Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 19 de 19
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Circulation ; 141(10): 843-862, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-31992065

RESUMO

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

4.
J Am Heart Assoc ; 9(1): e014328, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31852422

RESUMO

Background The contemporary impact of glycemic control on patients with diabetes mellitus at high cardiovascular risk remains unclear. We evaluated the utility of hemoglobin A1c (HbA1c) as a marker of risk on the composite end point of cardiovascular death, nonfatal myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization in an optimally treated population with diabetes mellitus and established coronary artery disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with established diabetes mellitus and measured HbA1c (N=8145) and estimated Kaplan-Meier (KM) events rates, stratified by increasing baseline HbA1c levels censored at 30 months. We then performed a multivariable regression for the primary end point. Increasing baseline HbA1c was strongly associated with the occurrence of the primary end point (KM estimate, 12.6-18.2; P<0.001). Increasing baseline HbA1c was also associated with the triple end point of death, nonfatal myocardial infarction, and stroke (KM estimate, 7.8-11.3; P=0.003) as well as the individual end points of nonfatal myocardial infarction (KM estimate, 3.1-7.0; P<0.001), hospitalization for unstable angina (KM estimate, 1.8-5.0; P=0.003), and revascularization (KM estimate, 7.3-11.1; P=0.001), although not stroke (KM estimate, 1.4-2.4; P=0.45). The rates of cardiovascular mortality (KM estimate, 2.6-4.3; P=0.21) and all-cause mortality (KM estimate, 4.8-5.9; P=0.21) were similar regardless of baseline HbA1c levels. When adjusting for relevant baseline characteristics, baseline HbA1c was an independent predictor for the primary end point (hazard ratio, 1.06; 95% CI, 1.02-1.11; P=0.003). Conclusions Glycemic control, as measured by HbA1c, remains strongly and independently associated with cardiovascular outcomes in high-risk patients with diabetes mellitus on statin therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT01687998.

5.
J Am Heart Assoc ; 8(23): e013790, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31752637

RESUMO

Background The failure of cholesteryl ester transfer protein inhibitor torcetrapib was associated with an off-target increase in plasma aldosterone. We sought to evaluate the impact of evacetrapib on plasma aldosterone level and determine the association between plasma aldosterone level and major adverse cardiovascular events among patients with stable high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. Methods and Results We included all patients with a plasma aldosterone level (N=1624) and determined the impact of evacetrapib exposure compared with placebo on plasma aldosterone levels after 12 months of treatment. Using baseline and postexposure aldosterone levels, hazard ratios for major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, cerebrovascular accident, hospitalization for unstable angina, and revascularization) with increasing quartile of baseline and percentage change in plasma aldosterone level at follow-up were calculated. The average age was 65.2 years, 75.7% were men, 93.7% were hypertensive, 73.3% were diabetic, and 57.6% had a prior myocardial infarction. Baseline plasma aldosterone level (85.2 [43, 150] versus 86.8 [43, 155] pmol/L; P=0.81) and follow-up percentage change (13.6% [-29, 88] versus 17.9% [-24, 87]; P=0.23) were similar between those who received evacetrapib and placebo. During median follow-up of 28 months, major adverse cardiovascular events occurred in 263 patients (16.2%). The hazard ratios for increasing quartile of baseline or percentage change in plasma aldosterone level at follow-up were not significant for major adverse cardiovascular events. These findings remained consistent when adjusting for significant characteristics. Conclusions Exposure to evacetrapib did not result in significant change in plasma aldosterone levels compared with placebo. Among patients with stable high-risk vascular disease, plasma aldosterone levels were not a predictor for future cardiovascular events. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01687998.

6.
Lancet ; 394(10193): 121-130, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189511

RESUMO

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Acidente Vascular Cerebral/prevenção & controle
7.
Diab Vasc Dis Res ; 16(2): 171-177, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31014095

RESUMO

BACKGROUND: Despite optimal treatment, type II diabetes mellitus remains associated with an increased risk for future cardiovascular events. We sought to determine the association between baseline fasting plasma insulin levels and major adverse cardiovascular outcomes in patients with type II diabetes mellitus and high-risk vascular disease enrolled in the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial. METHODS: We included all patients with type II diabetes mellitus who had a central laboratory measured fasting plasma insulin level drawn at baseline as part of the study protocol. Hazard ratios were generated for the risk of major adverse cardiovascular outcomes (composite of cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization) with increasing quartile of baseline fasting plasma insulin level. We then performed a multivariable regression adjusting for significant baseline characteristics. RESULTS: Among 12,092 patients in ACCELERATE, 2042 patients with type II diabetes mellitus had a baseline fasting plasma insulin level drawn. Median follow-up was 28 months. The study population had a mean age of 66.6 years, 79.2% male and 96.2% had established coronary artery disease. During follow-up, major adverse cardiovascular outcomes occurred in 238 patients (11.6%); of these events, 177 were coronary revascularization (8.7%). We observed a statistically significant relationship between rates of revascularization and rising quartile of baseline fasting plasma insulin level which was not noted for the other individual components of major adverse cardiovascular outcomes. Patients with type II diabetes mellitus who underwent revascularization were noted to have significantly higher baseline fasting plasma insulin levels (27.7 vs 21.4 mU/L, p-value = 0.009) although baseline haemoglobin A1c (6.63% vs 6.55%), body mass index (31.5 vs 31.1 kg/m2) and medical therapy were otherwise similar to the group not undergoing revascularization. Following multivariable regression adjusting for significant characteristics including exposure to evacetrapib, the log of baseline fasting plasma insulin level was found to be an independent predictor for major adverse cardiovascular outcomes (hazard ratio = 1.36, 95% confidence interval = 1.09-1.69, p-value = 0.007); this was driven by need for future revascularization (hazard ratio = 1.56, 95% confidence interval = 1.21-2.00, p-value = 0.001). CONCLUSION: In a contemporary population of patients with type II diabetes mellitus and high-risk vascular disease on optimum medical therapy, baseline hyperinsulinaemia was an independent predictor for major adverse cardiovascular outcomes and need of future coronary revascularization. These results suggest a pathophysiological link between hyperinsulinaemia and progression of atherosclerotic vascular disease among diabetics.


Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/sangue , Jejum/sangue , Hiperinsulinismo/sangue , Insulina/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/mortalidade , Hiperinsulinismo/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo
8.
Diabetes Obes Metab ; 21(6): 1299-1304, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30714309

RESUMO

AIM: To examine the generalizability of results from glucagon-like peptide-1 receptor agonist (GLP-1 RA) cardiovascular outcome trials (CVOTs) in the US type 2 diabetes (T2D) population. MATERIALS AND METHODS: Patients enrolled or eligible for inclusion in four CVOTs (EXSCEL, LEADER, REWIND, and SUSTAIN-6) were examined in reference to a retrospective clinical database weighted to match the age and sex distribution of the US adult T2D population. We descriptively compared key baseline characteristics of the populations enrolled in each trial to those of the reference population and estimated the proportions of individuals in the reference population represented by those in the trials for each characteristic. We also estimated the proportions of individuals in the reference population that might have been enrolled in each trial based upon meeting the trial inclusion and exclusion (I/E) criteria. RESULTS: No trial's enrolled population perfectly matched the reference population in key characteristics. The EXSCEL population most closely matched in mean age (62.7 vs. 60.5 years) and percentage with estimated glomerular filtration rate <60 (18.6 vs. 17.3%), while REWIND most closely matched in HbA1c, sex distribution, and proportion with a prior myocardial infarction. Based on I/E criteria, 42.6% of the reference population were eligible for enrolment in REWIND, versus 15.9% in EXSCEL, 13.0% in SUSTAIN-6, and 12.9% in LEADER. CONCLUSIONS: Although none of the trials are fully representative of the general population, among the four trials examined, results from baseline REWIND were found to be more generalizable to the US adult T2D population than those of other GLP-1 RA CVOTs.

9.
JAMA Cardiol ; 3(5): 401-408, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29525816

RESUMO

Importance: A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial. Objective: To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease. Design, Setting, and Participants: A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092-patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017. Exposures: Evacetrapib, 130 mg, or matching placebo. Main Outcomes and Measures: The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. Results: For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59. Conclusions and Relevance: Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.


Assuntos
Adenilil Ciclases/genética , Anticolesterolemiantes/uso terapêutico , Benzodiazepinas/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Polimorfismo de Nucleotídeo Único/genética , Idoso , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Fatores de Risco , Resultado do Tratamento
10.
Circ J ; 82(1): 183-191, 2017 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-28768921

RESUMO

BACKGROUND: Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal.Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia. The primary efficacy measure was percent change from baseline to week 12 in LDL-C (ß quantification). Treatment with evacetrapib 130 mg daily for 12 weeks resulted in a statistically significant treatment difference of -25.70% compared with placebo in percentage decrease in LDL-C (95% CI: -34.73 to -16.68; P<0.001). Treatment with evacetrapib 130 mg also resulted in a statistically significant difference of 126.39% in the change in high-density lipoprotein cholesterol (HDL-C) compared with placebo (95% CI: 113.54-139.24; P<0.001). No deaths or serious adverse events were reported. Four patients (3 in the evacetrapib group and 1 in the ezetimibe group) discontinued due to adverse events. CONCLUSIONS: Evacetrapib daily in combination with atorvastatin was superior to placebo in lowering LDL-C after 12 weeks, and resulted in a statistically significant increase of HDL-C compared with placebo. Also, no new safety risks were identified.


Assuntos
Atorvastatina/administração & dosagem , Benzodiazepinas/administração & dosagem , LDL-Colesterol/efeitos dos fármacos , Idoso , Grupo com Ancestrais do Continente Asiático , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , HDL-Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Circ J ; 81(11): 1686-1692, 2017 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-28652529

RESUMO

BACKGROUND: Inhibition of cholesteryl ester transfer protein with evacetrapib may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal with statins or patients who cannot tolerate statins.Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib in reducing LDL-C in 54 Japanese patients (27 evacetrapib, 27 placebo) with primary hypercholesterolemia. Primary efficacy measure was the percent change from baseline to week 12 in LDL-C (ß quantification). Treatment with evacetrapib 130 mg once daily for 12 weeks resulted in statistically significant (P<0.001) change in LDL-C (ß quantification) compared with placebo. Least-squares mean percentage changes from baseline were -34.3% in the evacetrapib group vs. 0.0% in the placebo group. Treatment with evacetrapib 130 mg also resulted in a statistically significant (P<0.001) increase in high-density lipoprotein cholesterol compared with placebo in mean percent change from baseline, with a least-squares mean difference of 124.0% (95% confidence interval: 104.6-143.5). No deaths, serious adverse events, or discontinuations because of adverse events were reported; 5 patients (18.5%) in the evacetrapib group and 7 patients (26.9%) in the placebo group experienced treatment-emergent adverse events. CONCLUSIONS: Once-daily evacetrapib 130 mg monotherapy was superior to placebo in lowering LDL-C after 12 weeks. No new safety risks were identified.


Assuntos
Benzodiazepinas/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/efeitos dos fármacos , Humanos , Japão , Resultado do Tratamento
12.
N Engl J Med ; 376(20): 1933-1942, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28514624

RESUMO

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .).


Assuntos
Anticolesterolemiantes/uso terapêutico , Benzodiazepinas/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Idoso , Anticolesterolemiantes/efeitos adversos , Benzodiazepinas/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Arteriosclerose Intracraniana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/tratamento farmacológico , Doenças Vasculares Periféricas/tratamento farmacológico , Risco , Falha de Tratamento
13.
Atherosclerosis ; 261: 12-18, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28412650

RESUMO

BACKGROUND AND AIMS: The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters. METHODS: 366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States. Lipid parameters, safety and tolerability were measured. RESULTS: Addition of evacetrapib significantly reduced LDL-C (-33%) compared with ezetimibe (-27%, p=0.045), increasing statin dose (-6%) and statin alone (0%, p<0.001). Evacetrapib also decreased apoB by 23% compared to 19% with ezetimibe (p=0.06) and 7% with increased statin dose (p<0.001), and reduced Lp(a) by 29% (p<0.001 vs. other groups). Evacetrapib increased HDL-C (+125%), apoA-I (+46%), apoC-III (+50%) and apoE (+28%) (p<0.001 vs. other groups). Non-ABCA1-mediated efflux increased by 53% (p<0.001 vs. other groups) with evacetrapib. ABCA1-mediated efflux also increased by 13% with evacetrapib (p<0.001 vs. ezetimibe, p=0.002 vs. increasing statin dose, and p=0.004 vs. statin alone). Addition of evacetrapib to atorvastatin produced an increase in hsCRP compared with ezetimibe (p=0.02). CONCLUSIONS: While evacetrapib improved traditional atherogenic and putative protective lipid measures compared with ezetimibe and increasing statin dose in patients with ASCVD and/or diabetes, it also adversely affected novel atherogenic risk factors. These findings may contribute to the lack of clinical benefit observed in the ACCELERATE trial.


Assuntos
Anticolesterolemiantes/administração & dosagem , Aterosclerose/tratamento farmacológico , Atorvastatina/administração & dosagem , Benzodiazepinas/administração & dosagem , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Ezetimiba/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipídeos/sangue , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/diagnóstico , Atorvastatina/efeitos adversos , Benzodiazepinas/efeitos adversos , Biomarcadores/sangue , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Ezetimiba/efeitos adversos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
14.
J Hematol Oncol ; 6: 17, 2013 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-23414938

RESUMO

BACKGROUND: Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. METHODS: The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. RESULTS: There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. CONCLUSIONS: Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.


Assuntos
Anemia Falciforme/tratamento farmacológico , Dor/prevenção & controle , Piperazinas/uso terapêutico , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Adolescente , Adulto , Biomarcadores Tumorais/análise , Moléculas de Adesão Celular/metabolismo , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Fosfoproteínas/metabolismo , Cloridrato de Prasugrel , Prognóstico , Adulto Jovem
15.
Cardiovasc Ther ; 30(4): e174-82, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21883999

RESUMO

Prasugrel, a third-generation thienopyridine antiplatelet agent, demonstrated superior efficacy to clopidogrel but with an increased risk of bleeding in the phase III pivotal registration Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). This article reviews and discusses select components of a large literature of prasugrel data that has emerged since the TRITON-TIMI 38 (TRITON) study primary disclosure.


Assuntos
Síndrome Coronariana Aguda/terapia , Angioplastia Coronária com Balão/efeitos adversos , Piperazinas/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Tiofenos/uso terapêutico , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/mortalidade , Angioplastia Coronária com Balão/mortalidade , Interações de Medicamentos , Resistência a Medicamentos , Medicina Baseada em Evidências , Hemorragia/induzido quimicamente , Humanos , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/farmacocinética , Cloridrato de Prasugrel , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Tiofenos/efeitos adversos , Tiofenos/farmacocinética , Trombose/etiologia , Trombose/mortalidade , Trombose/prevenção & controle , Fatores de Tempo , Resultado do Tratamento
16.
J Clin Pharmacol ; 52(6): 789-97, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21628601

RESUMO

In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras-AM and clinical outcomes was assessed in 1159 prasugrel-treated patients enrolled in the substudy using multivariable logistic regression analysis. There was no relationship between pras-AM exposure and efficacy through 3 days or after 3 days. Higher estimated pras-AM exposure was associated with a higher incidence of non-CABG-related TIMI major or minor bleeding after 3 days (P < .05) but not through 3 days from start of study drug. Factors associated with increased risk for non-CABG-related TIMI bleeding (≥75 years and <60 kg) also identified subgroups with higher exposure to the pras-AM. Within low body weight and very elderly subgroups, bleeding was largely confined to patients having the highest exposure to the pras-AM, indicating that a prasugrel lower dose in these subgroups may reduce the risk of bleeding while maintaining efficacy.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Hemorragia/induzido quimicamente , Piperazinas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacocinética , Pró-Fármacos/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Tiofenos/farmacocinética , Trombose/prevenção & controle , Síndrome Coronariana Aguda/metabolismo , Síndrome Coronariana Aguda/fisiopatologia , Fatores Etários , Idoso , Biotransformação , Peso Corporal , Relação Dose-Resposta a Droga , Método Duplo-Cego , Hemorragia/epidemiologia , Hemorragia/fisiopatologia , Humanos , Incidência , Masculino , Modelos Biológicos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/sangue , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/sangue , Cloridrato de Prasugrel , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/sangue , Receptores Purinérgicos P2Y12/química , Índice de Gravidade de Doença , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Tiofenos/sangue , Trombose/etiologia
17.
J Thromb Thrombolysis ; 19(3): 147-53, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16082601

RESUMO

OBJECTIVES: To examine the frequency of cerebrovascular complications among patients receiving abciximab (AB) undergoing PCI with prior intracranial hemorrhage (ICH) or recent (< 2 years) ischemic strokes. BACKGROUND: AB improves clinical outcomes in high-risk patients undergoing percutaneous coronary intervention (PCI); however, the safety of AB in patients with prior stroke has not been adequately studied. METHODS: A database review of 7,244 consecutive PCIs, from 7/97 to 10/01, identified 6,190 PCIs performed with AB among which 515 interventions were performed in patients with prior stroke history [ICH or recent ischemic stroke, (n = 101) and remote (> 2 years) ischemic stroke, (n = 414)]. RESULTS: The post-PCI stroke rate was significantly higher in patients with prior stroke (2.06% vs. 0.35%, p < 0.001 for all stroke; 0.38% vs. 0.03%, p = 0.023 for ICH). The incidence of ICH among the AB-treated group was 0.065%; a history of prior stroke did not increase the incidence of ICH in the AB-treated group (0.39% vs. 0.0%, p = ns). Moreover, the post-PCI stroke rate was similar between the prior ICH or recent ischemic stroke-group and remote ischemic stroke-group (2 vs. 1.9%; OR: 1.03; 95% CI: 0.21-4.90; p = ns for all strokes; 2% vs. 1.5%; OR: 1.4; 95% CI: 0.27-6.91; p = ns for ischemic stroke). Importantly, no ICH occurred in patients with recent ischemic or any prior ICH stroke. CONCLUSIONS: Abciximab, in addition to aspirin, heparin and ADP-inhibitors does not increase the risk of stroke in patients with prior stroke undergoing PCI.


Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Acidente Vascular Cerebral/induzido quimicamente , Abciximab , Idoso , Angioplastia Coronária com Balão/métodos , Anticorpos Monoclonais/efeitos adversos , Anticoagulantes/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Incidência , Hemorragias Intracranianas , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação de Plaquetas/uso terapêutico , Recidiva , Estudos Retrospectivos , Risco , Acidente Vascular Cerebral/complicações
18.
Am J Health Syst Pharm ; 60(12): 1251-6, 2003 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-12845921

RESUMO

Outcomes in patients with acute myocardial infarction (AMI) who received adjunctive therapy with glycoprotein (GP) IIb/IIIa-receptor inhibitors during percutaneous coronary intervention (PCI) were studied. Data from a national all-payer database for the period from January 2000 to July 2001 were analyzed to compare in-hospital mortality, complications, incremental costs, and length of stay between AMI patients who did and did not receive a GP IIb/IIIa-receptor inhibitor during PCI. Risk adjustment was performed by logistic regression to account for differences in patient and institutional characteristics. Complications were evaluated as a composite of cardiac, noncardiac, procedural, and nonprocedural complications. Incremental costs and length of stay were analyzed by least-squares regression. A total of 32,529 patients in 99 hospitals were included. Only abciximab had a significant benefit for risk-adjusted mortality (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.59-0.92, p = 0.007) and shorter length of stay (0.21 day, 95% CI = 0.09-0.34 day, p = 0.0013) compared with the controls. Eptifibatide was associated with fewer complications (OR = 0.86, 95% CI = 0.75-0.98, p = 0.02), and tirofiban incurred the lowest incremental cost ($644, OR = $252-$1,036, p < 0.0001), but abciximab had the most favorable cost-effectiveness ratio ($14,515 per life-year gained). Information from a large database supported the use of GP IIb/IIIa-receptor inhibitors in patients with AMI undergoing PCI. Treatment with abciximab was associated with favorable differences in survival, cost-effectiveness, and length of stay compared to treatment without a GP IIb/IIIa-receptor inhibitor.


Assuntos
Angioplastia Coronária com Balão/estatística & dados numéricos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/cirurgia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Abciximab , Idoso , Anticorpos Monoclonais/economia , Anticorpos Monoclonais/uso terapêutico , Estudos de Casos e Controles , Custos de Medicamentos/estatística & dados numéricos , Eptifibatida , Feminino , Custos Hospitalares/estatística & dados numéricos , Mortalidade Hospitalar , Humanos , Fragmentos Fab das Imunoglobulinas/economia , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Peptídeos/economia , Peptídeos/uso terapêutico , Inibidores da Agregação de Plaquetas/economia , Inibidores da Agregação de Plaquetas/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/economia , Tirofibana , Resultado do Tratamento , Tirosina/análogos & derivados , Tirosina/economia , Tirosina/uso terapêutico , Estados Unidos/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA