RÉSUMÉ
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.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Aténolol/usage thérapeutique , Fibrillation auriculaire/étiologie , Cholestérol HDL/sang , Hypertension artérielle/complications , Hypertrophie ventriculaire gauche/complications , Losartan/usage thérapeutique , Sujet âgé , Fibrillation auriculaire/sang , Fibrillation auriculaire/traitement médicamenteux , Femelle , Études de suivi , Humains , Hypertension artérielle/sang , Hypertension artérielle/traitement médicamenteux , Hypertrophie ventriculaire gauche/sang , Hypertrophie ventriculaire gauche/traitement médicamenteux , Incidence , Mâle , Adulte d'âge moyen , Facteurs de risqueRÉSUMÉ
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.
Sujet(s)
Gastroentérite/immunologie , Gastroentérite/prévention et contrôle , Immunogénicité des vaccins , Infections à rotavirus/immunologie , Infections à rotavirus/prévention et contrôle , Rotavirus/immunologie , Vaccins antiviraux/immunologie , Anticorps neutralisants/sang , Anticorps neutralisants/immunologie , Anticorps antiviraux/sang , Anticorps antiviraux/immunologie , Chine , Femelle , Humains , Immunoglobuline A/sang , Immunoglobuline A/immunologie , Nourrisson , Mâle , Vaccination , Vaccins antiviraux/administration et posologie , Vaccins antiviraux/effets indésirablesRÉSUMÉ
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.
Sujet(s)
Aténolol/usage thérapeutique , Électrocardiographie , Hypertension artérielle/complications , Hypertrophie ventriculaire gauche/diagnostic , Losartan/usage thérapeutique , Sujet âgé , Antihypertenseurs/usage thérapeutique , Femelle , Humains , Hypertension artérielle/traitement médicamenteux , Hypertension artérielle/physiopathologie , Hypertrophie ventriculaire gauche/épidémiologie , Hypertrophie ventriculaire gauche/étiologie , Incidence , Mâle , Facteurs de risque , Taux de survie/tendances , Résultat thérapeutique , États-Unis/épidémiologieRÉSUMÉ
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.
Sujet(s)
Infections à rotavirus/immunologie , Infections à rotavirus/prévention et contrôle , Vaccins anti-rotavirus/immunologie , Rotavirus/immunologie , Vaccins atténués/immunologie , Animaux , Asiatiques , Bovins , Méthode en double aveugle , Femelle , Gastroentérite/immunologie , Gastroentérite/prévention et contrôle , Humains , Nourrisson , Santé infantile , Mâle , Indice de gravité de la maladie , Vaccination/méthodesRÉSUMÉ
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.
Sujet(s)
Gastroentérite/épidémiologie , Gastroentérite/prévention et contrôle , Infections à rotavirus/épidémiologie , Infections à rotavirus/prévention et contrôle , Vaccins anti-rotavirus/usage thérapeutique , Vaccination/statistiques et données numériques , Bangladesh , Pays en voie de développement , Femelle , Ghana , Humains , Nourrisson , Nouveau-né , Mâle , Mali , Essais contrôlés randomisés comme sujet , Rotavirus , Vaccins anti-rotavirus/administration et posologieRÉSUMÉ
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).
Sujet(s)
Anticorps monoclonaux/usage thérapeutique , Tumeurs osseuses/traitement médicamenteux , Ostéosarcome/traitement médicamenteux , Récepteur IGF de type 1/antagonistes et inhibiteurs , Sarcome d'Ewing/traitement médicamenteux , Adolescent , Adulte , Sujet âgé , Anticorps monoclonaux/effets indésirables , Anticorps monoclonaux humanisés , Tumeurs osseuses/mortalité , Enfant , Femelle , Humains , Antigène KI-67/analyse , Mâle , Adulte d'âge moyen , Ostéosarcome/mortalité , Sarcome d'Ewing/mortalitéRÉSUMÉ
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.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Maladies cardiovasculaires/épidémiologie , Rythme cardiaque/physiologie , Ventricules cardiaques/physiopathologie , Hypertension artérielle/traitement médicamenteux , Infarctus du myocarde/épidémiologie , Accident vasculaire cérébral/épidémiologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Antagonistes du récepteur de type 1 de l'angiotensine-II/pharmacologie , Antagonistes du récepteur de type 1 de l'angiotensine-II/usage thérapeutique , Antihypertenseurs/pharmacologie , Aténolol/pharmacologie , Aténolol/usage thérapeutique , Pression sanguine/effets des médicaments et des substances chimiques , Pression sanguine/physiologie , Maladies cardiovasculaires/physiopathologie , Femelle , Rythme cardiaque/effets des médicaments et des substances chimiques , Ventricules cardiaques/effets des médicaments et des substances chimiques , Ventricules cardiaques/métabolisme , Humains , Hypertension artérielle/complications , Hypertension artérielle/physiopathologie , Hypertrophie ventriculaire gauche/épidémiologie , Hypertrophie ventriculaire gauche/physiopathologie , Losartan/pharmacologie , Losartan/usage thérapeutique , Mâle , Adulte d'âge moyen , Infarctus du myocarde/physiopathologie , Oxygène/métabolisme , Prévalence , Accident vasculaire cérébral/physiopathologie , Résultat thérapeutiqueRÉSUMÉ
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.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Aténolol/usage thérapeutique , Fibrillation auriculaire/épidémiologie , Pression sanguine/physiologie , Hypertension artérielle/complications , Hypertension artérielle/traitement médicamenteux , Losartan/usage thérapeutique , Sujet âgé , Antihypertenseurs/pharmacologie , Aténolol/pharmacologie , Fibrillation auriculaire/physiopathologie , Pression sanguine/effets des médicaments et des substances chimiques , Méthode en double aveugle , Électrocardiographie , Femelle , Rythme cardiaque/physiologie , Humains , Hypertension artérielle/physiopathologie , Hypertrophie ventriculaire gauche/complications , Hypertrophie ventriculaire gauche/physiopathologie , Incidence , Losartan/pharmacologie , Mâle , Adulte d'âge moyen , Analyse de régression , Facteurs de risque , Systole/effets des médicaments et des substances chimiques , Systole/physiologie , Résultat thérapeutiqueRÉSUMÉ
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: .
Sujet(s)
Antiarythmiques/effets indésirables , Fibrillation auriculaire/traitement médicamenteux , Digoxine/effets indésirables , Hypertension artérielle/mortalité , Sujet âgé , Antiarythmiques/usage thérapeutique , Antihypertenseurs/usage thérapeutique , Aténolol/usage thérapeutique , Fibrillation auriculaire/étiologie , Pression sanguine , Digoxine/usage thérapeutique , Électrocardiographie , Femelle , Défaillance cardiaque/épidémiologie , Rythme cardiaque , Humains , Hypertension artérielle/complications , Hypertension artérielle/traitement médicamenteux , Hypertrophie ventriculaire gauche/complications , Hypertrophie ventriculaire gauche/traitement médicamenteux , Lipoprotéines HDL/sang , Losartan/usage thérapeutique , Mâle , Adulte d'âge moyen , RisqueRÉSUMÉ
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.
Sujet(s)
Fibrillation auriculaire/épidémiologie , Hypertension artérielle/traitement médicamenteux , Losartan/usage thérapeutique , Sujet âgé , Antihypertenseurs/usage thérapeutique , Fibrillation auriculaire/mortalité , Fibrillation auriculaire/physiopathologie , , Femelle , Humains , Hypertrophie ventriculaire gauche/physiopathologie , Incidence , Mâle , Adulte d'âge moyen , Modèles des risques proportionnels ,RÉSUMÉ
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.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Aténolol/usage thérapeutique , Hypertension artérielle/traitement médicamenteux , Hypertension artérielle/anatomopathologie , Hypertrophie ventriculaire gauche/anatomopathologie , Sujet âgé , Méthode en double aveugle , Électrocardiographie , Femelle , Humains , Hypertension artérielle/mortalité , Mâle , Pronostic , Études prospectives , Systole , Résultat thérapeutiqueRÉSUMÉ
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.
Sujet(s)
Antiémétiques/usage thérapeutique , Antinéoplasiques/effets indésirables , Cisplatine/effets indésirables , Morpholines/usage thérapeutique , Nausée/prévention et contrôle , Vomissement/prévention et contrôle , Antiémétiques/effets indésirables , Antinéoplasiques/usage thérapeutique , Aprépitant , Asiatiques , Cisplatine/administration et posologie , Cisplatine/usage thérapeutique , Méthode en double aveugle , Femelle , Humains , Mâle , Adulte d'âge moyen , Morpholines/effets indésirables , Nausée/induit chimiquement , Vomissement/induit chimiquementRÉSUMÉ
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.
Sujet(s)
Fibrillation auriculaire/complications , Mort subite cardiaque/étiologie , Électrocardiographie , Hypertension artérielle/complications , Hypertrophie ventriculaire gauche/complications , Losartan/administration et posologie , Antagonistes du récepteur de type 1 de l'angiotensine-II/administration et posologie , Fibrillation auriculaire/mortalité , Fibrillation auriculaire/physiopathologie , Intervalles de confiance , Mort subite cardiaque/épidémiologie , Relation dose-effet des médicaments , Méthode en double aveugle , Études de suivi , Rythme cardiaque , Humains , Hypertension artérielle/mortalité , Hypertension artérielle/physiopathologie , Hypertrophie ventriculaire gauche/mortalité , Hypertrophie ventriculaire gauche/physiopathologie , Incidence , Odds ratio , Études prospectives , Facteurs de risque , Taux de survie/tendances , Facteurs temps , Résultat thérapeutique , États-Unis/épidémiologieRÉSUMÉ
BACKGROUND: Hypertensive patients with ECG left-ventricular hypertrophy (LVH) are at increased risk of cardiovascular morbidity and mortality, and regression of ECG LVH is associated with improved cardiovascular outcomes. Although tighter control of systolic blood pressure (SBP) has been associated with a lower rate of ECG LVH, whether tighter vs. standard control of SBP is associated with greater reduction of cardiovascular risk is unclear. METHODS AND RESULTS: Risk of stroke, myocardial infarction (MI), cardiovascular death, the composite endpoint of these events and all-cause mortality were examined in relation to in-treatment achieved SBP in 9193 hypertensive patients with ECG LVH randomly assigned to losartan or atenolol-based treatment. Patients with in-treatment SBP 130 mmHg or less (lowest quintile at last measurement) and SBP between 131 and 141 mmHg were compared with patients with in-treatment SBP at least 142 mmHg (median SBP at last measurement). In univariate analyses, compared with in-treatment SBP at least 142 mmHg, in-treatment SBP between 131 and 141 mmHg entered as a time-varying covariate identified patients with significantly lower risk of all events. In contrast, patients with SBP 130 mmHg or less had less reduction in MI, stroke and composite endpoint and no significant decrease in cardiovascular or all-cause mortality. In multivariate Cox analyses adjusting for baseline risk factors and randomized treatment as standard covariates and in-treatment diastolic BP, heart rate and Cornell product LVH as time-varying covariates, an in-treatment achieved SBP of 131 to 141 mmHg remained associated with a significantly decreased risk of MI, stroke and the LIFE composite endpoint. In contrast, patients who achieved a SBP 130 mmHg or less had no significant reduction in risk of MI, stroke or composite endpoint, had a trend to increased cardiovascular mortality [hazard ratio 1.32, 95% confidence interval (CI) 0.97-1.81, Pâ=â0.078] and a statistically significant 37% increased risk of death from any cause (hazard ratio 1.37, 95% CI 1.10-1.71, Pâ=â0.005). CONCLUSIONS: Achieved SBP 130 mmHg or less is not associated with lower cardiovascular risk than SBP of 131 to 141 mmHg and is associated with a significantly increased risk of death and trend towards increased cardiovascular mortality. These findings support the need for randomized evaluation of treatment to more aggressive vs. conventional SBP targets.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Aténolol/usage thérapeutique , Pression sanguine/effets des médicaments et des substances chimiques , Maladies cardiovasculaires/traitement médicamenteux , Hypertension artérielle/traitement médicamenteux , Losartan/usage thérapeutique , Sujet âgé , Sujet âgé de 80 ans ou plus , Maladies cardiovasculaires/mortalité , Maladies cardiovasculaires/physiopathologie , Cause de décès , Comorbidité , Femelle , Humains , Hypertension artérielle/mortalité , Hypertension artérielle/physiopathologie , Mâle , Adulte d'âge moyen , Facteurs de risque , Résultat thérapeutique , États-Unis/épidémiologieRÉSUMÉ
BACKGROUND: Complicated intra-abdominal infections (cIAI) are a common problem in surgical practice. The effect of body mass index (BMI) on the outcome is poorly understood. We compared the association of BMI and type of antibiotic therapy for cIAI described in a previously published trial of ertapenem vs. piperacillin-tazobactam (Namias N, Solomkin JS, Jensen EH, et al. Randomized, multicenter, double-blind study of efficacy, safety, and tolerability of intravenous ertapenem versus piperacillin/tazobactam in treatment of complicated intra-abdominal infections in hospitalized adults. Surg Infect 2007;8:15-28). METHODS: A post-hoc analysis was performed using data obtained from the published study. The effect of BMI and type of antibiotic used for therapy were calculated for clinically favorable outcomes at early follow-up assessment (EFA). RESULTS: The 231 patients who were microbiologically evaluable at EFA were stratified by BMI (<30 or ≥30 kg/m(2)). Twelve patients were excluded because of missing BMI data, leaving 219 patients for analysis. There were some differences in baseline characteristics between patients with a BMI <30 kg/m(2), including the source of intra-abdominal infection (more appendicitis in BMI <30 group; p=0.01) and gender (more men in the BMI <30 group; p=0.03). There was no difference in cure rates between the groups (82.9% for BMI <30 kg/m(2) vs. 74.5% for those with BMI ≥30 kg/m(2); 8% difference in proportions, 95% confidence interval [CI] -5%, 25%). There was an 80% favorable clinical response to ertapenem in the BMI <30 group compared with an 81% favorable rate in the BMI ≥30 group (-1% difference in proportions; 95% CI -22%, 19%). This compared with an 86% favorable response rate to piperacillin-tazobactam in the BMI <30 group vs. a 65% favorable clinical response rate in the BMI ≥30 group (21% difference in proportions; 95% CI -1%, 47%). CONCLUSIONS: There was no difference in the cure rate of patients with cIAI in the BMI <30 and BMI ≥30 kg/m(2) groups. There were no statistically significant differences in the likelihood of response to an antibiotic regimen. However, there was a nominally 21% lower cure rate in the high BMI group receiving piperacillin-tazobactam (86% vs. 65%; 21% difference in proportions; 95% CI -1%, 47%), whereas there was only a 1% difference in the cure rate between BMI groups in the patients receiving ertapenem. This difference may be related to gender and etiology of infection. Although limited by the small number of high BMI patients and post-hoc methodology, these results merit consideration of the design of future prospective antibiotic trials to include stratification for BMI and consideration of the effect of BMI on pharmacokinetics and pharmacodynamics.
Sujet(s)
Antibactériens/usage thérapeutique , Indice de masse corporelle , Infections intra-abdominales/traitement médicamenteux , bêta-Lactames/usage thérapeutique , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Ertapénem , Femelle , Humains , Mâle , Adulte d'âge moyen , Études multicentriques comme sujet , Obésité morbide/chirurgie , Acide pénicillanique/analogues et dérivés , Acide pénicillanique/usage thérapeutique , Pipéracilline/usage thérapeutique , Association de pipéracilline et de tazobactam , Essais contrôlés randomisés comme sujet , Jeune adulteRÉSUMÉ
An elevated heart rate (HR) at rest at baseline is associated with an increased risk of incident heart failure (HF) and with greater cardiovascular event rates in patients with chronic HF. However, despite the high attributable risk of hypertension for HF, whether the in-treatment HR predicts incident HF in patients with treated hypertension has not been evaluated. The HR was evaluated on annual electrocardiograms from 9,024 patients with hypertension without HF who were treated with losartan- or atenolol-based regimens. During a mean follow-up of 4.7 ± 1.1 years, HF developed in 285 patients (3.2%). On multivariate Cox analyses adjusted for randomized treatment, the baseline risk factors for HF, baseline and in-treatment blood pressure, QRS duration, and electrocardiographic left ventricular hypertrophy, a greater in-treatment HR predicted a 45% greater adjusted risk of new HF for every 10-beats/min increase in the HR (95% confidence interval [CI] 34% to 57%) or a 159% greater risk of HF in patients with the persistence or development of a HR of ≥84 beats/min (95% CI 88% to 257%). In contrast, with adjustment for the same covariates, the baseline HR as a continuous variable was a significantly less powerful predictor of new HF (hazard ratio 1.15 per 10 beats/min, 95% CI 1.03 to 1.28) and a baseline HR of ≥84 beats/min did not predict new HF (hazard ratio 1.00, 95% CI 0.63 to 1.58). In conclusion, a greater in-treatment HR on the serial electrocardiograms predicts a greater risk of incident HF during antihypertensive treatment, independent of the covariates, in patients with hypertension with electrocardiographic left ventricular hypertrophy. These findings support serial HR assessment to improve the risk stratification of patients with hypertension.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Électrocardiographie , Défaillance cardiaque/épidémiologie , Rythme cardiaque/physiologie , Hypertension artérielle/physiopathologie , Losartan/usage thérapeutique , Sujet âgé , Antihypertenseurs/administration et posologie , Relation dose-effet des médicaments , Méthode en double aveugle , Femelle , Études de suivi , Défaillance cardiaque/étiologie , Défaillance cardiaque/physiopathologie , Rythme cardiaque/effets des médicaments et des substances chimiques , Humains , Hypertension artérielle/complications , Hypertension artérielle/traitement médicamenteux , Incidence , Losartan/administration et posologie , Mâle , Pronostic , Études prospectives , Facteurs de risqueRÉSUMÉ
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.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Maladies cardiovasculaires/mortalité , Hypertension artérielle/traitement médicamenteux , Hypertrophie ventriculaire gauche/physiopathologie , Sujet âgé , Troubles du rythme cardiaque/complications , Troubles du rythme cardiaque/mortalité , Aténolol/usage thérapeutique , Cause de décès , Méthode en double aveugle , Électrocardiographie , Femelle , Humains , Hypertension artérielle/physiopathologie , Estimation de Kaplan-Meier , Losartan/usage thérapeutique , Mâle , Adulte d'âge moyen , Résultat thérapeutiqueRÉSUMÉ
BACKGROUND: Treatment of hypertensive patients with a losartan-based regimen was associated with greater regression of electrocardiographic (ECG) left ventricular hypertrophy (LVH) than atenolol-based therapy in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, independent of blood pressure (BP) changes. However, whether concomitant hydrochlorothiazide (HCTZ) therapy in >70% of LIFE patients was associated with greater regression of LVH independent of BP changes and whether this effect differed between treatment arms has not been examined. METHODS: Changes in Cornell product and Sokolow-Lyon voltage LVH were assessed in 9,193 hypertensive patients randomly assigned to treatment with losartan or atenolol, with additional HCTZ therapy added as necessary to achieve target BP goal per study protocol. RESULTS: After controlling for baseline and change in systolic and diastolic pressure, age, sex, race, prior antihypertensive treatment, baseline and year-4 body mass index and baseline LVH by either Cornell product or Sokolow-Lyon voltage, at year-4 follow-up HCTZ therapy was associated with greater regression of Cornell product LVH (-244 +/- 788 vs. -172 +/- 771 mm.msec, P < 0.05) and Sokolow-Lyon voltage (-4.2 +/- 6.7 vs. -3.0 +/- 7.0 mm, P < 0.001) and this effect was significantly greater in patients on losartan (-341 +/- 743 vs. -189 +/- 775 mm.msec and -5.2 +/- 6.6 vs. -3.3 +/- 6.6 mm) than in patients on atenolol (-142 +/- 822 vs. -158 +/- 765 mm.msec and -3.1 +/- 6.6 vs. -2.7 +/- 7.4 mm; both P < 0.001 for interaction of HCTZ with losartan vs. atenolol therapy). CONCLUSIONS: HCTZ use was associated with greater regression of ECG LVH and this effect was greater in patients on losartan- than atenolol-based therapy, independent of baseline severity of ECG LVH and hypertension and changes in BP.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Hydrochlorothiazide/usage thérapeutique , Hypertension artérielle/traitement médicamenteux , Hypertrophie ventriculaire gauche/physiopathologie , Sujet âgé , Sujet âgé de 80 ans ou plus , Aténolol/usage thérapeutique , Association de médicaments , Électrocardiographie , Femelle , Humains , Hypertension artérielle/complications , Hypertrophie ventriculaire gauche/étiologie , Losartan/usage thérapeutique , Mâle , Adulte d'âge moyen , Essais contrôlés randomisés comme sujetRÉSUMÉ
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.
Sujet(s)
Antihypertenseurs/usage thérapeutique , Hypertension artérielle/traitement médicamenteux , Hypertrophie ventriculaire gauche/traitement médicamenteux , Mutation de type INDEL/génétique , Peptidyl-Dipeptidase A/génétique , Peptidyl-Dipeptidase A/métabolisme , Polymorphisme génétique , Sujet âgé , Sujet âgé de 80 ans ou plus , Antihypertenseurs/pharmacologie , Pression sanguine/effets des médicaments et des substances chimiques , Détermination du point final , Femelle , Génotype , Rythme cardiaque/effets des médicaments et des substances chimiques , Humains , Hypertension artérielle/complications , Hypertension artérielle/physiopathologie , Hypertrophie ventriculaire gauche/complications , Hypertrophie ventriculaire gauche/physiopathologie , Losartan/pharmacologie , Losartan/usage thérapeutique , Mâle , Adulte d'âge moyen , Résultat thérapeutiqueRÉSUMÉ
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.