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BACKGROUND AND AIMS: ALLHAT, a randomized, double-blind, active-controlled, multicenter clinical trial of high risk hypertensive participants, compared treatment with an ACE-inhibitor (lisinopril) or calcium channel blocker (amlodipine) with a diuretic (chlorthalidone). Primary outcome was the occurrence of fatal coronary heart disease or nonfatal myocardial infarction. For this report, post-hoc analyses were conducted to determine the contribution of baseline characteristics of participants with or without baseline or incident atrial fibrillation (AF) and atrial flutter (AFL) to stroke, heart failure (HF), coronary heart disease (CHD), and mortality outcomes. METHODS AND RESULTS: Minnesota Coding of baseline and biennial in-trial ECGs was used to determine the 334 baseline and 537 incident AF/AFL cases, respectively participants with AF/AFL: Cox regression was used to estimate hazard ratios of presence versus absence of either baseline or incident AF/AFL (as time-dependent covariate) for occurrence of stroke, CHD, HF, or mortality, while adjusting for selected baseline characteristics. Adjusted Cox regression was used to obtain hazard ratios (HRs) for presence versus absence of selected baseline characteristics among those with and without either baseline or incident AF/AFL. After adjusting for baseline characteristics, baseline AF/AFL was associated with stroke, HF, and mortality (HRs [95% CIs] 3.18, [2.34-4.33]; 2.65 [2.02-3.49]; and 2.10 [CI, 1.73-2.55], respectively, P < 0.05). Incident AF/AFL was a significant risk factor for HF and mortality (HRs 2.80 and 2.06, respectively, P < 0.05). Risk factor profiles for clinical outcomes for those with and without baseline or incident AF/AFL were largely similar. CONCLUSIONS: AF/AFL is a significant risk factor for stroke, HF, and mortality. Additional risk factors for these outcomes were generally similar for participants with and without baseline or incident AF/AFL.
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Anti-Hipertensivos/uso terapêutico , Fibrilação Atrial/complicações , Doença das Coronárias/mortalidade , Hipertensão/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anlodipino/uso terapêutico , Flutter Atrial/complicações , Clortalidona/uso terapêutico , Doença das Coronárias/etiologia , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão/complicações , Lisinopril/uso terapêutico , Masculino , Infarto do Miocárdio/etiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/etiologiaRESUMO
AIMS: Limited information is available on long-term antihypertensive and lipid-lowering therapy effects on hypertensive patients with atrial fibrillation/flutter (AF/AFL) compared to those without. AF/AFL at baseline or during the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (mean follow-up 4.9 years) markedly increased risk of stroke, heart failure, CHD, and all-cause mortality. We aimed to determine if AF/AFL continued to impact outcomes during post-trial follow-up (mean 3.8 years). METHODS: Patients were randomized to chlorthalidone, amlodipine, or lisinopril, and to pravastatin vs. usual care in the lipid-lowering trial (LLT). Of 31,473 available subjects, AF/AFL occurred in 854; 383/14,371 chlorthalidone (2.7%), 247/8565 amlodipine (2.9%), and 224/8537 lisinopril (2.6%). Post-hoc analyses utilized administrative databases for post-trial data. Individuals with AF/AFL were compared to those without during post-trial. Outcomes were analyzed by treatment groups for the antihypertensive and LLT trials. RESULTS: Among 854 AF/AFL participants, 491 (57.5%) died: 220 in-trial, 271 post-trial. Ten-year all-cause mortality rates for those with in-trial AF/AFL were similar for chlorthalidone and lisinopril, but lower for amlodipine (68, 66, and 49 per 100 persons, respectively); adjusted HR for amlodipine vs. chlorthalidone was 0.68 (95% CI, 0.54-0.87). Ten-year all-cause mortality rates were 57 vs. 65 per 100 persons (pravastatin vs. usual care); non-CVD mortality rates, 18 vs. 39 per 100 persons (pravastatin vs. usual care) (adjusted HR = 0.46, 95% CI, 0.24-0.86). CONCLUSION: Post-trial follow-up revealed continued deleterious AF/AFL effects. The amlodipine (ALLHAT) and pravastatin (ALLHAT-LLT) treatment groups showed lower all-cause and non-CVD mortality compared to the chlorthalidone and usual-care groups, respectively.
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Anti-Hipertensivos/uso terapêutico , Fibrilação Atrial/complicações , Hiperlipidemias/tratamento farmacológico , Hipertensão/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/epidemiologia , Estudos de Casos e Controles , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/mortalidade , Hipertensão/complicações , Hipertensão/mortalidade , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND/OBJECTIVES: Chronic kidney disease (CKD) and cancer are both common in older patients; whether CKD increases risk for cancer is unclear. This study evaluated CKD as a risk factor for cancer mortality in a large cohort of hypertensive patients. STUDY DESIGN: We did post-hoc analyses of in-trial and post-trial data from participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). SETTING AND PARTICIPANTS: Participants were ≥ 55 years old with hypertension and one other additional risk factor for coronary heart disease. PREDICTOR: Baseline estimated glomerular filtration rate (eGFR). OUTCOMES: Cancer mortality was ascertained by cancer-related deaths reported in national databases during and after the trial. Cox proportional hazard models were used to calculate hazard ratios (HRs) adjusted for possible confounders and were stratified by baseline GFR. RESULTS: Participants' mean age was 66.9 years. After a mean follow-up of 8.9 years, there were 2,338 reported cancer-related deaths. Participants with GFR < 45 mL/min/1.73 m2 were at increased risk of cancer mortality compared to those with GFR ≥ 90 mL/min/1.73 m2 (adjusted HR 1.54 (1.22 - 1.94), p-value for trend 0.004). These findings were consistent across subgroups defined by race, gender, and diabetes. Participants with GFR < 45 mL/min/1.73 m2 were at higher risk for mortality related to colon cancer (p-value for trend 0.048, HR 2.28 (1.12 - 4.62)) and urinary tract cancer (p-value for trend 0.001, adjusted HR 2.95 (1.14 - 7.65)). LIMITATIONS: This is a post hoc analysis of clinical trial data. CONCLUSIONS: In a large cohort of hypertensive patients, GFR < 45 mL/min/1.73 m2 was associated with a higher risk of cancer-related mortality.
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Taxa de Filtração Glomerular , Hipertensão/complicações , Neoplasias/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Idoso , Anti-Hipertensivos/uso terapêutico , Feminino , Seguimentos , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/complicações , Fatores de RiscoRESUMO
BACKGROUND: Patient characteristics are associated with adherence, which has implications for planning clinical research or designing payment systems that reward superior outcomes. It is unclear to what extent clinician efforts to improve adherence can attenuate these associations. METHODS: To identify factors predicting visit and medication adherence in settings designed to optimize adherence, we did a retrospective analysis of participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants at 632 sites in North America, Puerto Rico, and the U.S. Virgin Islands for random assignment to antihypertensive treatment with amlodipine, chlorthalidone, or lisinopril. Site investigators reported clinic characteristics at the time they applied to participate in the study and research coordinators used standardized methods to measure patient characteristics. We defined adequate visit adherence as attending at least 80 % of scheduled visits; adequate medication adherence was defined as taking 80 % or more of the randomly assigned medication at all study visits. RESULTS: The 31,250 ALLHAT participants eligible for the visit adherence analysis attended 78.5 % of scheduled study visits; 68.9 % attended more than 80 % of scheduled visits. Clinic setting was predictive of both forms of adherence; adherence was worst at private clinics; clinics that enrolled more study participants had superior adherence. Adjusting for clinic characteristics and clinical factors, women, younger participants, Blacks and smokers were less likely to have adequate visit adherence. Among the 28,967 participants eligible for the medication adherence analysis, 21,261 (73.4 %) reported adequate medication adherence. In adjusted analyses, younger and less educated participants, Blacks, and smokers were less likely to report adequate adherence. CONCLUSIONS: Participant demographics were associated with adherence despite strenuous efforts to optimize adherence. Our results could inform decisions by researchers planning trials and policymakers designing payment systems. TRIAL REGISTRATION: NCT00000542 . Registered 27 October 1999.
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Agendamento de Consultas , Adesão à Medicação , Cooperação do Paciente , Idoso , Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , População Negra , Clortalidona/uso terapêutico , Demografia , Método Duplo-Cego , Feminino , Humanos , Hipertensão/tratamento farmacológico , Lisinopril/uso terapêutico , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , América do Norte , Cooperação do Paciente/estatística & dados numéricos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Thiazide-type diuretics have been recommended for initial treatment of hypertension in most patients, but should this recommendation differ for patients with and without coronary heart disease (CHD)? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized, double-blind hypertension treatment trial in 42,418 participants with high risk of combined cardiovascular disease (CVD) (25% with preexisting CHD). This post hoc analysis compares long-term major clinical outcomes in those assigned amlodipine (n = 9048) or lisinopril (n = 9,054) with those assigned chlorthalidone (n = 15,255), stratified by CHD status. After 4 to 8 years, randomized treatment was discontinued. Total follow-up (active treatment + passive surveillance using national databases for deaths and hospitalizations) was 8 to 13 years. For most CVD outcomes, end-stage renal disease, and total mortality, there were no differences across randomized treatment arms regardless of baseline CHD status. In-trial rates of CVD were significantly higher for lisinopril compared with chlorthalidone, and rates of heart failure were significantly higher for amlodipine compared with chlorthalidone in those with and without CHD (overall hazard ratios [HRs] 1.10, p <0.001, and 1.38, p <0.001, respectively). During extended follow-up, significant outcomes according to CHD status interactions (p = 0.012) were noted in amlodipine versus chlorthalidone comparison for CVD and CHD mortality (HR 0.88, p = 0.04, and 0.84, p = 0.04, respectively) in those with CHD at baseline (HR 1.06, p = 0.15, and 1.08, p = 0.17) and in those without. The results of the overall increased stroke mortality in lisinopril compared with chlorthalidone (HR 1.2; p = 0.03) and hospitalized heart failure in amlodipine compared with chlorthalidone (HR 1.12; p = 0.01) during extended follow-up did not differ by baseline CHD status. In conclusion, these results provide no reason to alter our previous recommendation to include a properly dosed diuretic (such as chlorthalidone 12.5 to 25 mg/day) in the initial antihypertensive regimen for most hypertensive patients.
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Anti-Hipertensivos/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Dislipidemias/complicações , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Guias de Prática Clínica como Assunto/normas , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/complicações , Método Duplo-Cego , Dislipidemias/sangue , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Previous studies have reported that risk of cardiovascular morbidity and mortality substantially increases in hypertensive patients, especially among those with inadequate blood pressure control. Two common antihypertensive drug classes including thiazide diuretics and angiotensin-converting enzyme (ACE) inhibitors affect different enzymes in the renin-angiotensin-aldosterone system (RAAS). In the RAAS, angiotensinogen is converted into angiotensin II which increases blood pressure through vasoconstriction. Using a case-only design with 3448 high-risk hypertensive individuals from the Genetics of Hypertension Associated Treatment (GenHAT) study, we examined whether seven single nucleotide polymorphisms (SNPs) in the angiotensinogen gene (AGT) interact with three classes of antihypertensive drugs including chlorthalidone (a thiazide diuretic), lisinopril (an ACE inhibitor), and amlodipine (a calcium channel blocker) to modify the risk of incident coronary heart disease (CHD) and heart failure (HF) among Caucasian and African American participants, separately. We found no gene by treatment interactions to be statistically significant after correction for multiple testing. However, some suggestive results were found. African American participants with the minor allele of rs11122576 had over two-fold higher risk of CHD when using chlorthalidone compared to using amlodipine, or lisinopril compared to amlodipine (p = 0.006 and p = 0.01, respectively). Other marginal associations are also reported among both race groups. The findings reported here suggest that rs11122576 could contribute to future personalization of antihypertensive treatment among African Americans though more studies are needed.
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OBJECTIVE: The aim of this study was to investigate whether there is a genotype-by-treatment interaction in patients experiencing stroke and treated with one of three antihypertensive drugs, that is chlorthalidone, amlodipine, or lisinopril. PARTICIPANTS AND METHODS: A population of 436 African Americans and 539 whites who had experienced stroke in the GenHAT study were genotyped for 768 single nucleotide polymorphisms (SNPs) in 280 candidate genes. To detect a genotype-by-treatment interaction, we used the Pearson's χ-test to assess whether the genotype frequencies differed at the single SNP level for the three drug treatment groups. From these single SNP analyses, we derived a summary statistic for the degree of association at the gene and gene complex levels. This was done by grouping SNPs using information on gene locations and defining gene complexes on the basis of protein-protein interactions. To assess the statistical significance of the observed test statistic, we derived an empirical P-value by simulating data under the null hypothesis. RESULTS: We found that, in patients who have experienced stroke, there is a significant genetic difference between hypertension drug treatment groups. In African Americans, SNP rs12143842 showed a significant association (P<0.001) with drug treatment. At the gene level, HNRNPA1P4 and NOS1AP in African Americans and PRICKLE1 and NINJ2 in non-Hispanic whites were significantly associated (P<0.01) with drug treatment, whereas none of the gene complexes tested showed significance. CONCLUSION: On the basis of the genetic differences between drug treatment groups, we conclude that there may be an interaction between certain genotypes and antihypertensive treatment in stroke patients. This needs to be replicated in other studies.
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Farmacogenética , Acidente Vascular Cerebral/genética , Idoso , Anlodipino/uso terapêutico , Clortalidona/uso terapêutico , Feminino , Genótipo , Humanos , Lisinopril/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Treatment resistant hypertension (TRH) is defined as uncontrolled hypertension (HTN) despite the use of ≥3 antihypertensive medication classes or controlled HTN while treated with ≥4 antihypertensive medication classes. Risk factors for TRH include increasing age, diminished kidney function, higher body mass index, diabetes, and African American (AA) race. Importantly, previous studies suggest a genetic role in TRH, although the genetics of TRH are largely understudied. With 2203 treatment resistant cases and 2354 treatment responsive controls (36% AA) from the Genetics of Hypertension Associated Treatment Study (GenHAT), we assessed the association of 78 candidate gene polymorphisms with TRH status using logistic regression. After stratifying by race and adjusting for potential confounders, there were 2 genetic variants in the AGT gene (rs699, rs5051) statistically significantly associated with TRH among white participants. The Met allele of rs699 and the G allele of rs5051 were positively associated with TRH: OR = 1.27 (1.12-1.44), P = 0.0001, and OR = 1.36 (1.20-1.53), P < 0.0001, respectively. There was no similar association among AA participants (race interaction P = 0.0004 for rs699 and P = 0.0001 for rs5051). This research contributes to our understanding of the genetic basis of TRH, and further genetic studies of TRH may help reach the goal of better clinical outcomes for hypertensive patients.
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Calcium channel blockers (CCBs) are an important class of medication useful in the treatment of hypertension. Several observational studies have suggested an association between CCB therapy and gastrointestinal (GI) hemorrhage. Using administrative databases, the authors re-examined in a post-hoc analysis whether the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants randomized to the CCB amlodipine had a greater risk of hospitalized GI bleeding (a prespecified outcome) compared with those randomized to the diuretic chlorthalidone or the angiotensin-converting enzyme inhibitor lisinopril. Participants randomized to chlorthalidone did not have a reduced risk for GI bleeding hospitalizations compared with participants randomized to amlodipine (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.92-1.28). Those randomized to lisinopril were at increased risk of GI bleeding compared with those randomized to chlorthalidone (HR, 1.16; 95% CI, 1.00-1.36). In a post-hoc comparison, participants assigned to lisinopril therapy had a higher risk of hospitalized GI hemorrhage (HR, 1.27; 95% CI, 1.06-1.51) vs those assigned to amlodipine. In-study use of atenolol prior to first GI hemorrhage was related to a lower incidence of GI bleeding (HR, 0.69; 95% CI, 0.57-0.83). Hypertensive patients on amlodipine do not have an increased risk of GI bleeding hospitalizations compared with those taking either chlorthalidone or lisinopril.
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Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Diuréticos/efeitos adversos , Hemorragia Gastrointestinal/epidemiologia , Hospitalização , Hipertensão/tratamento farmacológico , Infarto do Miocárdio/prevenção & controle , Idoso , Anlodipino/efeitos adversos , Anlodipino/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Clortalidona/efeitos adversos , Clortalidona/uso terapêutico , Diuréticos/uso terapêutico , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Hipertensão/complicações , Incidência , Lisinopril/efeitos adversos , Lisinopril/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do TratamentoRESUMO
The authors conducted a randomized, controlled, multicenter trial, in which they assigned well-controlled hypertensive participants aged 55 years and older with moderate hypercholesterolemia to receive pravastatin (n=5170) or usual care (n=5185) for 4 to 8 years, when trial therapy was discontinued. Passive surveillance using national databases to ascertain deaths and hospitalizations continued for a total follow-up of 8 to 13 years to assess whether mortality and morbidity differences persisted or new differences developed. During the post-trial period, fatal and nonfatal outcomes were available for 98% and 64% of participants, respectively. The primary outcome was all-cause mortality and the secondary outcomes included cardiovascular mortality, coronary heart disease (CHD), stroke, heart failure, cardiovascular disease, and end-stage renal disease. No significant differences appeared in mortality for pravastatin vs usual care (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.89-1.03) or other secondary outcomes. Similar to the previously reported in-trial result, there was a significant treatment effect for CHD in black patients (HR, 0.79; 95% CI, 0.64-0.98). However, the in-trial result showing a significant treatment by race effect did not remain significant during the entire follow-up (P=.08). These findings are consistent with evidence from other large trials that show statins prevent CHD and add evidence that they are effective for CHD prevention in black patients.
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Anticolesterolemiantes/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Pravastatina/uso terapêutico , Idoso , População Negra , Estudos de Coortes , Doença das Coronárias/mortalidade , Doença das Coronárias/prevenção & controle , Feminino , Seguimentos , Humanos , Hipercolesterolemia/etnologia , Hipercolesterolemia/mortalidade , Hipertensão/etnologia , Hipertensão/mortalidade , Falência Renal Crônica/mortalidade , Falência Renal Crônica/prevenção & controle , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Fatores de Risco , Resultado do TratamentoRESUMO
To determine whether an angiotensin-converting enzyme inhibitor (lisinopril) or calcium channel blocker (amlodipine) is superior to a diuretic (chlorthalidone) in reducing cardiovascular disease incidence in sex subgroups, we carried out a prespecified subgroup analysis of 15 638 women and 17 719 men in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Total follow-up (active treatment + passive surveillance using national administrative databases to ascertain deaths and hospitalizations) was 8 to 13 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction. Secondary outcomes included all-cause mortality, stroke, combined cardiovascular disease (coronary heart disease death, nonfatal myocardial infarction, stroke, angina, coronary revascularization, heart failure [HF], or peripheral vascular disease), and end-stage renal disease. In-trial rates of HF, stroke, and combined cardiovascular disease were significantly higher for lisinopril compared with chlorthalidone, and rates of HF were significantly higher for amlodipine compared with chlorthalidone in both men and women. There were no significant treatment sex interactions. These findings did not persist through the extension period with the exception of the HF result for amlodipine versus chlorthalidone, which did not differ significantly by sex. For both women and men, rates were not lower in the amlodipine or lisinopril groups than in the chlorthalidone group for either the primary coronary heart disease outcome or any other cardiovascular disease outcome, and chlorthalidone-based treatment resulted in the lowest risk of HF. Neither lisinopril nor amlodipine is superior to chlorthalidone for initial treatment of hypertension in either women or men. Clinical Trial Registration- clinicaltrials.gov; Identifier: NCT00000542.
Assuntos
Anti-Hipertensivos/uso terapêutico , Doença das Coronárias/mortalidade , Doença das Coronárias/prevenção & controle , Hipertensão/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/prevenção & controle , Fatores Sexuais , Idoso , Idoso de 80 Anos ou mais , Anlodipino/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Clortalidona/uso terapêutico , Doença das Coronárias/epidemiologia , Diuréticos/uso terapêutico , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão/complicações , Incidência , Lisinopril/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controleRESUMO
The debate over whether certain antihypertensive medications have benefits beyond what would be expected from their blood pressure lowering spurred the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, which randomized 42,418 participants to chlorthalidone (15,255), amlodipine (9048), lisinopril (9054), or doxazosin (9061). We compared chlorthalidone, the active control, with each of the other three agents with respect to the primary outcome, fatal coronary heart disease or nonfatal myocardial infarction, and several other clinical endpoints. The arms were similar with respect to the primary endpoint, although some differences were found for other endpoints, most notably heart failure. Although the desire was to achieve similar blood pressure reductions in the four arms, we found some systolic blood pressure and diastolic blood pressure differences. A natural question is to what degree can observed treatment group differences in cardiovascular outcomes be attributed to these blood pressure differences. The purpose of this paper was to delineate the problems inherent in attempting to answer this question, and to present analyses intended to overcome these problems.
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Anti-Hipertensivos/uso terapêutico , Bioestatística/métodos , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Anlodipino/uso terapêutico , Clortalidona/uso terapêutico , Doença das Coronárias/prevenção & controle , Determinação de Ponto Final/estatística & dados numéricos , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Lisinopril/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Análise de Regressão , Resultado do TratamentoRESUMO
Background. Tuberculosis (TB) disease diagnosis in Vietnam relies on symptom screening, chest radiography (CXR), and acid fast bacilli (AFB) sputum smear which have a poor sensitivity in HIV patients. We evaluated the performance of clinical algorithms in screening and diagnosing AFB smear-negative TB in HIV patients. Methods. We enrolled 399 HIV-positive patients seeking care at a HIV clinic in Ho Chi Minh City (HCMC), Vietnam. Participants' demographics, medical history, common TB symptoms, CXR, and laboratory tests were collected. Results. Of 399 HIV patients, 390 had initial AFB-negative smears and 22/390 patients had positive cultures. Symptom screening missed 54% (12/22) of smear-negative pulmonary TB (PTB) cases. Multivariate analysis found CD4+ cell level and CXR were significant PTB predictors. An algorithm combining four TB symptoms and TST presented a high sensitivity (100%), but poorly specific (24%) diagnostic performance for smear-negative PTB. Conclusion. Up to 54% of PTB cases in the HIV-infected population may be missed in the routine screening and diagnostic procedures used in Vietnam. Symptom screening was a poor overall diagnostic measure in detecting smear-negative TB in HIV patients. Our study results suggest that routine sputum cultures should be implemented to achieve a more accurate diagnosis of TB in HIV patients.
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BACKGROUND AND OBJECTIVES: CKD is common among older patients. This article assesses long-term renal and cardiovascular outcomes in older high-risk hypertensive patients, stratified by baseline estimated GFR (eGFR), and long-term outcome efficacy of 5-year first-step treatment with amlodipine or lisinopril, each compared with chlorthalidone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a long-term post-trial follow-up of hypertensive participants (n=31,350), aged ≥55 years, randomized to receive chlorthalidone, amlodipine, or lisinopril for 4-8 years at 593 centers. Participants were stratified by baseline eGFR (ml/min per 1.73 m(2)) as follows: normal/increased (≥90; n=8027), mild reduction (60-89; n=17,778), and moderate/severe reduction (<60; n=5545). Outcomes were cardiovascular mortality (primary outcome), total mortality, coronary heart disease, cardiovascular disease, stroke, heart failure, and ESRD. RESULTS: After an average 8.8-year follow-up, total mortality was significantly higher in participants with moderate/severe eGFR reduction compared with those with normal and mildly reduced eGFR (P<0.001). In participants with an eGFR <60, there was no significant difference in cardiovascular mortality between chlorthalidone and amlodipine (P=0.64), or chlorthalidone and lisinopril (P=0.56). Likewise, no significant differences were observed for total mortality, coronary heart disease, cardiovascular disease, stroke, or ESRD. CONCLUSIONS: CKD is associated with significantly higher long-term risk of cardiovascular events and mortality in older hypertensive patients. By eGFR stratum, 5-year treatment with amlodipine or lisinopril was not superior to chlorthalidone in preventing cardiovascular events, mortality, or ESRD during 9-year follow-up. Because data on proteinuria were not available, these findings may not be extrapolated to proteinuric CKD.
Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Clortalidona/uso terapêutico , Taxa de Filtração Glomerular , Hipertensão/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Nefropatias/tratamento farmacológico , Rim/fisiopatologia , Lisinopril/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Canadá , Doença Crônica , Doença das Coronárias/etiologia , Doença das Coronárias/mortalidade , Doença das Coronárias/prevenção & controle , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipertensão/complicações , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Incidência , Estimativa de Kaplan-Meier , Nefropatias/complicações , Nefropatias/mortalidade , Nefropatias/fisiopatologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/prevenção & controle , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Modelos de Riscos Proporcionais , Porto Rico , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/prevenção & controle , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Ilhas Virgens AmericanasRESUMO
Nitric oxide synthase 3 (NOS3) catalyzes production of NO in the endothelium and may play a role in cardiovascular disease (CVD). We assessed the pharmacogenetic associations of three NOS3 polymorphisms and three antihypertensive drugs with CVD outcomes. Hypertensive subjects (nâ=â30,280) from a multi-center, double-blind clinical trial were randomized to chlorthalidone, amlodipine, or lisinopril treatment (mean follow up, 4.9 years). Outcomes included coronary heart disease (CHD: fatal CHD and nonfatal myocardial infarction); stroke; heart failure (fatal, requiring hospitalization, or outpatient treatment); all-cause mortality; and end-stage renal disease (ESRD). Main effects of NOS3 variants on outcome and genotype-treatment interactions were tested. For NOS3 -690 C>T (rs3918226), a higher hazard ratio (HR) was found in minor allele carriers for CHD (CCâ=â1.00, CT+TTâ=â1.12 (95% confidence interval (CI)â=â1.00-1.26), Pâ=â0.048). For NOS3 -922 A>G (rs1800779), a higher HR was found in minor allele carriers for heart failure (AAâ=â1.00, AG+GGâ=â1.10 (CIâ=â1.00-1.21), Pâ=â0.046). Significant pharmacogenetic findings were observed for stroke and all-cause mortality. For -690 C>T, a lower HR was observed for stroke in minor allele carriers when treated with amlodipine versus lisinopril (CCâ=â0.85 (CIâ=â0.73-0.99), CT+TTâ=â0.49 (CIâ=â0.31-0.80), Pâ=â0.04). For glu298asp G>T (rs1799983), a lower HR was observed for all-cause mortality in minor allele carriers when treated with amlodipine versus lisinopril (GGâ=â1.01 (CIâ=â0.91-1.13), GT+TTâ=â0.85 (CIâ=â0.75-0.97), Pâ=â0.04). We observed significant associations with NOS3 variants and CHD and heart failure and significant pharmacogenetic effects for stroke and all cause mortality. This suggests that NOS3 variants may potentially provide useful clinical information with respect to treatment decisions in the future.
Assuntos
Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/genética , Idoso , Alelos , Anlodipino/efeitos adversos , Anlodipino/uso terapêutico , Doenças Cardiovasculares/mortalidade , Clortalidona/efeitos adversos , Clortalidona/uso terapêutico , Método Duplo-Cego , Feminino , Seguimentos , Genótipo , Insuficiência Cardíaca/etiologia , Humanos , Hipertensão/genética , Lisinopril/efeitos adversos , Lisinopril/uso terapêutico , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Acidente Vascular Cerebral/etiologiaRESUMO
OBJECTIVE: To identify panels of genetic variants that predict treatment-related coronary heart disease (CHD) outcomes in hypertensive patients on one of four different classes of initial antihypertensive treatment. The goal was to identify subgroups of individuals on the basis of their genetic profile who benefit most from a particular treatment. METHODS: Candidate genetic variants (n=78) were genotyped in 39 114 participants from Genetics of Hypertension Associated Treatment study, ancillary to Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial. Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial randomized hypertensive participants (≥55 years) to one of four treatments (amlodipine, chlorthalidone, doxazosin, lisinopril). The primary outcome was fatal CHD or nonfatal myocardial infarction (mean follow-up=4.9 years). A pharmacogenetic panel was derived within each of the four treatment groups. Receiver-operating characteristic (ROC) curves estimated the discrimination rate between those with and without a CHD event, on the basis of the addition of the genetic panel risk score. RESULTS: For each treatment group, we identified a panel of genetic variants that collectively improved the prediction of CHD to a small but statistically significant extent. Chlorthalidone (A): NOS3 rs3918226; SELE rs5361; ICAM1 rs1799969; AGT rs5051; GNAS rs7121; ROC comparison, P=0.004; Amlodipine (B): MMP1 rs1799750; Factor5 (F5) rs6025; NPPA rs5065; PDE4D rs6450512; MMP9 rs2274756; ROC comparison, P=0.006; Lisinopril (C): AGT rs5051; PON1 rs705379; MMP12 rs652438; F12 rs1801020; GP1BA rs6065; PDE4D rs27653; ROC comparison, P=0.01; Doxazosin (D): F2 rs1799963; PAI1 rs1799768; MMP7 rs11568818; AGT rs5051; ACE rs4343; MMP2 rs243865; ROC comparison, P=0.007. Each panel was tested for a pharmacogenetic effect; panels A, B, and D showed such evidence (P=0.009, 0.006, and 0.001, respectively) and panel C did not (P=0.09). CONCLUSION: Because each panel was associated with CHD in a specific treatment group but not the others, this research provides evidence that it may be possible to use gene panel scores as a tool to better assess antihypertensive treatment choices to reduce CHD risk in hypertensive individuals.
Assuntos
Anlodipino/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Clortalidona/efeitos adversos , Doxazossina/efeitos adversos , Hipertensão/tratamento farmacológico , Lisinopril/efeitos adversos , Polimorfismo Genético , Idoso , Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Clortalidona/administração & dosagem , Doença das Coronárias/induzido quimicamente , Doença das Coronárias/genética , Doxazossina/administração & dosagem , Feminino , Seguimentos , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão/complicações , Hipertensão/genética , Lisinopril/administração & dosagem , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/induzido quimicamente , Modelos de Riscos Proporcionais , Fatores de Risco , Resultado do TratamentoRESUMO
Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a large practice-based clinical trial, made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone (C) versus amlodipine or lisinopril as a first-step drug were stratified by year-1 potassium. Postyear-1 outcomes among hypokalemics (potassium, <3.5 mmol/L) and hyperkalemics (potassium, >5.4 mmol/L) were compared with normokalemics (potassium, 3.5-5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in C (12.9%) differed from amlodipine (2.1%; P<0.001) and lisinopril (1.0%; P<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than in C (1.2%; P<0.01) or amlodipine (1.9%; P<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than in normokalemics (Cox hazard ratio, 1.21 [95% CI, 1.02-1.44]) with statistically significant (interaction, P<0.01) disparity in hazard ratios for the 3 treatment arms (hazard ratios, C=1.21, amlodipine=1.60, lisinopril=3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio, 1.58 [95% CI, 1.15-2.18]) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of C. Thus, for most patients, concerns about potassium levels should not influence the clinician's decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5-25.0 mg of C).
Assuntos
Anti-Hipertensivos/efeitos adversos , Hiperpotassemia/induzido quimicamente , Hipertensão/tratamento farmacológico , Hipopotassemia/induzido quimicamente , Infarto do Miocárdio/prevenção & controle , Idoso , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Análise Química do Sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Clortalidona/administração & dosagem , Clortalidona/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hiperpotassemia/mortalidade , Hipertensão/diagnóstico , Hipertensão/mortalidade , Hipopotassemia/epidemiologia , Incidência , Estimativa de Kaplan-Meier , Lisinopril/administração & dosagem , Lisinopril/efeitos adversos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use. METHODS AND RESULTS: A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction). CONCLUSIONS: The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications.
Assuntos
Doenças Cardiovasculares/mortalidade , Diabetes Mellitus/induzido quimicamente , Hipertensão/tratamento farmacológico , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Idoso , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Clortalidona/efeitos adversos , Doença das Coronárias/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged 55 years and older with hypertension and ≥ 1 other coronary heart disease risk factors to receive chlorthalidone (n=15,002), amlodipine (n=8898), or lisinopril (n=8904) for 4 to 8 years, when double-blinded therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed during the extended follow-up. Primary outcome was cardiovascular mortality and secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels. No significant differences (P<.05) appeared in cardiovascular mortality for amlodipine (hazard ratio [HR], 1.00; 95% confidence interval [CI], 0.93-1.06) or lisinopril (HR, 0.97; CI, 0.90-1.03), each compared with chlorthalidone. The only significant differences in secondary outcomes were for heart failure, which was higher with amlodipine (HR, 1.12; CI, 1.02-1.22), and stroke mortality, which was higher with lisinopril (HR, 1.20; CI, 1.01-1.41), each compared with chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment-by-race interaction for cardiovascular disease for lisinopril vs chlorthalidone. Black participants had higher risk than non-black participants taking lisinopril compared with chlorthalidone. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin-converting enzyme inhibitors are superior to diuretics for the long-term prevention of major cardiovascular complications of hypertension.