RESUMEN
Low-density lipoprotein cholesterol (LDL-C) has been identified as a causative factor for atherosclerosis and related coronary heart disease, and as the main target for cholesterol- and lipid-lowering therapy. Statin drugs inhibit cholesterol synthesis in the liver and are typically the first line of therapy to lower elevated levels of LDL-C. On the other hand, a different drug, Ezetimibe, inhibits the absorption of cholesterol by the small intestine and provides a different mechanism of action. Many clinical trials have been carried out on safety and efficacy evaluation of cholesterol lowering drugs. To synthesize the results from different clinical trials, we examine treatment level (aggregate) network meta-data from 29 double-blind, randomized, active, or placebo-controlled statins +/$-$ Ezetimibe clinical trials on adult treatment-naïve patients with primary hypercholesterolemia. In this article, we propose a new approach to carry out Bayesian inference for arm-based network meta-regression. Specifically, we develop a new strategy of grouping the variances of random effects, in which we first formulate possible sets of the groups of the treatments based on their clinical mechanisms of action and then use Bayesian model comparison criteria to select the best set of groups. The proposed approach is especially useful when some treatment arms are involved in only a single trial. In addition, a Markov chain Monte Carlo sampling algorithm is developed to carry out the posterior computations. In particular, the correlation matrix is generated from its full conditional distribution via partial correlations. The proposed methodology is further applied to analyze the network meta-data from 29 trials with 11 treatment arms.
Asunto(s)
Anticolesterolemiantes/farmacología , LDL-Colesterol/efectos de los fármacos , Hipercolesterolemia/tratamiento farmacológico , Modelos Estadísticos , Metaanálisis en Red , Teorema de Bayes , LDL-Colesterol/sangre , Humanos , Hipercolesterolemia/sangre , Análisis de RegresiónRESUMEN
We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100â mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5â h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h-1) over 24â h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38â years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0â mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100â mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.
Asunto(s)
Tos/tratamiento farmacológico , Tos/fisiopatología , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Antitusígenos/efectos adversos , Antitusígenos/uso terapéutico , Pruebas de Provocación Bronquial , Enfermedad Crónica , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antagonistas del Receptor Purinérgico P2X/efectos adversos , Pirimidinas/efectos adversos , Sulfonamidas/efectos adversos , Reino Unido , Escala Visual AnalógicaRESUMEN
BACKGROUND: Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. METHODS: Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. RESULTS: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73-1.00; P=0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67-0.94; P=0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93-2.04; P=0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70-0.98; P=0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63-0.91; P=0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38-0.95; P=0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31-0.86; P=0.011) with ezetimibe added to simvastatin therapy. CONCLUSIONS: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00202878.
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Anticolesterolemiantes/uso terapéutico , Ezetimiba/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Simvastatina/uso terapéutico , Accidente Cerebrovascular/prevención & control , Síndrome Coronario Agudo/mortalidad , Síndrome Coronario Agudo/patología , Anciano , Fibrilación Atrial/complicaciones , LDL-Colesterol/sangre , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Efecto Placebo , Modelos de Riesgos Proporcionales , Recurrencia , Factores de Riesgo , Resultado del TratamientoRESUMEN
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.).
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Simvastatina/uso terapéutico , Anciano , Anticolesterolemiantes/efectos adversos , Azetidinas/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Método Doble Ciego , Quimioterapia Combinada , Ezetimiba , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
BACKGROUND: Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). METHODS AND RESULTS: The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets. CONCLUSIONS: Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov; Unique identifier: NCT00202878.
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , Anticolesterolemiantes/uso terapéutico , Proteína C-Reactiva/análisis , LDL-Colesterol/sangre , Ezetimiba/uso terapéutico , Simvastatina/uso terapéutico , Síndrome Coronario Agudo/sangre , Anciano , Anticolesterolemiantes/administración & dosificación , Biomarcadores , Enfermedades Cardiovasculares/mortalidad , Revascularización Cerebral , Comorbilidad , Creatinina/sangre , Método Doble Ciego , Monitoreo de Drogas , Quimioterapia Combinada , Electrocardiografía , Ezetimiba/administración & dosificación , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/tratamiento farmacológico , Revascularización Miocárdica , Simvastatina/administración & dosificación , Resultado del TratamientoRESUMEN
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 125 mg/dL and who received Ez 10 mg/d with S 40 mg/d (Ez/S) or placebo with simvastatin 40 mg/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.
Asunto(s)
Síndrome Coronario Agudo , LDL-Colesterol/sangre , Ezetimiba , Simvastatina , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/tratamiento farmacológico , Anciano , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas/métodos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Quimioterapia Combinada/estadística & datos numéricos , Ezetimiba/administración & dosificación , Ezetimiba/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Simvastatina/administración & dosificación , Simvastatina/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Recent evidence points to an increased incidence of new-onset diabetes and a negative impact on glucose parameters with statin use. This study examined the safety of ezetimibe vs placebo for change from baseline to week 24 in HbA1c (primary endpoint), glycoalbumin, and fasting plasma glucose (secondary endpoints) in Japanese subjects with type 2 diabetes and hypercholesterolemia. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-site trial. Adults with type 2 diabetes and hypercholesterolemia whose LDL-C measured <140 mg/dl (subjects receiving lipid-lowering drugs) or <160 mg/dl (subjects not receiving lipid-lowering drugs) at the start of the screening phase, were randomized after a 5-week wash-out period to ezetimibe 10 mg or placebo (1:1) for 24 weeks. Changes in HbA1c, glycoalbumin and fasting plasma glucose from baseline to week 24 were evaluated. The non-inferiority margin was set at 0.5% for HbA1c. RESULTS: Overall, 152 subjects were randomized (75 to ezetimibe and 77 to placebo). From baseline to 24 weeks, HbA1c significantly increased in both the ezetimibe and placebo groups (between-treatment difference 0.08 [95% CI: -0.07 to 0.23]). Ezetimibe was statistically non-inferior to placebo. At 24 weeks, the mean change from baseline in glycoalbumin levels (between-treatment differences 0.00 [95% CI: -0.47, 0.47]) and fasting plasma glucose (between-treatment differences -4.8 [95% CI: -12.1, 2.1]) were similar in both treatment groups. CONCLUSIONS: These results suggest that ezetimibe 10 mg does not result in dysregulation of glucose metabolism in Japanese patients with type 2 diabetes and hypercholesterolemia over 24 weeks of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01611883 .
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ezetimiba/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Femenino , Hemoglobina Glucada/análisis , Productos Finales de Glicación Avanzada , Humanos , Hipercolesterolemia/complicaciones , Masculino , Persona de Mediana Edad , Albúmina Sérica/análisis , Triglicéridos/sangre , Albúmina Sérica GlicadaRESUMEN
BACKGROUND: Metabolic syndrome (MetS) and insulin resistance (IR) are increasing in prevalence, are associated with higher risk for coronary heart disease (CHD), and may potentially influence the responses to lipid-altering drug therapy. This study evaluated the effects of MetS factors (abdominal obesity, depleted high-density lipoprotein cholesterol [HDL-C], and elevated triglycerides, blood pressure, and fasting glucose) and IR on ezetimibe/simvastatin and atorvastatin treatment efficacy in patients with MetS. METHODS: This post-hoc analysis of a multicenter, 6-week, double-blind, randomized, parallel group study of 1128 subjects with hypercholesterolemia, MetS, and moderately high/high CHD risk evaluated the effects of baseline MetS factors/IR on percent change from baseline in lipids, apolipoproteins, and high-sensitivity C-reactive protein (hs-CRP), after treatment with the usual starting doses of ezetimibe/simvastatin (10/20 mg) versus atorvastatin (10 mg, 20 mg) and next higher doses (10/40 mg versus 40 mg). RESULTS: Ezetimibe/simvastatin and atorvastatin efficacy was generally consistent across MetS factor/IR subgroups. Ezetimibe/simvastatin produced greater incremental percent reductions in LDL-C, non-HDL-C, apolipoprotein B, total cholesterol, and lipoprotein ratios for all subgroups, and larger percent increases in HDL-C and apolipoprotein AI for all but non-obese and HDL-C ≥ 40 mg/dL subgroups than atorvastatin at the doses compared. Triglycerides, very-LDL-C, and hs-CRP results were more variable but similar between treatment groups. CONCLUSION: The magnitude of lipid-altering effects produced by each treatment regimen was generally similar across all MetS and IR subgroups. Ezetimibe/simvastatin produced greater percent reductions in most lipid fractions than atorvastatin at the dose comparisons studied, and all treatments were generally well tolerated. (Registered at clinicaltrials.gov: NCT00409773).
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Atorvastatina/uso terapéutico , Enfermedad Coronaria/tratamiento farmacológico , Ezetimiba/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Síndrome Metabólico/tratamiento farmacológico , Simvastatina/uso terapéutico , Anciano , Glucemia/metabolismo , Presión Sanguínea , Proteína C-Reactiva/metabolismo , LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/patología , Enfermedad Coronaria/sangre , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/patología , Método Doble Ciego , Femenino , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/complicaciones , Hipercolesterolemia/patología , Resistencia a la Insulina , Lipoproteínas HDL/sangre , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/complicaciones , Síndrome Metabólico/patología , Persona de Mediana Edad , Obesidad Abdominal/sangre , Obesidad Abdominal/complicaciones , Obesidad Abdominal/patología , Factores de Riesgo , Resultado del Tratamiento , Triglicéridos/sangreRESUMEN
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 ~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.
Asunto(s)
Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/tratamiento farmacológico , Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , LDL-Colesterol/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Simvastatina/uso terapéutico , Síndrome Coronario Agudo/sangre , Anciano , Anticolesterolemiantes/farmacología , Azetidinas/farmacología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , LDL-Colesterol/sangre , Quimioterapia Combinada , Ezetimiba , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Few clinical studies have focused on the efficacy of lipid-lowering therapies in patients ≥65 years. METHODS: After stabilization on atorvastatin 10 mg, hypercholesterolemic subjects ≥65 years at high/very high risk for CHD and not at LDL-C <1.81 mmol/L (with atherosclerotic vascular disease [AVD]) or <2.59 mmol/L (without AVD) were randomized to ezetimibe 10 mg plus atorvastatin 10 mg or uptitration to atorvastatin 20 mg (6 weeks) followed by uptitration to 40 mg (additional 6 weeks). A post-hoc analysis compared between-group differences in percent attainment of individual and combined LDL-C, non-HDL-C and Apo B targets based on recommendations from 2012 European and Canadian Cardiovascular Society (CCS) guidelines for dyslipidemia treatment. RESULTS: Atorvastatin 10 mg plus ezetimibe produced significantly greater attainment of LDL-C, non-HDL-C, and Apo B individual and dual/triple targets vs. atorvastatin 20 mg for the entire cohort and very high-risk groups at 6 weeks. After 12 weeks, very high-risk subjects maintained significantly greater achievement of LDL-C <1.8 mmol/L (47% vs. 35%), non-HDL-C <2.6 mmol/L (63% vs. 53%) and Apo B <0.8 g/L (47% vs. 38%) single targets and dual/triple targets with atorvastatin 10 mg plus ezetimibe vs. atorvastatin 40 mg, while attainment of European target for high-risk subjects was generally similar for both treatments. Achievement of Canadian targets was significantly greater with combination therapy vs. atorvastatin 20 mg (6 weeks) or atorvastatin 40 mg (12 weeks). CONCLUSIONS: Atorvastatin 10 mg plus ezetimibe provided more effective treatment than uptitration to atorvastatin 20/40 mg for attainment of most European and Canadian guideline-recommended lipid targets in older at-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00418834.
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Aterosclerosis/tratamiento farmacológico , Azetidinas/administración & dosificación , LDL-Colesterol/sangre , Ácidos Heptanoicos/administración & dosificación , Hipercolesterolemia/tratamiento farmacológico , Pirroles/administración & dosificación , Anciano , Aterosclerosis/sangre , Atorvastatina , Canadá , Método Doble Ciego , Europa (Continente) , Ezetimiba , Femenino , Humanos , Hipercolesterolemia/sangre , Masculino , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , Colesterol/metabolismo , Hipercolesterolemia/tratamiento farmacológico , Absorción Intestinal/efectos de los fármacos , Esterol O-Aciltransferasa/antagonistas & inhibidores , Animales , Transporte Biológico/efectos de los fármacos , Quimioterapia Combinada , Ezetimiba , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Despite documented benefits of lipid-lowering treatment in women, a considerable number are undertreated, and fewer achieve treatment targets vs. men. METHODS: Data were combined from 27 double-blind, active or placebo-controlled studies that randomized adult hypercholesterolemic patients to statin or statin+ezetimibe. Consistency of treatment effect among men (n = 11,295) and women (n = 10,499) was assessed and percent of men and women was calculated to evaluate the between-treatment ability to achieve specified treatment levels between sexes. RESULTS: Baseline lipids and hs-CRP were generally higher in women vs. men. Between-treatment differences were significant for both sexes (all p < 0.001 except apolipoprotein A-I in men = 0.0389). Men treated with ezetimibe+statin experienced significantly greater changes in LDL-C (p = 0.0066), non-HDL-C, total cholesterol, triglycerides, HDL-C, apolipoprotein A-I (all p < 0.0001) and apolipoprotein B (p = 0.0055) compared with women treated with ezetimibe+statin. The odds of achieving LDL-C < 100 mg/dL, apolipoprotein B < 90 mg/dL and the dual target [LDL-C < 100 mg/dL & apoliprotein B < 90 mg/dL] was significantly greater for women vs. men and the odds of achieving hs-CRP < 1 and < 2 mg/L and dual specified levels of [LDL-C < 100 mg/dL and hs-CRP < 2 mg/L] were significantly greater for men vs. women. Women reported significantly more gall-bladder-related, gastrointestinal-related, and allergic reaction or rash-related adverse events (AEs) vs. men (no differences between treatments). Men reported significantly more CK elevations (no differences between treatments) and hepatitis-related AEs vs. women (significantly more with ezetimibe+simvastatin vs. statin). CONCLUSIONS: These results suggest that small sex-related differences may exist in response to lipid-lowering treatment and achievement of specified lipid and hs-CRP levels, which may have implications when managing hypercholesterolemia in women.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticolesterolemiantes/administración & dosificación , Anticolesterolemiantes/efectos adversos , Azetidinas/administración & dosificación , Azetidinas/efectos adversos , Proteína C-Reactiva/análisis , Método Doble Ciego , Quimioterapia Combinada/efectos adversos , Ezetimiba , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hiperlipidemias/sangre , Lípidos/sangre , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores SexualesRESUMEN
BACKGROUND: The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL despite maximally tolerated statin. OBJECTIVES: The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS). METHODS: IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke. RESULTS: Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints. CONCLUSIONS: Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).
Asunto(s)
Síndrome Coronario Agudo/tratamiento farmacológico , LDL-Colesterol/sangre , Ezetimiba/uso terapéutico , Simvastatina/uso terapéutico , Anciano , Angina Inestable/epidemiología , Anticolesterolemiantes/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Revascularización MiocárdicaRESUMEN
BACKGROUND: Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels <150 mg/dL or ≥150 mg/dL. RESULTS: Both treatments significantly reduced LDL-C (and the cholesterol content of most LDL subfractions [LDL1-4]) apolipoprotein B, non-HDL-C levels, but did not reduce the proportion of smaller, more dense LDL particles; in fact, the proportion of Pattern B was numerically increased. Results were generally similar in patients with triglyceride levels <150 or ≥150 mg/dL. CONCLUSIONS: When assessing the effects of escalating cholesterol-lowering therapy, effects upon Pattern B alone to assess coronary heart disease risk may be misleading when interpreted without considerations of other lipid effects, such as reductions in LDL-C, atherogenic lipoprotein particle concentration, and non-HDL-C levels. TRIAL REGISTRATION: (Registered at clinicaltrials.gov: Clinical trial # NCT00276484).
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , LDL-Colesterol/sangre , Ácidos Heptanoicos/uso terapéutico , Pirroles/uso terapéutico , Anciano , Atorvastatina , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Ezetimiba , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
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). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).
RESUMEN
OBJECTIVE: We evaluated whether early response to NSAIDs predicted later response, and when this was established. METHODS: We evaluated pooled data from two identical 26-week, double-blind, randomized trials comparing once-daily etoricoxib 30 mg (n = 475), celecoxib 200 mg (n = 488) and placebo (n = 244) in patients with knee or hip OA. The present analysis was limited to the 12-week placebo-controlled period. Patient-level OMERACT-OARSI response was determined at 2, 4, 8 and 12 weeks. The proportion of patients who maintained response status between these times was determined from binomial distribution using the exact method. RESULTS: After 12 weeks of treatment, there were significantly more responders in the etoricoxib (59.8%) and celecoxib (57%) groups compared with placebo (34%; P < 0.001 for etoricoxib or celecoxib vs placebo). About 77.2% of the patients receiving etoricoxib, 75.4% celecoxib and 58% placebo (P = 0.001 vs etoricoxib; P = 0.003 vs celecoxib) who were responders at 2 weeks were also responders at 12 weeks. When comparing response agreement (responder or non-responder) at 2 weeks and 12 weeks, 74.3% of the patients receiving etoricoxib, 73.2% celecoxib and 71.3% placebo had the same response status (kappa-coefficient 0.459, 0.449 and 0.357, respectively). There were small incremental increases in agreement between Weeks 4 and 8 and 12 weeks. Logistic regression showed that agreement was not affected by index joint (P = 0.965). CONCLUSIONS: The overwhelming majority of the patients who responded to treatment by 2 weeks remained responders at 12 weeks, with response status largely established within 2 weeks of treatment initiation. Early identification of NSAID response or non-response may allow clinicians to better and more rapidly adjust symptomatic OA management.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Osteoartritis de la Cadera/tratamiento farmacológico , Osteoartritis de la Rodilla/tratamiento farmacológico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Sulfonamidas/uso terapéutico , Sulfonas/uso terapéutico , Anciano , Celecoxib , Métodos Epidemiológicos , Etoricoxib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo , Resultado del TratamientoRESUMEN
Improvements in hypertension treatment and control are challenged by the increasing incidence of metabolic risk factors for hypertension, in particular, obesity and insulin resistance. Such risk factors can increase the severity of hypertension and can interact via a multitude of hormonal and inflammatory pathways. Their presence may affect antihypertensive agent choice with regard to antihypertensive efficacy as well as potential synergistic or antagonistic effects on inflammatory status and progression to diabetes. Furthermore, an increasing number of pharmacologic options are available to promote weight loss and insulin sensitivity that may affect blood pressure directly and indirectly. This review considers the metabolic basis for the complex interactions of hypertension with obesity and insulin resistance, and it assesses the clinical evidence for an impact of weight loss and insulin-sensitizing treatment on blood pressure. Awareness of these pathophysiologic interrelations and their implications for treatment are likely to be of increasing importance for successful blood pressure management.
Asunto(s)
Hipertensión/etiología , Resistencia a la Insulina , Obesidad/complicaciones , Humanos , Hipertensión/fisiopatología , Hipertensión/terapia , Estilo de Vida , Obesidad/fisiopatología , Obesidad/terapia , Factores de Riesgo , Pérdida de PesoRESUMEN
BACKGROUND: Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. OBJECTIVE: To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. METHODS: This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. RESULTS: Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29-0.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P < .01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: -5.0 and -12.0, -2.0 and -5.4, and -1.5 and -12.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: -5.0 and -19.9 and -2.0 and -7.3) in second-line studies. CONCLUSION: Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements.