Efficacy of chlorthalidone and hydrochlorothiazide in combination with amiloride in multiple doses on blood pressure in patients with primary hypertension: a protocol for a factorial randomized controlled trial

Vítor Magnus Martins, Lucas Helal, Filipe Ferrari, Leonardo Grabinski Bottino, Sandra Costa Fuchs, Flávio Danni Fuchs, Vítor Magnus Martins, Lucas Helal, Filipe Ferrari, Leonardo Grabinski Bottino, Sandra Costa Fuchs, Flávio Danni Fuchs

Abstract

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.

Keywords: Amiloride; Blood pressure; Diuretics; Hypertension; Thiazides; Treatment.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schedule of enrollment, interventions and assessments. ABPM ambulatory blood pressure monitoring, BP blood pressure
Fig. 2
Fig. 2
Allocation of participants and timeline. ABPM ambulatory blood pressure monitoring, BP blood pressure

References

    1. Freis ED, Wanko A, Wilson IM, Parrish AE. Treatment of essential hypertension with chlorothiazide (Diuril): its use alone and combined with other antihypertensive agents. J Am Med Assoc. 1958;166(2):137–140. doi: 10.1001/jama.1958.02990020025004.
    1. Moser M, Macaulay AI. Chlorothiazide as an adjunct in the treatment of essential hypertension. Am J Cardiol. 1959;3(2):214–219. doi: 10.1016/0002-9149(59)90289-9.
    1. Materson BJ, Oster JR, Michael UF, Bolton SM, Burton ZC, Stambaugh JE, et al. Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose. Clin Pharmacol Ther. 1978;24(2):192–198. doi: 10.1002/cpt1978242192.
    1. Carlsen JE, Køber L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990;300(6730):975–978. doi: 10.1136/bmj.300.6730.975.
    1. Materson BJ, Cushman WC, Goldstein G, Reda DJ, Freis ED, Ramirez EA, et al. Treatment of hypertension in the elderly: I. Blood pressure and clinical changes. Results of a Department of Veterans Affairs Cooperative Study. Hypertension. 1990;15(4):348–360. doi: 10.1161/01.HYP.15.4.348.
    1. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289(19):2534–2544. doi: 10.1001/jama.289.19.2534.
    1. Harper R, Ennis CN, Sheridan B, Atkinson AB, Johnston GD, Bell PM. Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. BMJ. 1994;309(6949):226–230. doi: 10.1136/bmj.309.6949.226.
    1. Freis ED, Thomas JR, Fisher SG, Hamburger R, Borreson RE, Mezey KC, et al. Effects of reduction in drugs or dosage after long-term control of systemic hypertension. Am J Cardiol. 1989;63(11):702–708. doi: 10.1016/0002-9149(89)90255-5.
    1. Savage PJ, Pressel SL, Curb JD, Schron EB, Applegate WB, Black HR, et al. Influence of long-term, low-dose, diuretic-based, antihypertensive therapy on glucose, lipid, uric acid, and potassium levels in older men and women with isolated systolic hypertension: The Systolic Hypertension in the Elderly Program. SHEP Cooperative Research Group. Arch Intern Med. 1998;158(7):741–751. doi: 10.1001/archinte.158.7.741.
    1. Musini VM, Nazer M, Bassett K, Wright JM. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. Cochrane Database Syst Rev. 2014;(5):CD003824. 10.1002/14651858.CD003824.pub2.
    1. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004;43(1):4–9. doi: 10.1161/01.HYP.0000103632.19915.0E.
    1. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47(3):352–358. doi: 10.1161/01.HYP.0000203309.07140.d3.
    1. Peterzan MA, Hardy R, Chaturvedi N, Hughes AD. Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthalidone, and bendroflumethiazide on blood pressure, serum potassium, and urate. Hypertension. 2012;59(6):1104–1109. doi: 10.1161/HYPERTENSIONAHA.111.190637.
    1. Pareek AK, Messerli FH, Chandurkar NB, Dharmadhikari SK, Godbole AV, Kshirsagar PP, et al. Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure monitoring. J Am Coll Cardiol. 2016;67(4):379–389. doi: 10.1016/j.jacc.2015.10.083.
    1. Roush GC, Ernst ME, Kostis JB, Tandon S, Sica DA. Head-to-head comparisons of hydrochlorothiazide with indapamide and chlorthalidone: antihypertensive and metabolic effects. Hypertension. 2015;65(5):1041–1046. doi: 10.1161/HYPERTENSIONAHA.114.05021.
    1. Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009;361(22):2153–2164. doi: 10.1056/NEJMra0907219.
    1. Sica DA. Chlorthalidone - a renaissance in use? Expert Opin Pharmacother. 2009;10(13):2037–2039. doi: 10.1517/14656560903158956.
    1. Leung AA, Wright A, Pazo V, Karson A, Bates DW. Risk of thiazide-induced hyponatremia in patients with hypertension. Am J Med. 2011;124(11):1064–1072. doi: 10.1016/j.amjmed.2011.06.031.
    1. Siegel D, Hulley SB, Black DM, Cheitlin MD, Sebastian A, Seeley DG, et al. Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. JAMA. 1992;267(8):1083–1089. doi: 10.1001/jama.1992.03480080053026.
    1. Flack JM, Cushman WC. Evidence for the efficacy of low-dose diuretic monotherapy. Am J Med. 1996;101(3A):53S–60S. doi: 10.1016/S0002-9343(96)00268-9.
    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. doi: 10.1136/bmj.b1665.
    1. Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006;48(2):219–224. doi: 10.1161/01.HYP.0000231552.10054.aa.
    1. Franse LV, Pahor M, Di Bari M, Somes GW, Cushman WC, Applegate WB. Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program. Hypertension. 2000;35(5):1025–1030. doi: 10.1161/01.HYP.35.5.1025.
    1. Brown MJ, Williams B, Morant SV, Webb DJ. Caulfield MJ5, Cruickshank JK. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. Lancet Diabetes Endocrinol. 2016;4(2):136–147. doi: 10.1016/S2213-8587(15)00377-0.
    1. Heran BS, Chen JM, Wang JJ, Wright JM. Blood pressure lowering efficacy of potassium-sparing diuretics (that block the epithelial sodium channel) for primary hypertension. Cochrane Database Syst Rev. 2012;11:CD008167.
    1. Saha C, Eckert GJ, Ambrosius WT, Chun TY, Wagner MA, Zhao Q, et al. Improvement in blood pressure with inhibition of the epithelial sodium channel in blacks with hypertension. Hypertension. 2005;46(3):481–487. doi: 10.1161/01.HYP.0000179582.42830.1d.
    1. Hood SJ, Taylor KP, Ashby MJ, Brown MJ. The spironolactone, amiloride, losartan, and thiazide (SALT) double-blind crossover trial in patients with low-renin hypertension and elevated aldosterone-renin ratio. Circulation. 2007;116(3):268–275. doi: 10.1161/CIRCULATIONAHA.107.690396.
    1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA. 2002;288(23):2981–2997. doi: 10.1001/jama.288.23.2981.
    1. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887–1898. doi: 10.1056/NEJMoa0801369.
    1. Kaplan NM. Chlorthalidone versus hydrochlorothiazide: a tale of tortoises and a hare. Hypertension. 2011;58(6):994–995. doi: 10.1161/HYPERTENSIONAHA.111.183525.
    1. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–3104. doi: 10.1093/eurheartj/ehy339.
    1. Blood Pressure Lowering Treatment Trialists’ Collaboration. Turnbull F, Neal B, Algert C, Arima H, Barzi F, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. 2008;336(7653):1121–1123. doi: 10.1136/.
    1. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957–967. doi: 10.1016/S0140-6736(15)01225-8.
    1. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure-lowering treatment on cardiovascular outcomes and mortality: 14 - effects of different classes of antihypertensive drugs in older and younger patients: overview and meta-analysis. J Hypertens. 2018;36(8):1637–1647. doi: 10.1097/HJH.0000000000001777.
    1. Saghaei M. Random allocation software for parallel group randomized trials. BMC Med Res Methodol. 2004;4:26. doi: 10.1186/1471-2288-4-26.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Whelton PK, Carey RM, Aronow WS, Casey DE, Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC / AHA / AAPA / ABC / ACPM / AGS / APhA / ASH / ASPC / NMA / PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13–e115.
    1. Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. doi: 10.1136/bmj.e7586.
    1. Taichman DB, Sahni P, Pinborg A, Peiperl L, Laine C, James A, et al. Data Sharing statements for clinical trials: A requirement of the International Committee of Medical Journal Editors. Ann Intern Med. 2017;167(1):63–65. doi: 10.7326/M17-1293.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する