RESUMO
Purpose: Hypertensive patients are at increased risk of atrial fibrillation (AF). Although low baseline high density lipoprotein (HDL) cholesterol has been associated with a higher risk of AF, this has not been verified in recent population-based studies. Whether changing levels of HDL over time are more strongly related to the risk of new AF in hypertensive patients has not been examined.Material and methods: Incident AF was examined in relation to baseline and on-treatment HDL levels in 8267 hypertensive patients with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. HDL levels at baseline and each year of testing were categorised into quartiles according to baseline HDL levels.Results: During 4.7 ± 1.10 years of follow-up, 645 patients (7.8%) developed new AF. In univariate Cox analyses, compared with the highest quartile of HDL levels (>1.78 mmol/l), patients with on-treatment HDL in the lowest quartile (≤ 1.21 mmol/l) had a 53% greater risk of new AF. Patients with on-treatment HDL in the second and third quartiles had intermediate increased risks of AF. Baseline HDL in the lowest quartile was not a significant predictor of new AF (hazard ratio (HR): 1.14, 95% confidence interval (CI): 0.90-1.43). In multivariable Cox analyses adjusting for multiple baseline and time-varying covariates, the lowest quartile of on-treatment HDL remained associated with a nearly 54% increased risk of new AF (HR: 1.54, 95% CI: 1.16-2.05) whereas a baseline HDL≤ ⩽1.21 mmol/l was not predictive of new AF (HR: 1.01, 95% CI: 0.78-1.31).Conclusion: Lower on-treatment HDL is strongly associated with risk of new AF. These findings suggest that serial assessment of HDL can estimate AF risk better than baseline HDL in hypertensive patients with left ventricular hypertrophy. Future studies may investigate whether therapies that increase HDL can lower risk of developing AF.Clinical Trials Registration: http://clinicaltrials.gov/ct/show/NCT00338260?order=1.
Assuntos
Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , Fibrilação Atrial/etiologia , HDL-Colesterol/sangue , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/complicações , Losartan/uso terapêutico , Idoso , Fibrilação Atrial/sangue , Fibrilação Atrial/tratamento farmacológico , Feminino , Seguimentos , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Robatumumab (19D12; MK-7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin-like growth factor receptor-1 (IGF-1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). PROCEDURE: Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. RESULTS: Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET-CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25-115 doses of robatumumab with remissions of >4 years duration (N = 6). CONCLUSIONS: These findings show that although the IGF-1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF-1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Sarcoma de Ewing/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Neoplasias Ósseas/mortalidade , Criança , Feminino , Humanos , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Osteossarcoma/mortalidade , Sarcoma de Ewing/mortalidadeRESUMO
PURPOSE: Aprepitant, an oral neurokinin-1 receptor antagonist, has demonstrated improved control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of aprepitant in patients receiving highly emetogenic chemotherapy (HEC) in Asian countries. METHODS: This multicenter, double-blind, placebo-controlled trial assessed the prevention of CINV during the acute phase (AP), delayed phase (DP), and overall phase (OP). Patients receiving HEC were randomized to either an aprepitant group (day 1, aprepitant 125 mg; days 2-3, aprepitant 80 mg) or a standard therapy group (days 1-3, placebo). Both groups received intravenous granisetron and oral dexamethasone. The primary end point was complete response (CR; no emesis and no use of rescue therapy) during the OP. RESULTS: Of the 421 randomized patients, 411 (98%) were assessable for efficacy; 69.6% (142/204) and 57.0% (118/207) of patients reported CR during the OP in the aprepitant and standard therapy groups, respectively (P = 0.007). CR rates in the aprepitant group were higher during the DP (74.0% vs. 59.4%, P = 0.001) but were similar during the AP (79.4% vs. 79.3%, P = 0.942). Toxicity and adverse events were comparable in both groups. CONCLUSIONS: The addition of aprepitant to standard antiemetic treatment regimens for Chinese patients undergoing HEC provided superior CINV prevention and was well tolerated.
Assuntos
Antieméticos/uso terapêutico , Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Morfolinas/uso terapêutico , Náusea/prevenção & controle , Vômito/prevenção & controle , Antieméticos/efeitos adversos , Antineoplásicos/uso terapêutico , Aprepitanto , Povo Asiático , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Náusea/induzido quimicamente , Vômito/induzido quimicamenteRESUMO
AIM: To determine if persistence of electrocardiographic (ECG) left ventricular hypertrophy (LVH) during aggressive systolic blood pressure (SBP) lowering would identify patients at increased risk. METHODS AND RESULTS: Adjudicated outcomes were examined in relation to the presence of LVH by mean in-treatment Cornell product (CP) in 463 hypertensive patients with mean in-treatment SBP ≤ 130 mmHg randomly assigned to losartan- or atenolol-based treatment. During mean follow-up of 4.4 ± 1.3 years, persistence of mean CP > 2440 mm ms in 211 patients (45.6%) was associated with significantly higher 4-year rates of cardiovascular death (8.9% vs 3.4%, p = 0.003), myocardial infarction (7.0% vs 3.3%, p = 0.010), stroke (8.5% vs 2.1%, p = 0.002), the composite endpoint of these events (20.0% vs 7.0%, p < 0.001) and all-cause mortality (14.9% vs 10.0%, p = 0.015). In multivariate Cox analyses, adjusting for a propensity score for CP LVH, randomized treatment and Framingham risk score entered as standard covariates and in-treatment diastolic BP and Sokolow-Lyon voltage LVH entered as time-varying covariates, persistence of CP LVH remained associated with statistically significant increased risks of cardiovascular death (hazard ratio, HR = 2.51, 95% CI 1.10-5.70), stroke (HR = 2.63, 95% CI 1.03-6.97) and the composite endpoint (HR = 2.46, 95% CI 1.36-4.45). CONCLUSIONS: These findings suggest that persistence of LVH in a subset of these patients may in part explain the lack of benefit found in hypertensive patients despite treatment to lower SBP.
Assuntos
Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/patologia , Idoso , Método Duplo-Cego , Eletrocardiografia , Feminino , Humanos , Hipertensão/mortalidade , Masculino , Prognóstico , Estudos Prospectivos , Sístole , Resultado do TratamentoRESUMO
BACKGROUND: Although higher heart rate (HR) at baseline has been associated with an increased risk of cardiovascular (CV) and all-cause mortality, the relationship of in-treatment HR over time to mortality in hypertensive patients with ECG left ventricular hypertrophy (LVH) has not been examined. METHODS AND RESULTS: Heart rate was evaluated over time in 9190 hypertensive patients treated with losartan- or atenolol-based regimens and followed with annual ECGs. During a mean follow-up of 4.8 ± 0.9 years, 814 patients (8.9%) died, 438 (4.8%) from CV causes. In univariate Cox analyses, every 10 bpm higher HR on in-treatment ECGs was associated with a 25% increased risk of CV death [95% confidence interval (CI): 14-32%] and a 27% greater risk of all-cause mortality (95% CI: 21-34%). In an alternative analysis, persistence or development of a HR ≥ 84 bpm (upper quintile of baseline HR) was associated with an 89% greater risk of CV death (95% CI: 49-141%) and a 97% increased risk of all-cause mortality (95% CI: 65-135%). After adjusting for treatment with losartan vs. atenolol, baseline risk factors for death, baseline HR, baseline and in-treatment systolic and diastolic pressure, incident myocardial infarction, and the known predictive value of baseline and in-treatment QRS duration and ECG LVH, higher in-treatment HR in time-varying multivariable Cox models remained strongly predictive of mortality: every 10 bpm higher HR was associated with a 16% increased adjusted risk of CV mortality (95% CI: 6-27%) and a 25% greater risk of all-cause mortality (95% CI: 17-33%), with persistence or development of a HR ≥ 84 associated with a 55% greater risk of CV death (95% CI: 16-105%) and a 79% greater adjusted risk of all-cause mortality (95% CI: 46-121%). CONCLUSION: Higher in-treatment HR on serial ECGs predicts greater likelihood of subsequent CV or all-cause mortality, independent of treatment modality, blood pressure lowering, regression of ECG LVH and changing QRS duration in hypertensive patients with ECG LVH. These findings support the value of serial assessment of HR for improved risk stratification in hypertensive patients. CLINICAL TRIALS REGISTRATION: http://clinicaltrials.gov/ct/show/NCT00338260?order=1cp.
Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/mortalidade , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/fisiopatologia , Idoso , Arritmias Cardíacas/complicações , Arritmias Cardíacas/mortalidade , Atenolol/uso terapêutico , Causas de Morte , Método Duplo-Cego , Eletrocardiografia , Feminino , Humanos , Hipertensão/fisiopatologia , Estimativa de Kaplan-Meier , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: This pharmacogenetics substudy from the Losartan Intervention for Endpoint reduction in Hypertension study in patients with hypertension and left ventricular hypertrophy (LVH) treated with the angiotensin receptor blocker losartan versus the beta-blocker atenolol for 4.8 years tested whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and 12 other previously well-characterized polymorphisms of hypertension susceptibility genes affected blood pressure reduction, heart rate reduction, cardiovascular events, and/or response to treatment. These polymorphisms were chosen because they could affect blood pressure control or the pharmacological action of losartan or atenolol. METHODS: We genotyped 3503 patients, 1774 on losartan and 1729 on atenolol. RESULTS: ACE and the 12 other genotypes did not affect the reduction in systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, or heart rate, or treatment differences between losartan and atenolol on these endpoints, as assessed by general linear models. Also, ACE and the 12 other genotypes did not affect risk of the primary composite endpoint or its components stroke, myocardial infarction, and cardiovascular death, or treatment differences between losartan and atenolol on these endpoints, as assessed by Cox proportional hazards models including baseline Framingham risk score and LVH. CONCLUSION: ACE insertion/deletion and 12 other polymorphisms of hypertension susceptibility genes did not affect blood pressure reduction, heart rate reduction, or cardiovascular events in patients with hypertension and LVH, or treatment differences between losartan and atenolol on these endpoints. These results suggest that the observed effects of losartan versus atenolol in the Losartan Intervention for Endpoint reduction in hypertension study do not depend on ACE and 12 other polymorphisms of hypertension susceptibility genes.
Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Mutação INDEL/genética , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Polimorfismo Genético , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Determinação de Ponto Final , Feminino , Genótipo , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/fisiopatologia , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
OBJECTIVE: We assessed readily available patient characteristics, including albuminuria (not included in traditional cardiovascular risk scores), as predictors of cardiovascular events in hypertension with left ventricular hypertrophy (LVH) and developed risk algorithms/scores for outcomes. METHODS: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared effects of losartan-based versus atenolol-based therapy on cardiovascular events in 9193 patients with hypertension and LVH. Univariate and multivariate analyses identified baseline variables with significant impact on development of the primary composite endpoint (cardiovascular death, stroke and myocardial infarction) and its components. Multivariate analysis used a Cox regression model with stepwise selection process. Risk scores were developed from coefficients of risk factors from the multivariate analysis, validated internally using naïve and jack-knife procedures, checked for discrimination and calibration, and compared with Framingham coronary heart disease and other risk scores. RESULTS: LIFE risk scores showed increasing endpoint rates with increasing quintile (first to fifth quintile, composite endpoint 2.8-26.7%, cardiovascular death 0.5-14.4%, stroke 1.2-11.3%, myocardial infarction 1.4-8.1%) and were confirmed with a jack-knife approach that adjusts for potentially optimistic bias. The Framingham coronary heart disease and other risk scores overestimated risk in lower risk patients and underestimated risk in higher risk patients, except for myocardial infarction. CONCLUSION: A number of patient characteristics predicted cardiovascular events in patients with hypertension and LVH. Risk scores developed from these patient characteristics, including albuminuria, strongly predicted outcomes and may improve risk assessment of patients with hypertension and LVH and planning of clinical trials.
Assuntos
Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Losartan/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: A phase III, randomized, double-blind, placebo-controlled clinical study was conducted in China to assess the efficacy, safety, and immunogenicity of the pentavalent rotavirus vaccine (RotaTeqTM, RV5) among Chinese infants. The efficacy and safety data have been previously reported. This report presents the immunogenicity data of the study. METHODS: 4,040 infants aged 6-12â¯weeks were randomly assigned in a 1:1 ratio to receive 3 oral doses of RV5 or placebo. Trivalent oral poliovirus vaccine (tOPV) and diphtheria, tetanus, and acellular pertussis vaccine (DTaP) were administered in a staggered-use (Nâ¯=â¯3,240) or concomitant-use (Nâ¯=â¯800) schedule. Immunogenicity of RV5 was evaluated in 800 participants (400 participants from each staggered- and concomitant-use immunogenicity subgroup). Geometric mean titers (GMTs) and seroresponse rates (≥3-fold rise from baseline to PD3) were measured for anti-rotavirus IgA in the staggered- and concomitant-use subgroups and measured for serum neutralizing antibodies (SNAs) to human rotavirus serotypes G1, G2, G3, G4, P1A[8] in the staggered-use subgroup. Immune responses to tOPV and DTaP co-administered with RV5 were also evaluated in the concomitant-use immunogenicity subgroup. (ClinicalTrials.gov registry: NCT02062385) RESULTS: The PD3 GMT and seroresponse rate of anti-rotavirus IgA were higher in the RV5 group (82.42 units/mL, 89.4%) compared to the placebo group (0.33 units/mL, 10.1%). Rotavirus type-specific SNA responses were also higher in the RV5 group compared to the placebo group. In the concomitant-use subgroup, the seroprotection rates of anti-poliovirus type 1, 2, 3 in the participants who received RV5 were non-inferior to those who received placebo, and the antibody responses to DTaP antigens were comparable between the two vaccination groups. CONCLUSIONS: RV5 was immunogenic in Chinese infants. Immune responses induced by tOPV and DTaP were not affected by the concomitant use of RV5.
Assuntos
Gastroenterite/imunologia , Gastroenterite/prevenção & controle , Imunogenicidade da Vacina , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Rotavirus/imunologia , Vacinas Virais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , China , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Lactente , Masculino , Vacinação , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversosRESUMO
The optimal hemoglobin level in patients with hypertension or heart failure is not yet defined. The aim of the present investigation was to examine the relation of hemoglobin with cardiovascular outcomes in high-risk patients with isolated systolic hypertension (ISH) and left ventricular hypertrophy (LVH). In 1,326 patients with ISH in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, hemoglobin and cardiovascular outcomes were examined using Cox proportional hazard models. Baseline hemoglobin was negatively related to rate of cardiovascular death (hazard ratio 0.81 per 1 g/dl, 95% confidence interval [CI] 0.67 to 0.98, p = 0.032) after adjusting for baseline Framingham risk score, LVH, treatment, and estimated glomerular filtration rate. Hemoglobin decreased slightly during the study and the decrease was more pronounced in the losartan group (13.9 +/- 1.3 to 13.6 +/- 1.4 g/dl) than in the atenolol group (13.9 +/- 1.2 to 13.8 +/- 1.4 g/dl). Hemoglobin as a time-varying covariate was negatively associated with rate of cardiovascular death (hazard ratio 0.75, 95% CI 0.63 to 0.90, p <0.001) and stroke (hazard ratio 0.84, 95% CI 0.72 to 0.99, p = 0.040) after adjusting for baseline Framingham risk score, LVH, treatment, and estimated glomerular filtration rate. In conclusion, in this high-risk population with ISH and LVH, lower hemoglobin at baseline was associated with higher probability of cardiovascular death, and decrease in hemoglobin over time was associated with higher probability of cardiovascular death or stroke; this effect was attenuated by treatment with losartan.
Assuntos
Doenças Cardiovasculares/etiologia , Hemoglobinas/análise , Hipertensão/sangue , Hipertrofia Ventricular Esquerda/sangue , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , Causas de Morte , Método Duplo-Cego , Eletrocardiografia , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/complicações , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acidente Vascular Cerebral/etiologiaRESUMO
BACKGROUND: Patients with hypertension with ECG left ventricular hypertrophy (LVH) have higher cardiovascular morbidity and mortality, but single ECG criteria may underestimate risk. Whether continued presence or new development of ECG LVH by 2 criteria can further concentrate risk during blood pressure lowering is unclear. METHODS AND RESULTS: Incident stroke, myocardial infarction, cardiovascular death, the composite of these outcomes, and all-cause mortality were examined in relation to the presence of on-treatment ECG LVH by Cornell product and/or Sokolow-Lyon voltage during a mean of 4.8±0.9 years follow-up in 9193 patients with hypertension randomized to losartan- or atenolol-based regimens. Patients were categorized into 4 groups according to the presence or absence of ECG LVH by each criterion at baseline and yearly during the study. At baseline, LVH by both criteria was present in 960 patients (10.4%). Compared with the absence of ECG LVH by both criteria, persistence or development of ECG LVH by both criteria entered as a time-varying covariate was associated with >3-fold increased risks of events in multivariable Cox analyses adjusting for randomized treatment, baseline risk factors, and on-treatment heart rate and systolic and diastolic blood pressures. Patients with ECG LVH by either Cornell product or Sokolow-Lyon voltage had 45% to 140% higher risks of all end points. CONCLUSIONS: Persistence or development of ECG LVH by both Cornell product and Sokolow-Lyon voltage criteria during antihypertensive therapy is associated with markedly increased risks of cardiovascular end points and all-cause mortality. Further study is indicated to determine whether additional therapy in these patients can reduce their risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00338260.
Assuntos
Atenolol/uso terapêutico , Eletrocardiografia , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/diagnóstico , Losartan/uso terapêutico , Idoso , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/epidemiologia , Hipertrofia Ventricular Esquerda/etiologia , Incidência , Masculino , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Rotavirus is the leading cause of severe diarrhea worldwide in young children. Although rotavirus vaccine efficacy is high in developed countries, efficacy is lower in developing countries. Here, we investigated heterogeneity of rotavirus vaccine efficacy by infant characteristics in developing countries. METHODS: An exploratory, post hoc analysis was conducted using randomized controlled trial data of the pentavalent rotavirus vaccine (RV5) conducted in Africa and Asia (NCT00362648). Infants received either 3 doses of vaccine/placebo and were followed for up to 2 years. Within subgroups, vaccine efficacies and 95% confidence intervals (CIs) against rotavirus gastroenteritis (RVGE) were estimated using Poisson regression. We assessed heterogeneity of efficacy by age at first dose, gender, breastfeeding status and nutrition status. RESULTS: African children receiving the first dose at <8 weeks had lower efficacy (23.7%; 95% CI: -8.2%-46.3%) than those vaccinated at ≥8 weeks (59.1%; 95% CI: 34.0%-74.6%). Marginally statistically significant differences were observed by age at first dose, gender and underweight status in Ghana and gender in Asian countries. CONCLUSIONS: Heterogeneity of efficacy was observed for age at first dose in African countries. This was an exploratory analysis; additional studies are needed to validate these results.
Assuntos
Gastroenterite/epidemiologia , Gastroenterite/prevenção & controle , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/uso terapêutico , Vacinação/estatística & dados numéricos , Bangladesh , Países em Desenvolvimento , Feminino , Gana , Humanos , Lactente , Recém-Nascido , Masculino , Mali , Ensaios Clínicos Controlados Aleatórios como Assunto , Rotavirus , Vacinas contra Rotavirus/administração & dosagemRESUMO
BACKGROUND: A randomized, double-blind, placebo-controlled multicenter trial was conducted in healthy Chinese infants to assess the efficacy and safety of a pentavalent live human-bovine reassortant rotavirus vaccine (RotaTeq™, RV5) against rotavirus gastroenteritis (RVGE). METHODS: 4040 participants aged 6-12weeks were enrolled and randomly assigned to either 3 oral doses of RV5 (n=2020) or placebo (n=2020), administered â¼4weeks apart. The participants also received OPV and DTaP in a concomitant or staggered fashion. The primary objective was to evaluate vaccine efficacy (VE) against naturally-occurring RVGE at least 14days following the third dose. Key secondary objectives included: VE against naturally-occurring severe RVGE and VE against severe and any-severity RVGE caused by rotavirus serotypes contained in the vaccine, occurring at least 14days after the third dose. All adverse events (AEs) were collected for 30days following each dose. Serious AEs (SAEs) and intussusception cases were collected during the entire study. (ClinicalTrials.gov registry: NCT02062385). RESULTS: VE against RVGE of any-severity caused by any serotype was 69.3% (95% CI: 54.5, 79.7). The secondary efficacy analysis showed an efficacy of: 78.9% (95% CI: 59.1, 90.1) against severe RVGE caused by any serotype; 69.9% (95% CI: 55.2, 80.3) and 78.9% (95% CI: 59.1, 90.1) against any-severity and severe RVGE caused by serotypes contained in the vaccine, respectively. Within 30days following any vaccination, 53.5% (1079/2015) and 53.3% (1077/2019) of participants reported at least one AE, and 5.8% (116/2015) and 5.7% (116/2019) reported SAEs in the vaccine and placebo groups, respectively. No SAEs were considered vaccine-related in recipients of RV5. Two intussusception cases were reported in recipients of RV5 who recovered after receiving treatment. Neither was considered vaccine-related. CONCLUSIONS: In Chinese infants, RV5 was efficacious against any-severity and severe RVGE caused by any serotype and generally well-tolerated with respect to AEs.
Assuntos
Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/imunologia , Rotavirus/imunologia , Vacinas Atenuadas/imunologia , Animais , Povo Asiático , Bovinos , Método Duplo-Cego , Feminino , Gastroenterite/imunologia , Gastroenterite/prevenção & controle , Humanos , Lactente , Saúde do Lactente , Masculino , Índice de Gravidade de Doença , Vacinação/métodosRESUMO
BACKGROUND: Obesity may independently increase the risk of adverse events in hypertension with target-organ damage. We investigated whether body build was independently associated with higher cardiovascular risk and whether treatment with losartan relative to atenolol influenced the impact of body build on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and on cardiovascular death in patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. METHODS AND RESULTS: The population of 9079 patients was divided as follows: thin (body mass index [BMI] <20 kg/m2, 2%), normal weight (BMI 20 to 24.9, 24%), overweight (BMI 25 to 29.9, 45%), and obese (class I: BMI 30 to 34.9, 21%; class II: BMI 35 to 39.9, 6%; class III: BMI > or =40, 2%). Incident diabetes increased progressively with BMI and was somewhat higher in the atenolol arm. Differences in gender and race were detected among the body build groups. Rates (Cox proportional hazard analysis) of the primary composite end point did not differ among body build groups after adjustment for age, gender, race, smoking habit, prevalent cardiovascular disease, and left ventricular hypertrophy. Cardiovascular death was more frequent among thin (P<0.05) and pooled class II-III obesity (both P<0.04) than normal-weight groups. Risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan- as opposed to atenolol-based treatment. CONCLUSIONS: In the LIFE study, stratification for classes of body build identified increased risk of cardiovascular mortality in both thin and moderately-to-severely obese individuals. This risk was not attenuated significantly by losartan treatment, nor did it interfere with the greater benefit of losartan-based treatment as opposed to atenolol-based treatment.
Assuntos
Doenças Cardiovasculares/fisiopatologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Somatotipos/fisiologia , Idoso , Atenolol/uso terapêutico , Índice de Massa Corporal , Peso Corporal , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade , Modelos de Riscos Proporcionais , Medição de RiscoRESUMO
CONTEXT: Atrial fibrillation (AF) is associated with increased risk of mortality and cardiovascular events, particularly stroke, making prevention of new-onset AF a clinical priority. Although the presence and severity of electrocardiographic left ventricular hypertrophy (LVH) appear to predict development of AF, whether regression of electrocardiographic LVH is associated with a decreased incidence of AF is unclear. OBJECTIVE: To test the hypothesis that in-treatment regression or continued absence of electrocardiographic LVH during antihypertensive therapy is associated with a decreased incidence of AF, independent of blood pressure and treatment modality. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, parallel-group study conducted in 1995-2001 among 8831 men and women with hypertension, aged 55-80 years (median, 67 years), with electrocardiographic LVH by Cornell voltage-duration product or Sokolow-Lyon voltage, with no history of AF, without AF on the baseline electrocardiogram, and enrolled in the Losartan Intervention for Endpoint Reduction in Hypertension Study. INTERVENTIONS: Losartan- or atenolol-based treatment regimens, with follow-up assessments at 6 months and then yearly until death or study end. MAIN OUTCOME MEASURE: New-onset AF in relation to electrocardiographic LVH determined at baseline and subsequently. Electrocardiographic LVH was measured using sex-adjusted Cornell product criteria ({R(aVL) + S(V3) [+ 6 mm in women]} x QRS duration). RESULTS: After a mean (SD) follow-up of 4.7 (1.1) years, new-onset AF occurred in 290 patients with in-treatment regression or continued absence of Cornell product LVH for a rate of 14.9 per 1000 patient-years and in 411 patients with in-treatment persistence or development of LVH by Cornell product criteria for a rate of 19.0 per 1000 patient-years. In time-dependent Cox analyses adjusted for treatment effects, baseline differences in risk factors for AF, baseline and in-treatment blood pressure, and baseline severity of electrocardiographic LVH, lower in-treatment Cornell product LVH treated as a time-varying covariate was associated with a 12.4% lower rate of new-onset AF (adjusted hazard ratio [HR], 0.88; 95% CI, 0.80-0.97; P = .007) for every 1050 mm x msec (per 1-SD) lower Cornell product, with persistence of the benefit of losartan vs atenolol therapy on developing AF (HR, 0.83; 95% CI, 0.71-0.97; P = .01). CONCLUSIONS: Lower Cornell product electrocardiographic LVH during antihypertensive therapy is associated with a lower likelihood of new-onset AF, independent of blood pressure lowering and treatment modality in essential hypertension. These findings suggest that antihypertensive therapy targeted at regression or prevention of electrocardiographic LVH may reduce the incidence of new-onset AF.
Assuntos
Anti-Hipertensivos/uso terapêutico , Fibrilação Atrial/epidemiologia , Eletrocardiografia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Idoso , Atenolol/uso terapêutico , Fibrilação Atrial/prevenção & controle , Método Duplo-Cego , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Incidência , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Indução de Remissão , RiscoRESUMO
OBJECTIVE: Metabolic factors such as glycemic control, hyperlipidemia, and hyperkalemia are important considerations in the treatment of patients with type 2 diabetes and nephropathy. In the RENAAL (Reduction of End Points in Type 2 Diabetes With the Angiotensin II Antagonist Losartan) study, losartan reduced renal outcomes in the patient population. This post hoc analysis of the RENAAL study reports the effects of losartan on selected metabolic parameters and assesses the relationship between baseline values of metabolic parameters and the primary composite end point or end-stage renal disease (ESRD). RESEARCH DESIGN AND METHODS: Glycemic control (HbA(1c)) and serum lipid, uric acid, and potassium levels were compared between the losartan and placebo groups over time, and baseline levels were correlated with the risk of reaching the primary composite end point (doubling of serum creatinine, ESRD, or death) or ESRD alone. RESULTS: Losartan did not adversely affect glycemic control or serum lipid levels. Losartan-treated patients had lower total (227.4 vs. 195.4 mg/dl) and LDL (142.2 vs. 111.7 mg/dl) cholesterol. Losartan was associated with a mean increase of up to 0.3 mEq/l in serum potassium levels; however, the rate of hyperkalemia-related discontinuation was similar between the placebo and losartan groups. Univariate analysis revealed that baseline total and LDL cholesterol and triglyceride levels were associated with increased risk of developing the primary composite end point. Similarly, total and LDL cholesterol were also associated with increased risk of developing ESRD. CONCLUSIONS: Overall, losartan was well tolerated by patients with type 2 diabetes and nephropathy and was associated with a favorable effect on the metabolic profile of this population.
Assuntos
Colesterol/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Falência Renal Crônica/epidemiologia , Triglicerídeos/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Creatinina/sangue , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Hemoglobinas Glicadas/análise , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Digoxin is widely used for rate control of atrial fibrillation. However, recent studies have reported conflicting results on the association of digoxin with mortality when used in patients with atrial fibrillation. Moreover, the relationship of digoxin use to mortality in hypertensive patients with atrial fibrillation has not been examined. METHODS AND RESULTS: All-cause mortality was examined in relation to in-treatment digoxin use in 937 hypertensive patients with ECG left ventricular hypertrophy in atrial fibrillation at baseline (nâ=â134) or who developed atrial fibrillation during follow-up (nâ=â803), randomly assigned to losartan or atenolol-based treatment, in post-hoc analysis of a substudy of the Losartan Intervention For Endpoint Reduction in hypertension (LIFE) trial. During 4.7â±â1.1 years of mean follow-up, 167 patients died (17.8%) and 372 (39.7%) were treated with digoxin. In univariate Cox analyses, in-treatment digoxin use, entered as a time-varying covariate, was associated with a 61% higher risk of dying (hazard ratio 1.61, 95% confidence interval 1.18-2.19, Pâ=â0.003). After adjusting for other univariate predictors of death in this population, including age, diabetes, history of ischemic heart disease, stroke, or heart failure, baseline Cornell product, QRS duration, heart rate, serum glucose, creatinine and high-density lipoprotein cholesterol, and a propensity score for digoxin use entered as standard covariates, and for in-treatment heart rate, pulse pressure, and Sokolow-Lyon voltage treated as time-varying covariates, digoxin use was no longer a significant predictor of mortality (hazard ratio 1.04, 95% confidence interval 0.73-1.48, Pâ=â0.839). CONCLUSION: In hypertensive patients with ECG left ventricular hypertrophy with existing or new atrial fibrillation, digoxin use is not associated with a significantly increased risk of all-cause mortality after adjusting for other independent predictors of death and for the factors associated with the propensity to use digoxin in this population. These findings suggest that factors other than digoxin use may account for the increased mortality found with digoxin use in some studies. CLINICAL TRIALS REGISTRATION: .
Assuntos
Antiarrítmicos/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Digoxina/efeitos adversos , Hipertensão/mortalidade , Idoso , Antiarrítmicos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , Fibrilação Atrial/etiologia , Pressão Sanguínea , Digoxina/uso terapêutico , Eletrocardiografia , Feminino , Insuficiência Cardíaca/epidemiologia , Frequência Cardíaca , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Lipoproteínas HDL/sangue , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , RiscoRESUMO
UNLABELLED: There is a well-established association between hypertension and atrial fibrillation (AF); indeed, even upper normal systolic blood pressures (SBP) are long-term predictors of incident AF. These findings suggest that more aggressive BP control may reduce the risk of new AF. However, whether lower achieved SBP is associated with a lower incidence of AF remains unclear. The risk of new-onset AF was examined in relation to last in-treatment SBP before AF diagnosis or last in-study measurement in the absence of new AF in 8831 hypertensive patients with ECG left ventricular hypertrophy with no history of AF, in sinus rhythm on their baseline ECG, randomly assigned to losartan- or atenolol-based treatment. Patients with in-treatment SBP ≤130 mm Hg (lowest quintile at last measurement) and SBP between 131 and 141 mm Hg were compared with patients with in-treatment SBP ≥142 mm Hg (median SBP at last measurement). During follow-up of 4.6±1.1 years, new-onset AF was diagnosed in 701 patients (7.9%). In multivariate Cox analyses, compared with in-treatment SBP ≥142 mm Hg, in-treatment SBP ≤130 mm Hg entered as a time-varying covariate was associated with a 40% lower risk (95% confidence interval, 18%-55%) and in-treatment SBP of 131 to 141 mm Hg with a 24% lower risk (95% confidence interval, 7%-38%) of new AF. Thus, achieved SBP ≤130 mm Hg is associated with a lower risk of new-onset AF in hypertensive patients with ECG left ventricular hypertrophy. Further study is needed to determine whether targeting hypertensive patients without AF to lower SBP goals can reduce the burden of new AF in this high-risk population. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00338260.
Assuntos
Anti-Hipertensivos/uso terapêutico , Atenolol/uso terapêutico , Fibrilação Atrial/epidemiologia , Pressão Sanguínea/fisiologia , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Idoso , Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Fibrilação Atrial/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Eletrocardiografia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/fisiopatologia , Incidência , Losartan/farmacologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco , Sístole/efeitos dos fármacos , Sístole/fisiologia , Resultado do TratamentoRESUMO
In the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study, 4.8 years' losartan- versus atenolol-based antihypertensive treatment reduced left ventricular hypertrophy and cardiovascular end points, including cardiovascular death and stroke. However, there was no difference in myocardial infarction (MI), possibly related to greater reduction in myocardial oxygen demand by atenolol-based treatment. Myocardial oxygen demand was assessed indirectly by the left ventricular mass×wall stress×heart rate (triple product) in 905 LIFE participants. The triple product was included as time-varying covariate in Cox models assessing predictors of the LIFE primary composite end point (cardiovascular death, MI, or stroke), its individual components, and all-cause mortality. At baseline, the triple product in both treatment groups was, compared with normal adults, elevated in 70% of patients. During randomized treatment, the triple product was reduced more by atenolol, with prevalences of elevated triple product of 39% versus 51% on losartan (both P≤0.001). In Cox regression analyses adjusting for age, smoking, diabetes mellitus, and prior stroke, MI, and heart failure, 1 SD lower triple product was associated with 23% (95% confidence interval 13%-32%) fewer composite end points, 31% (18%-41%) less cardiovascular mortality, 30% (15%-41%) lower MI, and 22% (11%-33%) lower all-cause mortality (all P≤0.001), without association with stroke (P=0.34). Although losartan-based therapy reduced ventricular mass more, greater heart rate reduction with atenolol resulted in larger reduction of the triple product. Lower triple product during antihypertensive treatment was strongly, independently associated with lower rates of the LIFE primary composite end point, cardiovascular death, and MI, but not stroke.
Assuntos
Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Frequência Cardíaca/fisiologia , Ventrículos do Coração/fisiopatologia , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/farmacologia , Atenolol/farmacologia , Atenolol/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/fisiopatologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/epidemiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Oxigênio/metabolismo , Prevalência , Acidente Vascular Cerebral/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: Blacks have a higher prevalence of risk factors for atrial fibrillation (AF), such as hypertension, obesity, and heart failure, than nonblacks. Although population-based studies have demonstrated a lower prevalence and incidence of AF in blacks, the relationship of incident AF to race among hypertensive patients undergoing blood pressure lowering has been less extensively examined. METHODS: Incident AF was examined in 518 black and 8,313 nonblack hypertensive patients with electrocardiographic left ventricular hypertrophy (LVH) with no history of AF in sinus rhythm on their baseline electrocardiogram, who were randomly assigned to losartan- or atenolol-based treatment. RESULTS: During a mean of 4.7±1.1 years of follow-up, new-onset AF occurred in 701 patients (7.9%); 5-year AF incidence was significantly lower in black than nonblack patients (6.1 vs. 8.3%; P = 0.03). In univariable Cox analyses, black race was associated with a 37% lower risk of new AF (hazard ratio (HR) = 0.63; 95% confidence interval (CI) = 0.45-1.00; P = 0.05). In multivariable Cox analyses adjusting for randomized treatment, age, sex, diabetes, history of heart failure, myocardial infarction, ischemic heart disease, stroke, peripheral vascular disease, smoking status, baseline body mass index, serum total and high-density lipoprotein cholesterol, creatinine, glucose, and urine albumin/creatinine ratio as standard risk factors, and for incident myocardial infarction, in-treatment heart rate, systolic and diastolic pressure, Cornell product, and Sokolow-Lyon voltage LVH treated as time-varying covariables, black race remained associated with a 45% decreased risk of developing new AF (HR = 0.55; 95% CI = 0.35-0.87; P = 0.01). CONCLUSIONS: Incident AF is substantially less common among black than nonblack hypertensive patients.
Assuntos
Fibrilação Atrial/epidemiologia , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Idoso , Anti-Hipertensivos/uso terapêutico , Fibrilação Atrial/mortalidade , Fibrilação Atrial/fisiopatologia , População Negra , Feminino , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , População BrancaRESUMO
BACKGROUND: Prevalent atrial fibrillation (AF) is associated with a higher sudden cardiac death (SCD) rate in some populations, and incident AF predicts increased mortality risk in the general population and after myocardial infarction. However, the relationship of SCD to new-onset AF is unclear. METHODS AND RESULTS: The relationship of SCD to new-onset AF was evaluated in 8831 hypertensive patients with electrocardiographic left ventricular hypertrophy with no history of AF, in sinus rhythm on their baseline electrocardiogram, randomly assigned to losartan- or atenolol-based treatment. During 4.7±1.1 years mean follow-up, new-onset AF occurred in 701 patients (7.9%) and SCD in 151 patients (1.7%). In univariate Cox analyses, new-onset AF was associated with a >4-fold higher risk of SCD (hazard ratio, 4.69; 95% CI interval, 2.96-7.45; P<0.001). In multivariate Cox analyses adjusting for age, sex, race, diabetes mellitus, history of heart failure, myocardial infarction, ischemic heart disease, stroke, smoking, serum high-density lipoprotein cholesterol, creatinine, glucose, and urine albumin/creatinine ratio as standard risk factors, and for incident myocardial infarction, in-treatment use of digoxin, systolic and diastolic pressure, heart rate, QRS duration, Cornell voltage-duration product, and Sokolow-Lyon voltage left ventricular hypertrophy treated as time-varying covariates, new-onset AF remained associated with a >3-fold increased risk of SCD (hazard ratio, 3.13; 95% confidence interval, 1.87-5.24; P<0.001). CONCLUSIONS: Development of new-onset AF identifies hypertensive patients at increased risk of SCD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00338260.