simvastatin-ezetimibe treatment effect was demonstrated for ICEs (p < 0.05) but not for AVEs (p = 0.10). In conclusion, the SEAS study results demonstrate a strong relation between baseline the severity of AS and the rate of cardiovascular events but no significant effect of lipid-lowering treatment on AVEs, even in the group with the mildest AS.

Lipid-altering efficacy of ezetimibe⁄simvastatin 10⁄40 mg compared with doubling the statin dose in patients admitted to the hospital for a recent coronary event: the INFORCE study

Background:  The aim of this study was to investigate the efficacy and safety profile of switching to ezetimibe/simvastatin (Eze/Simva) 10/40 mg compared with doubling the statin dose upon discharge in patients taking a statin and admitted to the hospital for the investigation of a coronary event.

Results of the Dyslipidemia International Study (DYSIS)-Middle East: Clinical Perspective on the Prevalence and Characteristics of Lipid Abnormalities in the Setting of Chronic Statin Treatment

Background Therapeutic intervention with low-density lipoprotein cholesterol-lowering agents known as statins has been demonstrated to reduce cardiovascular risk. However, many patients on statin treatment have persistent dyslipidemia and remain at a high risk of cardiovascular disease. Therefore, the objective of this study was to assess the frequency of lipid abnormalities in patients receiving chronic statin treatment. Methods As part of an international, cross-sectional, observational study, DYSIS-Middle East enrolled 2,182 patients in the United Arab Emirates (UAE), Saudi Arabia, Lebanon and Jordan. All patients were over 45 years of age and had been on statin treatment for at least three months. Data on demographics, lipid parameters and cardiovascular risk profile were recorded. Cardiovascular risk was defined according the guidelines of the European Society of Cardiology. Results The majority of patients (82.6%) were classified as being at very high risk of cardiovascular events, and 61.8% of all patients did not attain LDL-C target levels. Low high-density lipoprotein cholesterol levels and elevated triglyceride levels were noted in 55.5% and 48.5% of patients, respectively. Multivariate logistical regression modeling indicated that factors independently associated with LDL-C levels not being at goal were lifestyle choices, diabetes mellitus, ischemic heart disease, and blood pressure ≥ 140/90 mmHg. Conclusions Almost two-thirds of statin-treated patients in the United Arab Emirates, Saudi Arabia, Lebanon and Jordan had inadequately controlled lipid levels. More comprehensive surveillance, awareness and treatment regimens, as well as modification of lifestyle choices, is necessary to halt the rise in cardiovascular disease-related mortality.

A comparison of efficacy and safety of an ezetimibe/simvastatin combination compared with other intensified lipid-lowering treatment strategies in diabetic patients with symptomatic cardiovascular disease

The low-density lipoprotein cholesterol (LDL-C) lowering efficacy of switching to ezetimibe/simvastatin (EZ/S) 10/20 mg versus doubling the run-in statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg in subjects with cardiovascular disease (CVD) and diabetes was assessed. Endpoints included percentage change in LDL-C and percentage of patients achieving LDL-C <70 mg/dL. Significantly greater reductions in LDL-C occurred when switching to EZ/S versus statin doubling in the overall population and in subjects treated with simvastatin 20 mg or atorvastatin 10 mg (all p < 0.001). The LDL-C reduction was numerically greater when switching to EZ/S versus switching to rosuvastatin (p = 0.060). Significantly more subjects reached LDL-C <70 mg/dL with EZ/S (54.5%) versus statin doubling (27.0%) or rosuvastatin (42.5%) in the overall population (all p < 0.001) and within each stratum (all p < 0.001). Switching to EZ/S provided significantly greater reductions in LDL-C versus statin doubling and significantly greater achievement of LDL-C targets versus statin doubling or switching to rosuvastatin.

Achievement of recommended lipid and lipoprotein levels with combined ezetimibe/statin therapy versus statin alone in patients with and without diabetes

Treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy with secondary targets of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB). Data were pooled from 27 randomised, double-blind, active or placebo-controlled trials in 21,794 adult hypercholesterolaemic patients (LDL-C 1.81—6.48 mmol/L) receiving ezetimibe/statin or statin for 4—24 weeks. Percentages of patients achieving various targets were calculated among diabetes (n = 6541) and non-diabetes (n = 15,253) subgroups. Significantly more patients with and without diabetes achieved specified levels of LDL-C (< 2.59, < 1.99, < 1.81 mmol/L), non-HDL-C (< 3.37, < 2.59 mmol/L) and apoB (< 0.9, < 0.8 g/L) with ezetimibe/statin versus statin. Patients with diabetes had larger mean per cent reductions in LDL-C and non-HDL-C than non-diabetes patients. A greater percentage of patients achieved both the LDL-C and apoB targets and all three LDL-C, apoB, and non-HDL-C targets with ezetimibe/statin versus statin in both subgroups. Patients with diabetes benefitted at least as much as, and sometimes more than, non-diabetes patients following treatment with ezetimibe/statin.