RESUMO
OBJECTIVES: The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). BACKGROUND: Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. METHODS: Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. RESULTS: Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was ≥130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). CONCLUSIONS: Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.
Assuntos
Síndrome Coronariana Aguda/sangue , Doença da Artéria Coronariana/sangue , Lipoproteína(a)/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Biomarcadores/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Prevenção SecundáriaRESUMO
OBJECTIVES: This study sought to define the ability of AMG 145, a monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), to enable subjects at high risk for major adverse cardiovascular events to achieve National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) parameters for low-density lipoprotein cholesterol (LDL-C) and other lipid goals. BACKGROUND: Many patients at high risk for adverse cardiovascular events are unable to achieve the NCEP-ATP III LDL-C goal of <70 mg/dl, even with high-potency statin therapy. METHODS: In 282 subjects from the LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy-Thrombolysis In Myocardial Infarction 57) trial at high risk according to NCEP-ATP III criteria, we compared the proportion of subjects achieving the NCEP-ATP III recommended LDL-C goal of <70 mg/dl across treatment arms. Other outcomes included the triple goals of LDL-C <70 mg/dl, non-high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and apolipoprotein B (ApoB) <80 mg/dl. RESULTS: During the dosing interval, more than 90% of subjects in both of the top dose groups every 2 weeks and every 4 weeks attained this lipid target over the dosing interval, with similar success rates for the triple lipid goal. CONCLUSIONS: PCSK9 inhibition with AMG 145 enables high-risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing cardiovascular events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications.
Assuntos
Anticorpos Monoclonais/administração & dosagem , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Educação de Pacientes como Assunto , Pró-Proteína Convertases/antagonistas & inibidores , Terapia Trombolítica/métodos , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/complicações , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a). METHODS AND RESULTS: As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG145 70 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively (P<0.001 for each dose versus placebo). Likewise, AMG145 280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively (P<0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (ρ=0.33, P<0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values. CONCLUSIONS: AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient's atherogenic lipid profile.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Lipoproteína(a)/sangue , Pró-Proteína Convertases/imunologia , Serina Endopeptidases/imunologia , Idoso , Anticorpos Monoclonais Humanizados , Biomarcadores/sangue , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Pró-Proteína Convertase 9 , Fatores de Risco , Terapia TrombolíticaRESUMO
BACKGROUND: Children spend a significant amount of time in school. Little is known about the role of allergen exposure in school environments and asthma morbidity. OBJECTIVES: The School Inner-City Asthma Study (SICAS) is a National Institutes of Health (NIH)-funded prospective study evaluating the school/classroom-specific risk factors and asthma morbidity among urban children. METHODS/RESULTS: This article describes the design, methods, and important lessons learned from this extensive investigation. A single center is recruiting 500 elementary school-aged children, all of whom attend inner-city metropolitan schools. The primary hypothesis is that exposure to common indoor allergens in the classroom will increase the risk of asthma morbidity in children with asthma, even after controlling for home allergen exposures. The protocol includes screening surveys of entire schools and baseline eligibility assessments obtained in the spring prior to the academic year. Extensive baseline clinical visits are being conducted among eligible children with asthma during the summer prior to the academic school year. Environmental classroom/school assessments including settled dust and air sampling for allergen, mold, air pollution, and inspection data are collected twice during the academic school year and one home dust sample linked to the enrolled student. Clinical outcomes are measured every 3 months during the academic school year. CONCLUSION: The overall goal of SICAS is to complete the first study of its kind to better understand school-specific urban environmental factors on childhood asthma morbidity. We also discuss the unique challenges related to school-based urban research and lessons being learned from recruiting such a cohort.