Fuchs et al. Trials 2011, 12:53 http://www.trialsjournal.com/content/12/1/53 TRIALS STUDYPROTOCOL Open Access A comparison between diuretics and angiotensin- receptor blocker agents in patients with stage I hypertension (PREVER-treatment trial): study protocol for a randomized double-blind controlled trial Flávio D Fuchs1*,SandraCFuchs1, Leila B Moreira1,MiguelGus1, Antônio C Nóbrega2, Carlos E Poli-de-Figueiredo3, Décio Mion4, Luiz Bortolotto5,FernandaConsolim-Colombo5, Fernando Nobre6, Eduardo Barbosa Coelho6, José F Vilela-Martin7, Heitor Moreno Jr8, Evandro José Cesarino9,RobertoFranco10, Andréa Araujo Brandão11, Marcos R de Sousa12, Antônio Luiz Pinho Ribeiro12,PauloCesarJardim13, Abrahão Afiune Neto14,LuizCésarNScala15, Marco Mota16, Hilton Chaves17, João Guilherme Alves18, Dario C Sobral Filho19, Ricardo Pereira e Silva20, José A Figueiredo Neto21, Maria Cláudia Irigoyen22, Iran Castro22, André Avelino Steffens23, Rosane Schlatter1, Renato Bandeira de Mello1, Francisca Mosele1, Flávia Ghizzoni1, Otávio Berwanger24 Abstract 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 * Correspondence: [email protected] 1Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil Full list of author information is available at the end of the article © 2011 Fuchs et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Fuchs et al. Trials 2011, 12:53 Page 2 of 5 http://www.trialsjournal.com/content/12/1/53 Background 5-year period of follow-up, the primary outcome, did Cardiovascular disease (CVD) is the leading cause of not differ significantly between the placebo and treat- death in Brazil, and high blood pressure is its major ment groups. Moreover, the 5-year cumulative incidence risk. factor. The prevalence ofhypertensioninBrazilis of microalbuminuria was 17% with losartan versus 6% within 22.3 to 44% of adults [1]. The benefit of drug with placebo and 4% with enalapril (P = 0.01). treatment of hypertension to prevent major cardiovascu- There is no head-to-head comparison between diure- lar events was consistently demonstrated in a large ser- tics and ARB agents in the prevention of hard cardiovas- ies of clinical trials controlled by placebo. The cular outcomes, and even the comparison of their blood superiority of any particular agent among the groups of pressure-lowering effects was scarcely reported. Despite blood pressure-lowering drugs was investigated in var- this, ARB agents are the leading brands in terms of ious clinical trials. ALLHAT, the largest and better profits in various countries in the world, including Bra- designed trial, showed that chlorthalidone had similar zil. This leadership seems to be based on a strong com- efficacy to prevent fatal and non-fatal coronary events as mercial strategy, which may have introduced bias in the an ACE inhibitor (lisinopril) and a calcium channel evidences of clinical trials in favor of these drugs blocker agent (amlodipine) [2]. Chlorthalidone was [11,12]. The idea that they have blood pressure-indepen- superior to lisinopril in the prevention of other cardio- dent effects is accepted by most, despite the evidences of vascular outcomes, particularly of stroke in black partici- better designed trials and of the powerful meta-analysis pants, and it was superior to amlodipine in the of Law, Morris and Wald [4]. The option of an ARB prevention of heart failure. In the VALUE trial, amlodi- agent, instead of a diuretic, as the first line approach in pine was superior to valsartan, an angiotensin-receptor the public health system in Brazil would result in a large blocker (ARB) agent, in the prevention of CHD and expenditure of resources, and there is a pressure to stroke [3]. The most recent and extensive meta-analysis include them in the list of essential drugs provided by of trials that compared the efficacy of blood pressure- the government. lowering drugs against placebo and against each other Diuretics are at least as efficacious as other blood failed to demonstrated substantial advantage of any pressure-lowering drugs, are well tolerated, have longer group of agents [4]. Nonetheless, ARBs have been pre- duration of action and the advantage of very low cost to ferential drugs in the management of hypertension, be used in a population intervention [13]. Chlorthali- being five out of the ten agents more frequently pre- done is a more efficacious agent, and should be the pre- scribed in the USA in 2007 [5]. ferential choice of diuretic to be employed in clinical Data from some trials have shed some concern about practice [13]. Its main limitation is to induce hypokale- the safety of ARB agents [6], but these findings require mia in some patients, an adverse effect that can be corroboration in other studies. The main concern is antagonized by a potassium-sparing diuretic, such as with the guidelines’ supported preference for ARB amiloride [14]. agents to prevent renal damage, particularly in patients A study comparing diuretic with an ARB agent is with diabetes. Most data supporting such preference therefore scientifically required. It would be also impor- came from placebo controlled trials, not controlling for tant in Brazil, in order to support the decisions of the their blood pressure-lowering effect. These agents did Public Health System in regard to blood pressure drugs not show any superiority over angiotensin converting supply for the Brazilian population. Such a study was enzyme (ACE) inhibitors to prevent renal outcomes, and demanded and funded by the Health and Technology the association of these agents was clearly deleterious in Ministries in Brazil. the ONTARGET trial [7]. It is of note that even the beneficial effects of ACE inhibitors in this context were Trial rationale mostly demonstrated in studies not controlled by other ARB agents have good tolerability and putative pleiotro- blood pressure agents. In the only study that compared pic effects, particularly renal protection, which support an ACE inhibitor with a diuretic, the incidence of their preference by physicians as an antihypertensive microalbuminuria was similar [8]. In the ALLHAT trial, agent. Independent assessments of the evidence have the incidence of end-stage renal disease was about 70% questioned these advantages, and a concern with the higher in patients with diabetes and with glomerular fil- safety of these agents, such as the loss of nephroprotec- tration rate between 60 and 80 ml/min, randomized to tion in patients with diabetes, has emerged. Diuretics, lisinopril and anlodipine, instead of chlorthalidone [9]. particularly chlorthalidone, are as efficacious as newer A complex clinical trial investigated the efficacy of an agents in managing hypertension. Its main adverse ARBagentandofanACEinhibitortopreventrenal effect, hypokalemia, which is associated with arrhyth- damage in patients with type I diabetes [10]. Change in mias and hyperglycemia, can be circumvented by the mesangial fractional volume per glomerulus over the association of potassium-sparing diuretic, such as Fuchs et al. Trials 2011, 12:53 Page 3 of 5 http://www.trialsjournal.com/content/12/1/53 amiloride. Blood pressure has been a valid surrogate of POTENTIALLY ELIGIBLE (Time 0) the beneficial effects of blood pressure-lowering drugs. Consent form Males/ Females, 40 - 70 years old In this scenario,