Benefit of Combination Ezetimibe/Simvastatin Among High-Risk Populations: Lessons from the IMPROVE-IT Trial.

PURPOSE OF REVIEW: The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) demonstrated the clinical benefit of the combination of ezetimibe-simvastatin compared to placebo-simvastatin following acute coronary syndrome (ACS). This review highlights key findings from this study with particular attention to the practice-changing impact on guidelines for low-density lipoprotein cholesterol (LDL-C) reduction after ACS, especially among high-risk populations. RECENT FINDINGS: Consistent reductions in LDL-C have been reported with newer lipid-lowering therapies (proprotein convertase subtilisin/kexin type 9 inhibitors, cholesterol ester transfer proteins, bempedoic acid) in combination with statin in high-risk subgroups. Since high-risk subgroups remain a focus of guidelines, exploration of high-risk subgroups can help define the optimal use of new therapies. Ezetimibe reduced the LDL-C by 16.7 mg/dL compared to placebo at 1 year, resulting in a significant reduction in the primary composite endpoint (absolute risk difference 2.0%; relative risk difference 6.4%, hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). The benefits achieved with ezetimibe in both LDL-C reduction and the primary clinical composite across 10 pre-specified high-risk subgroups, including the elderly; women; patients with diabetes, prior coronary artery bypass graft, history of stroke, polyvascular disease, low baseline LDL-C, renal dysfunction, prior heart failure, and an elevated TIMI risk score for secondary prevention, were similar or greater than in the corresponding non-high-risk subgroups. Safety events were similar between ezetimibe and placebo across the high-risk subgroups. These data support the addition of ezetimibe to statin therapy in high-risk patients who require additional therapy to lower the LDL-C post-ACS.

Association of Serial High-Sensitivity Cardiac Troponin T With Subsequent Cardiovascular Events in Patients Stabilized After Acute Coronary Syndrome: A Secondary Analysis From IMPROVE-IT.

Importance: Studies have demonstrated an association between single measures of high-sensitivity troponin (hsTn) and future cardiovascular events in patients with chronic coronary syndromes. However, limited data exist regarding the association between changes in serial values of hsTn and subsequent cardiovascular events in this patient population. Objective: To evaluate the association between changes in high-sensitivity troponin T (hsTnT) and subsequent cardiovascular events in patients stabilized after acute coronary syndrome (ACS). Design, Setting, and Participants: This is a secondary analysis from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), a randomized clinical trial of ezetimibe vs placebo on a background of simvastatin in 18 144 patients hospitalized for an ACS across 1147 sites in 39 countries. The current biomarker substudy includes the 6035 participants consenting to the biomarker substudy with available hsTnT at months 1 and 4. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed from February 28, 2021, through August 14, 2022. Main Outcomes and Measures: The outcomes of interest were cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure (HHF). Associations of absolute and relative changes in hsTnT between month 1 and month 4 as a function of the starting month 1 hsTnT and the composite outcome were examined using landmark analyses. Results: Of 6035 patients in this analysis (median [IQR] age, 64 [57-71]), 1486 (24.6%) were female; 361 (6.0%) were Asian; 121 were (2.0%) Black; 252 (4.2%) were Spanish descent; 4959 were (82.2%) White; and 342 (5.7%) reported another race (consolidated owing to small numbers), declined to respond, or were not asked to report race owing to regulatory prohibitions. Most patients (4114 [68.2%]) had stable hsTnT values (change <3 ng/L), with 1158 (19.2%) and 763 (12.6%) having changes of 3 to less than 7 ng/L and 7 ng/L or more, respectively. After adjustment for clinical risk factors and stratification by the starting month 1 hsTnT level, an absolute increase in hsTnT of 7 ng/L or more was associated with a more than 3-fold greater risk of the composite outcome (adjusted hazard ratio [aHR], 3.33; 95% CI, 1.99-5.57; P < .001), whereas decreases of 7 ng/L or more were associated with similar to lower risk (aHR, 0.51; 95% CI, 0.26-1.03; P = .06) compared with stable values. There was a stepwise association moving from larger absolute decreases (aHR, 0.51; 95% CI, 0.26-1.03) to larger absolute increases (aHR, 3.33; 95% CI, 1.99-5.57) in hsTnT with future risk of the composite outcome (P trend <.001). A similar association was observed when analyzed on the basis of relative percent and continuous change. Conclusions and Relevance: Among stable patients post-ACS, changes in hsTnT were associated with a gradient of risk of subsequent cardiovascular events across the range of starting hsTnT values. Serial assessment of hsTnT may refine risk stratification with the potential to guide therapy decisions in this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT00202878.

Similar major cardiovascular outcomes between pure statin and ezetimibe-statin in comparable intensity for type 2 diabetes with extremely atherosclerotic risks.

Atorvastatin 40 mg (ATOR 40) and ezetimibe 10 mg/simvastatin 20 mg (EZ-SIM 20) have similar reductions of low-density lipoprotein cholesterol (LDL-C) but cardiovascular (CV) outcomes between these two therapies are unclear. Our real-world cohort study is to test the hypothesis of pleiotropic effects of purely higher dose statin on CV outcomes beyond similar reductions of LDL-C, especially for extremely CV risk patients. Between January 1, 2007 and December 31, 2013, a total of 3,372 patients with type 2 diabetes mellitus (T2DM) admitted due to acute coronary syndrome (ACS) or acute ischemic stroke (AIS) were selected as the study cohort from the Taiwan National Health Insurance Research Database. Clinical outcomes were evaluated by ATOR 40 group (n = 1686) matched with EZ-SIM 20 group (n = 1686). Primary composite outcome includes CV death, non-fatal myocardial infarction, and non-fatal stroke. Secondary composite outcome includes hospitalization for unstable angina (HUA), percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). With a mean follow-up of 2.4 years, no significant difference of primary composite outcome was observed between ATOR 40 and EZ-SIM 20 groups (subdistribution hazard ratio [SHR], 1.09; 95% confidence interval [CI], 0.95-1.25). Nevertheless, ATOR 40 group had lower risks of HUA (SHR, 0.50; 95% CI, 0.35-0.72), PCI (SHR, 0.82; 95% CI, 0.69-0.97) and CABG (SHR, 0.62; 95% CI, 0.40-0.97) than EZ-SIM 20 group. For T2DM patients after ACS or AIS, ATOR 40 and EZ-SIM 20 had similar major CV outcomes, which still supported the main driver for CV risk reductions is LDL-C lowering.

Aortic valvular stenosis: Novel therapeutic strategies.

BACKGROUND: Aortic stenosis (AS) prevalence is estimated to reach 4.5 million cases worldwide by the year 2030. AS is a progressive disease without a pharmacological treatment. In the current review, we aimed to investigate novel therapeutic approaches for non-surgical AS treatment, at least in patients with mild-to-moderate AS. MATERIALS AND METHODS: The most recent and relevant papers concerned with novel molecular pathways that have potential as therapeutic targets in AS were selected from searches of PubMed and Web of Science up to February 2021. RESULTS: Growing evidence indicates that therapies using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, simvastatin/ezetimibe combination, cholesteryl ester transfer protein inhibitors or antisense oligonucleotides targeting apolipoprotein(a) reduce the risk of AS progression. It has been shown that enhanced valvular lipid oxidation may drive AS development by leading to the activation of valvular interstitial cells (VICs), the most abundant valvular cells having a major contribution to valve calcification. Since VICs are able to release pro-inflammatory cytokines, clotting factors and proteins involved in calcification, strategies targeting these cell activations seem promising as therapeutic interventions. Recently, non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to inhibit activation of VICs. CONCLUSION: Several novel molecular pathways of AS development have been identified over the past few years. Therapies using PCSK9 inhibitors, simvastatin/ezetimibe combination, lipoprotein(a)-lowering therapy are highly promising candidates as therapeutics in the prevention of mild AS progression, while preclinical studies show that NOACs may inhibit valvular inflammation and coagulation activation and slower the rate of AS progression.

Frequency and Impact of Hyponatremia on All-Cause Mortality in Patients With Aortic Stenosis.

Asymptomatic aortic stenosis (AS) is a frequent condition that may cause hyponatremia due to neurohumoral activation. We examined if hyponatremia heralds poor prognosis in patients with asymptomatic AS, and whether AS in itself is associated with increased risk of hyponatremia. The study question was investigated in 1,677 individuals that had and annual plasma sodium measurements in the SEAS (Simvastatin and Ezetimibe in AS) trial; 1,873 asymptomatic patients with mild-moderate AS (maximal transaortic velocity 2.5 to 4.0 m/s) randomized to simvastatin/ezetimibe combination versus placebo. All-cause mortality was the primary endpoint and incident hyponatremia (P-Na+ <137 mmol/L) a secondary outcome. At baseline, 4% (n = 67) had hyponatremia. After a median follow-up of 4.3 (interquartile range 4.1 to 4.6) years, 140 (9%) of those with initial normonatremia had developed hyponatremia, and 174 (10%) had died. In multiple regression Cox models, both baseline hyponatremia (hazard ratio [HR] 2.1, [95% confidence interval 1.1 to 3.8]) and incident hyponatremia (HR 1.9, [95% confidence interval 1.0 to 3.4], both p ≤ .03) was associated with higher all-cause mortality as compared with normonatremia. This association persisted after adjustment for diuretics as a time-varying covariate. Higher N-terminal pro b-type natriuretic peptide levels and lower sodium levels at baseline was associated with higher risk of incident hyponatremia. Conversely, assignment to simvastatin/ezetimibe protected against incident hyponatremia. In conclusion, both prevalent and incident hyponatremia associate with increased mortality in patients with AS. The prevalence of hyponatremia is around 4% and the incidence about 2% per year, which is comparable to that of older adults without AS.

Apolipoprotein B, Triglyceride-Rich Lipoproteins, and Risk of Cardiovascular Events in Persons with CKD.

BACKGROUND AND OBJECTIVES: Triglyceride-rich lipoproteins may contribute to the high cardiovascular risk of patients with CKD. This study evaluated associations of apo-B and markers of triglyceride-rich lipoproteins with cardiovascular events in people with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Analyses were conducted in 9270 participants with CKD in the Study of Heart and Renal Protection (SHARP): 6245 not on dialysis (mean eGFR 26.5 ml/min per 1.73 m2), and 3025 on dialysis when recruited. Cox regression methods were used to evaluate associations of lipids with incident atherosclerotic and nonatherosclerotic vascular events, adjusting for demographics and clinical characteristics. Hazard ratios (HRs) were calculated per 1 SD higher level for apo-B, HDL cholesterol, LDL cholesterol, triglyceride-rich lipoprotein cholesterol (i.e., total cholesterol minus LDL cholesterol minus HDL cholesterol), non-HDL cholesterol, log triglyceride, and log ratio of triglyceride to HDL cholesterol. RESULTS: During a median follow-up of 4.9 years (interquartile range, 4.0-5.5 years), 1406 participants experienced at least one atherosclerotic vascular event. In multivariable adjusted models, positive associations with atherosclerotic vascular events were observed for apo-B (HR per 1 SD, 1.19; 95% confidence interval, 1.12 to 1.27), triglycerides (1.06; 1.00 to 1.13), the ratio of triglyceride to HDL cholesterol (1.10; 1.03 to 1.18), and triglyceride-rich lipoprotein cholesterol (1.14; 1.05 to 1.25). By contrast, inverse associations with nonatherosclerotic vascular events were observed for each of these lipid markers: apo-B (HR per 1 SD, 0.92; 0.85 to 0.98), triglycerides (0.86; 0.81 to 0.92), the ratio of triglyceride to HDL cholesterol (0.88; 0.82 to 0.94), and triglyceride-rich lipoprotein cholesterol (0.85; 0.77 to 0.94). CONCLUSIONS: Higher apo-B, triglycerides, ratio of triglyceride to HDL cholesterol, and triglyceride-rich lipoprotein cholesterol concentrations were associated with increased risk of atherosclerotic vascular events in CKD. Reducing triglyceride-rich lipoproteins using novel therapeutic agents could potentially lower the risk of atherosclerotic cardiovascular disease risk in the CKD population.

Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Limited evidence is available regarding the benefit and hazard of higher-intensity treatment to lower lipid levels among patients 75 years or older. As a result, guideline recommendations differ for this age group compared with younger patients. Objective: To determine the effect on outcomes and risks of combination ezetimibe and simvastatin compared with simvastatin monotherapy to lower lipid levels among patients 75 years or older with stabilized acute coronary syndrome (ACS). Design, Setting, Participants: In this prespecified secondary analysis of the global, multicenter, prospective clinical randomized Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), outcomes and risks were compared by age among patients 50 years or older after a hospitalization for ACS. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed May 29, 2015, through March 13, 2018, using Kaplan-Meier curves and Cox proportional hazards models. Interventions: Double-blind randomized assignment to combined simvastatin and ezetimibe or simvastatin and placebo with follow-up for a median of 6 years (interquartile range, 4.3-7.1 years). Main Outcomes and Measures: The primary composite end point consisted of death due to cardiovascular disease, myocardial infarction (MI), stroke, unstable angina requiring hospitalization, and coronary revascularization after 30 days. Individual adverse ischemic and safety end points and lipid variables were also analyzed. Results: Of 18 144 patients enrolled (13 728 men [75.7%]; mean [SD] age, 64.1 [9.8] years), 5173 (28.5%) were 65 to 74 years old, and 2798 (15.4%) were 75 years or older at randomization. Treatment with simvastatin-ezetimibe resulted in lower rates of the primary end point than simvastatin-placebo, including 0.9% for patients younger than 65 years (HR, 0.97; 95% CI, 0.90-1.05) and 0.8% for patients 65 to 74 years of age (hazard ratio [HR], 0.96; 95% CI, 0.87-1.06), with the greatest absolute risk reduction of 8.7% for patients 75 years or older (HR, 0.80; 95% CI, 0.70-0.90) (P = .02 for interaction). The rate of adverse events did not increase with simvastatin-ezetimibe vs simvastatin-placebo among younger or older patients. Conclusions and Relevance: In IMPROVE-IT, patients hospitalized for ACS derived benefit from higher-intensity therapy to lower lipid levels with simvastatin-ezetimibe compared with simvastatin monotherapy, with the greatest absolute risk reduction among patients 75 years or older. Addition of ezetimibe to simvastatin was not associated with any significant increase in safety issues among older patients. These results may have implications for guideline recommendations regarding lowering of lipid levels in the elderly. Trial Registration: ClinicalTrials.gov identifier: NCT00202878.

Estimación del porcentaje de pacientes con enfermedad coronaria estable candidatos a recibir inhibidores de la PCSK9 / Estimated percentage of patients with stable coronary heart disease candidates for PCSK9 inhibitors

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Estimación del porcentaje de pacientes con enfermedad coronaria estable candidatos a recibir inhibidores de PCSK9. Respuesta / Estimated percentage of patients with stable coronary heart disease candidates for PCSK9 inhibitors. Response

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Patient Phenotypes, Cardiovascular Risk, and Ezetimibe Treatment in Patients After Acute Coronary Syndromes (from IMPROVE-IT).

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p <0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.

Impact of Obesity on Persistent Left Ventricular Hypertrophy After Aortic Valve Replacement for Aortic Stenosis.

Normalization of left ventricular (LV) hypertrophy is expected after successful aortic valve replacement (AVR) in patients with aortic valve stenosis (AS), but is not always observed. We tested the impact of body mass index (BMI) ≥30 kg/m2 on persistent post-AVR LV hypertrophy. In the present subanalysis of Simvastatin Ezetimibe in Aortic Stenosis study, clinical and echocardiographic data of 399 patients with severe AS who underwent surgical AVR were analyzed. All patients had a standardized pre- and post-AVR echocardiogram. Patients were grouped by BMI categories into BMI <25 kg/m2, BMI 25 to 29.9 kg/m2, and BMI ≥30 kg/m2. LV hypertrophy was defined as LV mass/height2.7 >49.2 g/m2.7 in men and >46.7 g/m2.7 in women. Predictors of persistent LV hypertrophy after AVR were identified in logistic regression analysis. After a median follow-up of 196 days after AVR, LV hypertrophy was more prevalent in patients with BMI ≥30 kg/m2 compared with those with BMI 25 to 29.9 kg/m2 and those patients with BMI <25 kg/m2 (71% vs 47% and 37%, p <0.01). BMI ≥30 kg/m2 patients also remained with lower LV midwall shortening post-AVR compared with patients with normal weight (p <0.01), independent of patient prosthesis mismatch. In multivariable logistic regression analysis, the presence of BMI ≥30 kg/m2 before AVR was associated with an almost fourfold higher prevalence of post-AVR LV hypertrophy independent of significant associations with higher systolic blood pressure and lower LV midwall shortening preoperatively (odds ratio 3.75 [95% confidence interval 2.04 to 6.91], p <0.001). In conclusion, the presence of BMI ≥30 kg/m2 before AVR in patients with severe AS was strongly and independently associated with persistent post-AVR LV hypertrophy.

Ezetimibe in Combination With Simvastatin Reduces Remnant Cholesterol Without Affecting Biliary Lipid Concentrations in Gallstone Patients.

Background In randomized trials (SHARP [Study of Heart and Renal Protection], IMPROVE -IT [Improved Reduction of Outcomes: Vytorin Efficacy International Trial]), combination of statin and ezetimibe resulted in additional reduction of cardiovascular events. The reduction was greater in patients with type 2 diabetes mellitus (T2 DM ), where elevated remnant cholesterol and high cardiovascular disease risk is characteristic. To evaluate possible causes behind these results, 40 patients eligible for cholecystectomy, randomized to simvastatin, ezetimibe, combined treatment (simvastatin+ezetimibe), or placebo treatment during 4 weeks before surgery, were studied. Methods and Results Fasting blood samples were taken before treatment start and at the end (just before surgery). Bile samples and liver biopsies were collected during surgery. Hepatic gene expression levels were assessed with qPCR . Lipoprotein, apolipoprotein levels, and content of cholesterol, cholesteryl ester, and triglycerides were measured after lipoprotein fractionation. Lipoprotein subclasses were analyzed by nuclear magnetic resonance. Apolipoprotein affinity for human arterial proteoglycans ( PG ) was measured. Biomarkers of cholesterol biosynthesis and intestinal absorption and bile lipid composition were analyzed using mass spectrometry. Combined treatment caused a statistically significant decrease in plasma remnant particles and apolipoprotein B (ApoB)/lipoprotein content of cholesterol, cholesteryl esters, and triglycerides. All treatments reduced ApoB-lipoprotein PG binding. Simvastatin and combined treatment modified the composition of lipoproteins. Changes in biomarkers of cholesterol synthesis and absorption and bile acid synthesis were as expected. No adverse events were found. Conclusions Combined treatment caused atheroprotective changes on ApoB-lipoproteins, remnant particles, bile components, and in ApoB-lipoprotein affinity for arterial PG . These effects might explain the decrease of cardiovascular events seen in the SHARP and IMPROVE - IT trials. Clinical Trial Registration URL : www.clinicaltrialsregister.eu . Unique identifier: 2006-004839-30).

Differential association of ezetimibe-simvastatin combination with major adverse cardiovascular events in patients with or without diabetes: a retrospective propensity score-matched cohort study.

Clinical trials suggested that the benefits of ezetimibe-statin combination therapy on major adverse cardiovascular events (MACE) might be greater in patients with diabetes. We aimed to investigate the differential association of ezetimibe-statin combination with incident MACE by presence of diabetes. In this retrospective cohort study, subjects treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) between 2005 and 2015 were 1:1 matched using propensity score as stratified by diabetes. Primary outcome was newly-developed MACE composed of cardiovascular death, ACS, coronary revascularization, or non-hemorrhagic stroke. During 5,077 and 12,439 person-years, the incidence rates of MACE were 24.9, 20.1, 35.3, and 22.8/1000 person-years among no diabetes S, no diabetes S + E, diabetes S, and diabetes S + E, respectively. Relative to no diabetes S, adjusted HR (aHR) for MACE in diabetes S was 1.23 (p = 0.086), whereas S + E was associated with a lower risk of MACE in both non-diabetic patients (aHR 0.76, p = 0.047) and diabetic patients (aHR 0.60, p = 0.007) with significant difference (relative excess risk due to interaction = -0.39, p = 0.044). In conclusion, reduction of MACE risk associated with ezetimibe plus simvastatin therapy relative to simvastatin alone was greater in patients with diabetes than in patients without diabetes.

Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

BACKGROUND: Ezetimibe, when added to simvastatin, reduces cardiovascular events after acute coronary syndrome. We explored outcomes stratified by diabetes mellitus (DM). METHODS: In IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), 18 144 patients after acute coronary syndrome with low-density lipoprotein cholesterol 50 to 125 mg/dL were randomized to 40 mg ezetimibe/simvastatin (E/S) or 40 mg placebo/simvastatin. The primary composite end point was cardiovascular death, major coronary events, and stroke. DM was a prespecified subgroup. RESULTS: The 4933 (27%) patients with DM were more often older and female, had had a prior myocardial infarction and revascularization, and presented more frequently with non-ST segment elevation acute coronary syndrome compared with patients without DM (each P<0.001). The median admission low-density lipoprotein cholesterol was lower among patients with DM (89 versus 97 mg/dL, P<0.001). E/S achieved a significantly lower median time-weighted average low-density lipoprotein cholesterol compared with placebo/simvastatin, irrespective of DM (DM: 49 versus 67 mg/dL; no DM: 55 versus 71 mg/dL; both P<0.001). In patients with DM, E/S reduced the 7-year Kaplan-Meier primary end point event rate by 5.5% absolute (hazard ratio, 0.85; 95% confidence interval, 0.78-0.94); in patients without DM, the absolute difference was 0.7% (hazard ratio, 0.98; 95% confidence interval, 0.91-1.04; Pint=0.02). The largest relative reductions in patients with DM were in myocardial infarction (24%) and ischemic stroke (39%). No differences in safety outcomes by treatment were present regardless of DM. When stratified further by age, patients ≥75 years of age had a 20% relative reduction in the primary end point regardless of DM (Pint=0.91), whereas patients <75 years of age with DM had greater benefit than those without (Pint=0.011). When stratified by the TIMI (Thrombolysis in Myocardial Infarction) Risk Score for Secondary Prevention, all patients with DM demonstrated benefit with E/S regardless of risk. In contrast, among patients without DM, those with a high risk score experienced a significant (18%) relative reduction in the composite of cardiovascular death, myocardial infarction, and ischemic stroke with E/S compared with placebo/simvastatin, whereas patients without DM at low or moderate risk demonstrated no benefit with the addition of ezetimibe to simvastatin (Pint =0.034). CONCLUSIONS: In IMPROVE-IT, the benefit of adding ezetimibe to statin was enhanced in patients with DM and in high-risk patients without DM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.

Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation.

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.

Treatment of Alopecia Areata with Simvastatin/Ezetimibe.

Alopecia areata (AA) is an autoimmune disorder characterized by T lymphocytic infiltrates around the bulbar region of hair follicles. Statins have surfaced as potential therapeutic agents for AA, partly because of their modulation of the JAK/STAT pathway. Some data indicate that statins are a possible option for acute, but not chronic, longstanding AA. Animal studies suggest that treatment with statins increases CD4+/CD25+/Foxp3+ populations in AA-affected mice.

Lower Transaortic Flow Rate Is Associated With Increased Mortality in Aortic Valve Stenosis.

OBJECTIVES: The association of transaortic flow rate (FR) with outcomes was tested in 1,661 patients with aortic valve stenosis (AS) in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. BACKGROUND: Low transaortic flow may complicate grading of AS. However, the association of lower transaortic FR with adverse outcomes has not been reported. METHODS: Transaortic FR was calculated from Doppler-derived stroke volume in milliliters divided by systolic ejection time in seconds and considered low if <200 ml/s. The association of transaortic FR with cardiovascular and all-cause mortality during 4.3-year follow-up was tested in time-varying Cox regression models run with aortic valve replacement as competing risk and reported as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Low transaortic FR was found in 21% of patients at baseline. Patients with low transaortic FR were older, had lower systemic arterial compliance and left ventricular mass, and included more women and patients with inconsistently graded severe AS and low stroke volume index (<35 ml/m2) (p < 0.01 for all). Low in-study transaortic FR was associated with higher rates of cardiovascular and all-cause mortality both in unadjusted analyses (HR: 2.56 [95% CI: 1.62 to 4.04]; and HR: 1.93 [95% CI: 1.35 to 2.75], respectively; p < 0.001 for both) and after adjustment for age, sex, randomized study treatment, hypertension, stroke volume index <35 ml/m2, LV mass, and mean aortic gradient (HR: 2.79 [95% CI: 1.65 to 4.73]; and HR: 1.90 [95% CI: 1.27 to 2.84], respectively; p < 0.01 for both). CONCLUSIONS: In patients with AS without known cardiovascular disease or diabetes, low transaortic FR was independently associated with higher rates of cardiovascular and all-cause mortality. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis (Narrowing of the Major Blood Vessel of the Heart) (MK-0653A-043 AM4); NCT00092677).

Ezetimibe and simvastatin combination inhibits and reverses the pro-inflammatory and pro-atherogenic effects of cream in obese patients.

BACKGROUND AND AIMS: Inflammation and postprandial lipemia are associated with increased cardiovascular disease. We investigated whether ezetimibe and simvastatin combination, a lipid lowering combination of simvastatin and ezetimibe, exerts an anti-inflammatory effect in the fasting state and after dairy cream intake. METHODS: Twenty obese patients were randomized to either ezetimibe and simvastatin combination or placebo treatment for 6 weeks. All patients were asked to ingest 33 ml of dairy cream (300 Calories) at the beginning and at the end of intervention. Fasting and post-cream blood samples were obtained. RESULTS: At 0 week, ingestion of cream induced significant increases in MNC expression of IL-1ß (105 ± 18%), TNFα (97 ± 12%), CD68 (48 ± 8%), CD16 (141 ± 39%), MMP-9 (122 ± 31%), PECAM (66 ± 10%), TLR-4 (84 ± 11%) and TLR-2 (67 ± 9%) and in endotoxin (LPS) concentrations (49 ± 7%) (p < 0.05). Ezetimibe and simvastatin combination treatment lowered fasting total cholesterol, LDLc and Lp(a) concentrations and Apo B/A1 ratio and suppressed the MNC expression of IL-1ß and CD68 (by 21 ± 7 and 24 ± 10, p < 0.05) and the concentrations of LPS, CRP, FFA and IL-18 by 24 ± 7%, 32 ± 11%, 19 ± 8% 15 ± 4%, respectively, (p < 0.05). Cream-induced increases in the expression of IL-1ß, CD68, CD16, MMP-9, TNFα and PECAM were reduced in the ezetimibe and simvastatin combination group by 74 ± 15%, 68 ± 13%, 57 ± 13%, 64 ± 16%, 67 ± 14% and 45 ± 9%, respectively, while those of LPS and MMP-9 concentrations were reduced by 53 ± 9% and 38 ± 8%, respectively, compared to the increases at week 0 (p < 0.05). There was a suppression of TLR-2 and TLR-4 expression by 21 ± 8% and 18 ± 7%, respectively, compared to 0-h baseline, after cream intake following ezetimibe and simvastatin combination treatment. CONCLUSIONS: Ezetimibe and simvastatin combination exerts a profound anti-inflammatory effect both in the fasting state and acutely after the ingestion of saturated fat.