Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER-Prevention Randomized Clinical Trial (original) (raw)
Related papers
Journal of hypertension, 2017
To determine the effectiveness of low-dose diuretic therapy to achieve an optimal level of blood pressure (BP) in adults with prehypertension. The PREVER-prevention trial was a randomized, parallel, double-blinded, placebo-controlled trial, with 18 months of follow-up, conducted at 21 academic medical centers in Brazil. Of 1772 individuals evaluated for eligibility, 730 volunteers with prehypertension who were aged 30-70 years, and who did not reach optimal blood pressure after 3 months of lifestyle intervention, were randomized to a fixed association of chlorthalidone 12.5 mg and amiloride 2.5 mg or placebo once a day. The main outcomes were the percentage of participants who achieved an optimal level of BP. A total of 372 participants were randomly allocated to diuretics and 358 to placebo. After 18 months of treatment, optimal BP was noted in 25.6% of the diuretic group and 19.3% in the placebo group (P < 0.05). The mean net reduction in SBP and DBP for the diuretic group comp...
Trials, 2011
Background Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage. Methods This is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, 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 sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution. Discussion The early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil. Trial Registration Clinical Trials NCT00970931.
Cardiology Research, 2016
Background: Hypertension reduction strategies use blood pressure in the brachial artery as the primary endpoint. Individuals who achieve the target blood pressure reduction with antihypertensive treatment have residual cardiovascular risk attributed to the difference in pressure between the aorta and brachial artery. Antihypertensive treatment affects the intrinsic properties of the vascular wall and arterial stiffness markers and consequently the central pressure. Recent publications stress the importance of adequate control of the central compared to peripheral blood pressure. Related clinical implications suggest that individuals with normal peripheral but high central blood pressure should not receive antihypertensive drugs that act on the central pressure. Therefore, they are at greater cardiovascular risk. The aim of the study was to evaluate the effect of treatment with a thiazide diuretic versus losartan on the central blood pressure in stage 1 hypertensive patients. Methods: Twenty-five patients were randomized to the chlorthalidone 25 mg/amiloride 5 mg group (q.d.) and 25 patients received losartan 50 mg (b.i.d). The central systolic blood pressure (CSBP) and augmentation index (AIx 75) were assessed using applanation tonometry. The paired t-test was used to compare the systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), pulse pressure (PP), CSBP and AIx 75 between the thiazide and losartan groups at baseline and after 6 months of treatment. Results: Significant reductions in CSBP (123.3 ± 14.2 vs. 113.4 ± 111.4, P = 0.0103) and AIx 75 (87.7 ± 9.6 vs. 83.8 ± 8.9, P = 0.0289) were observed after 6 months of drug treatment with chlorthalidone 25 mg/amiloride 5 mg (q.d.). The administration of losartan 50 mg (b.i.d) did not reduce the CSBP and there were insignificant changes in the AIx 75. Conclusions: Six-month treatment of chlorthalidone/amiloride but not losartan reduces the CSBP and AIx 75 in adults with stage 1 hypertension.
Systolic Hypertension in the Elderly Program (SHEP): Antihypertensive efficacy of chlorthalidone
The American Journal of Cardiology, 1985
for the SHEP Research Group The Systolic Hypertension in the Elderly Program (SHEP) is a randomized, blinded test of the efficacy of antihypertensive drug treatment. in a large feasibility trial, 551 men and women who had isolated systolic hypertension and were at least 60 years old received chlorthalidone (25 to 50 mg/day) or matching placebo as the step I drug. After 1 year, 83% of the chlorthalidone group and 80% of the placebo group were still taking SHEP medications. Of those still taking chlorthalidone, 88% had reached goal blood pressure (BP) without requiring a step II drug, and most had responded to the lower dose (25 mg/day). The BP response was similar in all age, sex and race subgroups, with an overall mean difference between randomized groups of 17 mm Hg for systolic BP (p <O.OOl) and 6 mm Hg for diastolic BP (p <O.OOl). The only common adverse effects were asymptomatic changes in the serum levels of potassium (0.5 mEq/liter lower in the chlorthalidone group, p <O.OOl), uric acid (0.9 mg/dl higher, p <O.OOl) and creatinine (0.08 mg/dl higher, p = 0.02). This study indicates that chlorthalidone is effective for lowering BP in elderly patients with systolic hypertension and sets the stage for a larger trial of the effects of such treatment on the incidence of cardiovascular disease.
Association Between Chlorthalidone Treatment of Systolic Hypertension and Long-term Survival
JAMA, 2011
G therapy has been shown to decrease nonfatal and fatal cardiovascular events in controlled clinical trials and metaanalyses. 1-7 However, long-term data on gain in life expectancy are not available. In some trials, the benefit of therapy appeared or persisted after the end of the trials when all patients were advised to receive active therapy. 8-13 This "legacy effect" has been reported in hypertension, hyperlipidemia, and diabetes. 8-13 To examine whether the effect of blood pressure (BP) lowering during a trial was associated with long-term outcomes and extended life expectancy, we obtained long-term mortality data of participants in the Systolic Hypertension in the Elderly Program (SHEP) trial. The SHEP trial was a randomized, placebo-controlled, clinical trial designed to assess the effect of antihypertensive drug treatment in reducing the risk of stroke in patients with isolated systolic hypertension. 14 The trial showed that over a mean follow-up of 4.5 years chlorthalidone-based therapy resulted in the prevention of approximately 1 out of 2 admissions for heart failure, 1 out of 3 fatal or nonfatal strokes, and 1 out of 4 coronary heart disease events. 14-16 Although the decreases in cardiovascular events were statistically significant, the effects on allcause mortality (odds ratio [OR], 0.87; 95% CI, 0.73-1.05) and cardiovascular death (OR, 0.80; 95% CI, 0.60-1.05) were not. At the end of the ran-Author Affiliations: Cardiovascular Institute,
Effectiveness of chlorthalidone/amiloride versus losartan in patients with stage I hypertension
Journal of Hypertension, 2016
Objectives: To compare the blood pressure (BP)-lowering efficacy of a chlorthalidone/amiloride combination pill with losartan, during initial management of stage I hypertension. Methods: In a randomized, double-blind, controlled trial, 655 participants were followed for 18 months in 21 Brazilian academic centers. Trial participants were adult volunteers aged 30-70 years with stage I hypertension (BP 140-159 or 90-99 mmHg) following 3 months of a lifestyle intervention. Participants were randomized to 12.5/2.5 mg of chlorthalidone/amiloride (N ¼ 333) or 50 mg of losartan (N ¼ 322). If BP remained uncontrolled after 3 months, study medication dose was doubled, and if uncontrolled after 6 months, amlodipine (5 and 10 mg) and propranolol (40 and 80 mg twice daily) were added as open-label drugs in a progressive fashion. At the end of follow-up, 609 (93%) participants were evaluated. Results: The difference in SBP during 18 months of follow-up was 2.3 (95% confidence interval: 1.2 to 3.3) mmHg favoring chlorthalidone/amiloride. Compared with those randomized to diuretic, more participants allocated to losartan had their initial dose doubled and more of them used add-on antihypertensive medication. Levels of blood glucose, glycosilated hemoglobin, and incidence of diabetes were no different between the two treatment groups. Serum potassium was lower and serum cholesterol was higher in the diuretic arm. Microalbuminuria tended to be higher in patients with diabetes allocated to losartan (28.5 AE 40.4 versus 16.2 AE 26.7 mg, P ¼ 0.09). Conclusion: Treatment with a combination of chlorthalidone and amiloride compared with losartan yielded a greater reduction in BP. Clinical trials registration number: NCT00971165.
Journal of Hypertension, 2018
Background: To determine the effectiveness of low-dose diuretic therapy to achieve an optimal level of blood pressure (BP) in adults with prehypertension. Methods: The PREVER-prevention trial was a randomized, parallel, double-blinded, placebo-controlled trial, with 18 months of follow-up, conducted at 21 academic medical centers in Brazil. Of 1772 individuals evaluated for eligibility, 730 volunteers with prehypertension who were aged 30-70 years, and who did not reach optimal blood pressure after 3 months of lifestyle intervention, were randomized to a fixed association of chlorthalidone 12.5 mg and amiloride 2.5 mg or placebo once a day. The main outcomes were the percentage of participants who achieved an optimal level of BP. Results: A total of 372 participants were randomly allocated to diuretics and 358 to placebo. After 18 months of treatment, optimal BP was noted in 25.6% of the diuretic group and 19.3% in the placebo group (P < 0.05). The mean net reduction in SBP and DBP for the diuretic group compared with placebo was 2.8 mmHg (95% CI 1.1 to 4.5) and 1.1 mmHg (95% CI À0.09 to 2.4), respectively. Most participants in the active treatment group (74.5%) and in the placebo group (80.7%) continued to have BP in the prehypertension range or progressed to hypertension. Conclusion: Low-dose diuretic therapy increased the probability of individuals with prehypertension to achieve optimal BP but most of those treated continued to have a BP in the prehypertension range or progressed to having overt hypertension.
Parallel-Group 8-Week Study on Chlorthalidone Effects in Hypertensives With Low Kidney Function
Hypertension, 2014
C ardiovascular risk and renal risk are high in hypertensives of both sexes with low kidney function. 1,2 The 2012 guidelines of the Kidney Disease: Improving Global Outcomes state that blood pressure control is fundamental to the care of chronic kidney disease. 3 The US and European guidelines recommend that blood pressure be reduced to lower levels in chronic kidney disease. 4,5 Thiazides and thiazide-like diuretics are recommended as initial or additional antihypertensive drug for most patients but are conventionally considered ineffective in low kidney function in the absence of research data. 3-6 Chlorthalidone is a highly effective thiazide-like diuretic. 7-10 Long-term effects of a hydrochlorothiazide-based therapeutic regimen and of a chlorthalidone-based therapeutic regimen are investigated by large trials that included hypertensives with low kidney function also. 11-16 The antihypertensive effects of the diuretics per se are of difficult interpretation in those 2 trials because the design of both trials pursued an effective control of hypertension and, to this aim, allowed the sequential addition of other drugs besides the diuretic under investigation. Data about short-term effects in low kidney function were reported by small studies for hydrochlorothiazide. 17-20 One parallel-group study investigated the 8-week effects of chlorthalidone without giving separate data for hypertensives with low kidney function. 21 The present study focused on the 8-week effects of chlorthalidone as additional drug in hypertensives with low kidney function when compared with hypertensives without low kidney function. Methods This was a prospective, parallel-group, single-blind, single-center study for comparison of the effects of 25-mg chlorthalidone between hypertensives with low kidney function and hypertensives without low kidney function as assessed by estimated glomerular filtration rate (eGFR). 22 The study was registered in the public registry of the Italian Drug Agency (Agenzia Italiana del FArmaco, unique identifying number ID 671), was approved by the institutional review committee (Hospital Ethical Committee), and required the written informed consent of the participants. All procedures were in accordance with institutional guidelines, and the study adhered to the principles of the Declaration of Helsinki and Title 45 of US Code of Federal Regulations. The study comprised a 1-to 2-week screening period and an 8-week treatment period. The first screening visit was for the collection of medical history by questionnaires, the general physical examination, the measurements of anthropometry, pulse, systolic and diastolic blood
Trials, 2011
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.