RESUMO
AIMS: To compare the blood pressure (BP)-lowering efficacy of a chlorthalidone/amiloride combination pill with losartan, during initial management of JNC 7 Stage I hypertension in patients with type 2 diabetes mellitus. METHODS: In an a priori subgroup analysis of a randomized, double-blind, controlled trial, volunteers aged 30-70 years, with stage I hypertension and diabetes mellitus, were randomized to 12.5/2.5 mg of chlorthalidone/amiloride (N = 47) or 50 mg of losartan (N = 50), and followed for 18 months in 21 clinical centers. If BP remained uncontrolled after three months, study medication dose was doubled, and if uncontrolled after six months, amlodipine (5 and 10 mg) and propranolol (40 and 80 mg BID) were added as open label drugs in a progressive fashion. RESULTS: Systolic BP decreased to a greater extent in participants allocated to diuretics compared to losartan (P < 0.001). After 18 months of follow-up, systolic BP was 128.4 ± 10.3 mmHg in the diuretic group versus 133.5 ± 8.0 in the losartan group (P < 0.01). In the diuretic group, 36 out of 43 participants (83.7%) had a JNC 7 normal BP, compared to 31/47 (66%) in the losartan group (P = 0.089). Serum cholesterol was higher in the diuretic arm at the end of the trial. Other biochemical parameters and reports of adverse events did not differ by treatment. CONCLUSIONS: Treatment of hypertension based on a combination of chlorthalidone and amiloride is more effective for BP lowering compared to losartan in patients with diabetes mellitus and hypertension. TRIAL REGISTRATION: Clinical trials registration number: NCT00971165.
Assuntos
Amilorida/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Clortalidona/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipertensão/tratamento farmacológico , Losartan/administração & dosagem , Adulto , Idoso , Amilorida/efeitos adversos , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Brasil , Clortalidona/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/complicações , Hipertensão/patologia , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Thiazide diuretics have demonstrated favorable blood pressure lowering efficacy, but the equivalent doses of their more common agents, chlorthalidone and hydrochlorothiazide, are still unclear. Further, concerns exist regarding adverse metabolic effects, which may be attenuated with the concomitant administration of a potassium-sparing diuretic, such as amiloride. This trial aims to investigate the efficacy of chlorthalidone and hydrochlorothiazide, in combination with amiloride at different doses, for initial management of patients with primary hypertension. METHODS/DESIGN: This is a factorial (2 × 2) randomized double-blinded clinical trial comparing the association of a thiazide diuretic (chlorthalidone 25 mg/day or hydrochlorothiazide 50 mg/day) with a potassium-sparing diuretic (amiloride 10 mg/day or amiloride 20 mg/day) in patients with primary hypertension. The primary outcome will be the mean change from baseline in 24-h systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring. The secondary outcomes will be the mean change from baseline in daytime and nighttime systolic and diastolic blood pressure measured by ambulatory blood pressure monitoring, mean change from baseline in systolic and diastolic blood pressure measured by office blood pressure, incidence of adverse events, variation of laboratory parameters, and proportion of patients who achieved blood pressure control. The follow-up will last 12 weeks. For a P alpha of 0.05, power of 80%, standard deviation of 9 mmHg, and absolute difference of 6 mmHg on systolic blood pressure on 24-h ambulatory blood pressure monitoring, it will be necessary to study a total of 76 patients. The sample size will be increased by 10% to compensate for losses, resulting in 84 patients being randomized. DISCUSSION: Diuretics are pivotal drugs for the treatment of hypertension. Chlorthalidone and hydrochlorothiazide, in combination with amiloride in multiple doses, will be tested in terms of blood pressure lowering efficacy and safety. Since the intensity of blood pressure reduction is the major determinant of reduction in cardiovascular risk in hypertensive patients, this study will help to determine which combination of diuretics represents the most appropriate treatment for this population. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03928145. Registered on 25 April 2019. Last update on 29 April 2019.
Assuntos
Amilorida/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Clortalidona/administração & dosagem , Hidroclorotiazida/administração & dosagem , Hipertensão/tratamento farmacológico , Inibidores de Simportadores de Cloreto de Sódio/administração & dosagem , Amilorida/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Brasil , Clortalidona/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Humanos , Hidroclorotiazida/efeitos adversos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Antihypertensive treatment improves echocardiographic parameters of hypertensive target organ damage in stage II hypertension, but less is known about the effects in stage I hypertension. METHODS: In a cohort study nested in the randomized double-blind trial PREVER-treatment, 2-dimensional echocardiograms were performed in 110 individuals, aged 54.8 ± 7.9 years-old, with stage I hypertension at baseline and after 18 months of treatment with chlorthalidone/amiloride or losartan. RESULTS: At baseline, 66 (60%) participants had concentric remodeling. After antihypertensive treatment, systolic (SBP) and diastolic blood pressure (BP) were reduced from 141/90 to 130/83 mm Hg (P = 0.009). There was a significant reduction in left ventricular (LV) mass (LVM) index (82.7 ± 17.1 to 79.2 ± 17.5 g/m2; P = 0.005) and relative wall thickness (0.45 ± 0.06 to 0.42 ± 0.05; P < 0.001), increasing the proportion of participants with normal LV geometry (31% to 49%, P = 0.006). Left atrial (LA) volume index reduced (26.8 ± 7.3 to 24.9 ± 6.5 ml/m2; P = 0.001), and mitral E-wave deceleration time increased (230 ± 46 to 247 ± 67 ms; P = 0.005), but there was no change in other parameters of diastolic function. LVM reduction was significantly higher in the 2 higher tertiles of SBP reduction compared to the lower tertile. CONCLUSIONS: Treatment of patients with stage I hypertension for 18 months promotes favorable effects in the LA and LV remodeling. This improvement in cardiac end-organ damage might be associated with reduction of long term clinical consequences of hypertensive cardiomyopathy, particularly heart failure with preserved ejection fraction.
Assuntos
Amilorida/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Clortalidona/uso terapêutico , Ecocardiografia Doppler , Ventrículos do Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Adulto , Idoso , Amilorida/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Função do Átrio Esquerdo/efeitos dos fármacos , Remodelamento Atrial/efeitos dos fármacos , Clortalidona/efeitos adversos , Método Duplo-Cego , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Losartan/efeitos adversos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Cardiovascular disease is the leading cause of death in Brazil, and hypertension is its major risk factor. The benefit of its drug treatment to prevent major cardiovascular events was consistently demonstrated. Angiotensin-receptor blockers (ARB) have been the preferential drugs in the management of hypertension worldwide, despite the absence of any consistent evidence of advantage over older agents, and the concern that they may be associated with lower renal protection and risk for cancer. Diuretics are as efficacious as other agents, are well tolerated, have longer duration of action and low cost, but have been scarcely compared with ARBs. A study comparing diuretic and ARB is therefore warranted. METHODS/DESIGN: This is a randomized, double-blind, clinical trial, comparing the association of chlorthalidone and amiloride with losartan as first drug option in patients aged 30 to 70 years, with stage I hypertension. The primary outcomes will be variation of blood pressure by time, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new subclinical atherosclerosis and sudden death. The study will last 18 months. The sample size will be of 1200 participants for group in order to confer enough power to test for all primary outcomes. The project was approved by the Ethics committee of each participating institution. DISCUSSION: The putative pleiotropic effects of ARB agents, particularly renal protection, have been disputed, and they have been scarcely compared with diuretics in large clinical trials, despite that they have been at least as efficacious as newer agents in managing hypertension. Even if the null hypothesis is not rejected, the information will be useful for health care policy to treat hypertension in Brazil. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov: NCT00971165.