Effectiveness of Chlorthalidone Plus Amiloride for the Prevention of Hypertension: The PREVER-Prevention Randomized Clinical Trial

Sandra Costa Fuchs, Carlos E Poli-de-Figueiredo, José A Figueiredo Neto, Luiz César N Scala, Paul K Whelton, Francisca Mosele, Renato Bandeira de Mello, José F Vilela-Martin, Leila B Moreira, Hilton Chaves, Marco Mota Gomes, Marcos R de Sousa, Ricardo Pereira E Silva, Iran Castro, Evandro José Cesarino, Paulo Cesar Jardim, João Guilherme Alves, André Avelino Steffens, Andréa Araujo Brandão, Fernanda M Consolim-Colombo, Paulo Ricardo de Alencastro, Abrahão Afiune Neto, Antônio C Nóbrega, Roberto Silva Franco, Dario C Sobral Filho, Alexandro Bordignon, Fernando Nobre, Rosane Schlatter, Miguel Gus, Felipe C Fuchs, Otávio Berwanger, Flávio D Fuchs, Sandra Costa Fuchs, Carlos E Poli-de-Figueiredo, José A Figueiredo Neto, Luiz César N Scala, Paul K Whelton, Francisca Mosele, Renato Bandeira de Mello, José F Vilela-Martin, Leila B Moreira, Hilton Chaves, Marco Mota Gomes, Marcos R de Sousa, Ricardo Pereira E Silva, Iran Castro, Evandro José Cesarino, Paulo Cesar Jardim, João Guilherme Alves, André Avelino Steffens, Andréa Araujo Brandão, Fernanda M Consolim-Colombo, Paulo Ricardo de Alencastro, Abrahão Afiune Neto, Antônio C Nóbrega, Roberto Silva Franco, Dario C Sobral Filho, Alexandro Bordignon, Fernando Nobre, Rosane Schlatter, Miguel Gus, Felipe C Fuchs, Otávio Berwanger, Flávio D Fuchs

Abstract

Background: Prehypertension is associated with higher cardiovascular risk, target organ damage, and incidence of hypertension. The Prevention of Hypertension in Patients with PreHypertension (PREVER-Prevention) trial aimed to evaluate the efficacy and safety of a low-dose diuretic for the prevention of hypertension and end-organ damage.

Methods and results: This randomized, parallel, double-blind, placebo-controlled trial was conducted in 21 Brazilian academic medical centers. Participants with prehypertension who were aged 30 to 70 years and who did not reach optimal blood pressure after 3 months of lifestyle intervention were randomized to a chlorthalidone/amiloride combination pill or placebo and were evaluated every 3 months during 18 months of treatment. The primary outcome was incidence of hypertension. Development or worsening of microalbuminuria, new-onset diabetes mellitus, and reduction of left ventricular mass were secondary outcomes. Participant characteristics were evenly distributed by trial arms. The incidence of hypertension was significantly lower in 372 study participants allocated to diuretics compared with 358 allocated to placebo (hazard ratio 0.56, 95% CI 0.38-0.82), resulting in a cumulative incidence of 11.7% in the diuretic arm versus 19.5% in the placebo arm (P=0.004). Adverse events; levels of blood glucose, glycosylated hemoglobin, creatinine, and microalbuminuria; and incidence of diabetes mellitus were no different between the 2 arms. Left ventricular mass assessed through Sokolow-Lyon voltage and voltage-duration product decreased to a greater extent in participants allocated to diuretic therapy compared with placebo (P=0.02).

Conclusions: A combination of low-dose chlorthalidone and amiloride effectively reduces the risk of incident hypertension and beneficially affects left ventricular mass in patients with prehypertension.

Clinical trial registration: URL: http://www.ClinicalTrials.gov, www.ensaiosclinicos.gov. Unique identifiers: NCT00970931, RBR-74rr6s.

Keywords: amiloride; blood pressure; cardiovascular diseases; chlorthalidone; clinical trials; diuretics; hypertension; left ventricular mass; microalbuminuria; potassium‐sparing antihypertensive agents; prehypertension; prevention.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Study flow diagram of the PREVER‐Prevention trial, describing selection, randomization, and follow‐up process. *Patients were concurrently screened to participate in either the PREVER‐Treatment or PREVER‐Prevention trial. BP indicates blood pressure.
Figure 2
Figure 2
Incidence of hypertension according to treatment group during follow‐up. HR indicates hazard ratio.
Figure 3
Figure 3
Blood pressure according to treatment group during follow‐up.
Figure 4
Figure 4
Hazard ratio (95% CI) for hypertension in participants stratified by clinical and demographic characteristics.

References

    1. Moreira LB, Fuchs SC, Wiehe M, Gus M, Moraes RS, Fuchs FD. Incidence of hypertension in Porto Alegre, Brazil: a population‐based study. J Hum Hypertens. 2008;22:48–50.
    1. Kurioka S, Horie S, Inoue A, Mafune K, Tsuda Y, Otsuji Y. Risk of progression to hypertension in nonhypertensive Japanese workers aged 20‐64 years. J Hypertens. 2014;32:236–244.
    1. Kim SH, Cho G‐Y, Baik I, Lim SY, Choi CU, Lim HE, Kim EJ, Park CG, Park J, Kim J, Shin C. Early abnormalities of cardiovascular structure and function in middle‐aged Korean adults with prehypertension: the Korean Genome Epidemiology Study. Am J Hypertens. 2010;24:218–224.
    1. Markus MR, Stritzke J, Lieb W, Mayer B, Luchner A, Döring A, Keil U, Hense HW, Schunkert H. Implications of persistent prehypertension for ageing‐related changes in left ventricular geometry and function: the MONICA/KORA Augsburg study. J Hypertens. 2008;26:2040–2049.
    1. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.
    1. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA. Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta‐analysis. JAMA. 2011;305:913–922.
    1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta‐analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.
    1. The Trials of Hypertension Prevention Cooperative Research Group . The effects of nonpharmacologic interventions on blood pressure of persons with high normal levels. Results of the Trials of Hypertension Prevention, Phase I. JAMA. 1992;267:1213–1220.
    1. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, Black HR, Grimm RH Jr, Messerli FH, Oparil S, Schork MA; Trial of Preventing Hypertension (TROPHY) Study Investigators . Feasibility of treating prehypertension with an angiotensin‐receptor blocker. N Engl J Med. 2006;354:1685–1697.
    1. Lüders S, Schrader J, Berger J, Unger T, Zidek W, Böhm M, Middeke M, Motz W, Lübcke C, Gansz A, Brokamp L, Schmieder RE, Trenkwalder P, Haller H, Dominiak P; PHARAO Study Group . The PHARAO study: prevention of hypertension with the angiotensin‐converting enzyme inhibitor ramipril in patients with high‐normal blood pressure: a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens. 2008;26:1487–1496.
    1. Whelton PK. The elusiveness of population‐wide high blood pressure control. Annu Rev Public Health. 2015;36:109–130.
    1. Fuchs FD, de Mello RB, Fuchs SC. Preventing the progression of prehypertension to hypertension: role of antihypertensives. Curr Hypertens Rep. 2015;17:505.
    1. Fuchs FD, Fuchs SC, Moreira LB, Gus M, Nóbrega AC, Poli‐de‐Figueiredo CE, Mion D, Bortoloto L, Consolim‐Colombo F, Nobre F, Coelho EB, Vilela‐Martin JF, Moreno H Jr, Cesarino EJ, Franco R, Brandão AA, de Sousa MR, Ribeiro AL, Jardim PC, Neto AA, Scala LC, Mota M, Chaves H, Alves JG, Filho DC, Pereira e Silva R, Neto JA, Irigoyen MC, Castro I, Steffens AA, Schlatter R, de Mello RB, Mosele F, Ghizzoni F, Berwanger O. Prevention of hypertension in patients with pre‐hypertension: protocol for the PREVER‐prevention trial. Trials. 2011;12:65.
    1. Fuchs FD. Diuretics: still essential drugs for the management of hypertension. Expert Rev Cardiovasc Ther. 2009;7:591–598.
    1. Guerrero P, Fuchs FD, Moreira LM, Martins VM, Bertoluci C, Fuchs SC, Gus M. Blood pressure‐lowering efficacy of amiloride versus enalapril as add‐on drugs in patients with uncontrolled blood pressure receiving hydrochlorothiazide. Clin Exp Hypertens. 2008;30:553–564.
    1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee . The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560–2572.
    1. ESH/ESC Task Force for the Management of Arterial Hypertension . 2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens. 2013; 31:1925–1938.
    1. Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J. 1949;37:161–186.
    1. Okin PM, Roman MI, Devereux BB, Borer JS, KIigtieId P. Electrocardiographic diagnosis of left ventricular hypertrophy by the time‐voltage integral of the QRS. J Am Coll Cardiol. 1994;23:133–140.
    1. Fuchs SC, Guimarães SM, Sortica C, Wainberg F, Dias KO, Ughini M, Castro JA, Fuchs FD. Reliability of race assessment based on the race of the ascendants: a cross‐sectional study. BMC Public Health. 2002;2:1.
    1. Fuchs SC, Victora CG, Wannmacher L, Gonçalves C, Barbosa A, Menta L, Azevedo R. Reliability of environmental, biological and health characteristics of infants from a developing country. Int J Epidemiol. 1996;25:1005–1008.
    1. Turner MJ, van Schalkwyk JM. Blood pressure variability causes spurious identification of hypertension in clinical studies: a computer simulation study. Am J Hypertens. 2008;21:85–91.
    1. Julius S, Kaciroti N, Egan BM, Nesbitt S, Michelson EL; Trial of Preventing Hypertension (TROPHY) Investigators . TROPHY study: outcomes based on the seventh report of the Joint National Committee on Hypertension definition of hypertension. J Am Soc Hypertens. 2008;2:39–43.
    1. SPRINT Research Group . A randomized trial of intensive versus standard blood‐pressure control. N Engl J Med. 2015;373:2103–2116.
    1. Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, Lewis CE, Liebson PR, Raines J, Joffrion I, Allen RE, Jones L, Parker D, De Worth JK, Anzelone E, Gunn D, George A, Montgomery JA, Neri GS, Betz E, Mascitti B, Plank E, Peterson B, Remijas T, Washington W, Turner I, Stefanie L, Aye P, Madnek‐Oxman S, Jones H, Mascioli SR, Van Heel N, Bjerk C, Galle F, Laqua P, Miller M, Bell LM, Robinson ME, Thorson C, Townsend R, Caggiula A, Dianzumba S, Ciak C, Link M, Hall B, Monske M, Theobald TM, Berry M, Coyne T, Bunker CA, Kramer K, DuChene AG, Holland LA, Tze S, Sjolund S, Launer CA, Lagus J, Miller CM, Svendsen KH, Leon A, Laing B, McDonald M, Surbey D, Wiche MK, Kuiper K, Remington R, Coates TJ, Devereux R, Gifford RW Jr, Langford H, McCullough L, Tyroler HA. Treatment of mild hypertension study. Final results. Treatment of Mild Hypertension Study Research Group. JAMA. 1993;270:713–724.
    1. Liebson PR, Grandits GA, Dianzumba S, Prineas RJ, Grimm RH Jr, Neaton JD, Stamler J. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional‐hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation. 1995;91:698–706.
    1. Cuspidi C, Facchetti R, Bombelli M, Sala C, Grassi G, Mancia G. Accuracy and prognostic significance of electrocardiographic markers of left ventricular hypertrophy in a general population: findings from the Pressioni Arteriose Monitorate E Loro Associazioni population. J Hypertens. 2014;32:921–928.
    1. Bang CN, Okin PM. Does electrocardiography still have a place in hypertension? J Hypertens. 2016;34:842–844.
    1. Klag MJ, He J, Coresh J, Whelton PK, Chen JY, Mo JP, Qian MC, Mo PS, He GQ. The contribution of urinary cations to the blood pressure differences associated with migration. Am J Epidemiol. 1995;142:295–303.
    1. Guyton AC, Coleman TG, Cowley AV Jr, Scheel KW, Manning RD Jr, Norman RA Jr. Arterial pressure regulation. Overriding dominance of the kidneys in long‐term regulation and in hypertension. Am J Med. 1972;52:584–594.
    1. Powles P, Fahimi S, Micha R, Khatibzadeh S, Shi P, Ezzati M, Engell RE, Lim SS, Danaei G, Mozaffarian D; Global Burden of Diseases Nutrition and Chronic Diseases Expert Group (NutriCoDE) . Global, regional and national sodium intakes in 1990 and 2010: a systematic analysis of 24 h urinary sodium excretion and dietary surveys worldwide. BMJ Open. 2013; 3:e003733.
    1. SHEP Cooperative Research Group . Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265:3255–3264.
    1. The Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) . Major outcomes in high‐risk hypertensive patients randomized to angiotensin‐converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002;288:2981–2997.
    1. Barzilay JI, Davis BR, Cutler JA, Pressel SL, Whelton PK, Basile J, Margolis KL, Ong ST, Sadler LS, Summerson J; ALLHAT Collaborative Research Group . Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006;166:2191–2201.

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