The Choice of Thiazide Diuretics

Abstract

HomeHypertensionVol. 54, No. 5The Choice of Thiazide Diuretics Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Choice of Thiazide DiureticsWhy Chlorthalidone May Replace Hydrochlorothiazide Norman M. Kaplan Norman M. KaplanNorman M. Kaplan From the Hypertension Division, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Tex. Search for more papers by this author Originally published14 Sep 2009https://doi.org/10.1161/HYPERTENSIONAHA.109.135061Hypertension. 2009;54:951–953Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 14, 2009: Previous Version 1 Thiazide diuretics were introduced in the United States for the treatment of hypertension in 1957. The first of these, chlorothiazide, was soon accompanied by a large number of other sulfonamide derivatives, including chlorthalidone. Hydrochlorothiazide (HCTZ) rapidly became the most commonly prescribed antihypertensive drug in the United States, whereas bendroflumethiazide was most popular in the United Kingdom. The initial popularity of HCTZ in the United States was abetted by its use in the first controlled trial of the treatment of nonmalignant hypertension, the Veterans’ Affairs Cooperative Study.1 The starting dose of HCTZ was 50 mg/d, and it was used along with reserpine and hydralazine. A number of other trials published in the 1970s all used higher doses of diuretic, for example, ≥50 mg of HCTZ per day.2For reasons unknown to me, chlorthalidone was chosen to be the diuretic in the first large controlled trial of the treatment of hypertension, the Hypertension Detection and Follow-Up Program.3 In the Hypertension Detection and Follow-Up Program, all 10 940 patients were started on chlorthalidone from 25 to 100 mg/d. Other drugs were added to achieve control of the blood pressure. In addition, half were assigned to “referred” care and the other half to more closely monitored and intensively treated “stepped” care. The stepped care–treated half achieved a 4.4% further reduction in diastolic blood pressure and a 17.0% reduction in mortality.In other large, placebo controlled trials published in the early 1980s, other diuretics were used: chlorothiazide in the Australian trial,4 HCTZ in the Oslo study,5 and bendrofluazide in the United Kingdom Medical Research Council Trial.6 In all of these trials, the diuretic was combined with other drugs to achieve the goal of therapy.When the Multiple Risk Factor Intervention Trial was begun, either chlorthalidone or HCTZ, both at doses of 50 or 100 mg daily, could be used. In 6 clinics, chlorthalidone was chosen; in 9, HCTZ was used. After some 7 years, the Multiple Risk Factor Intervention Trial Policy Advisory Board recommended that all of the subjects be given chlorthalidone at a maximal dose of 50 mg/d, because the trend of mortality was unfavorable in the 9 clinics using HCTZ compared with the favorable trend in the 6 clinics using chlorthalidone.7Nonetheless, HCTZ has been much more widely prescribed in the United States than chlorthalidone and, except for combination with a β-blocker (atenolol) and a central α agonist (clonidine), all of the many other available combinations with a diuretic contain HCTZ at doses ranging from 6.25 mg to 25.00 mg per day.2 Moreover, the multiple Joint National Committee reports only recommend a thiazide diuretic without choosing the specific agent.8Overlooked FactsThese practices overlooked 2 facts. First, such low doses of HCTZ have never been shown to reduce cardiovascular morbidity or mortality, although they clearly increase the antihypertensive efficacy of whatever other drug with which they are combined. Second, chlorthalidone in doses from 12.5 to 25.0 mg/d has been shown repeatedly to reduce cardiovascular morbidity and mortality in randomized, controlled trials.3,7,9–11As an example of the failure to recognize these facts, in a widely referenced analysis of the various antihypertensive therapies used as first-line agents, Psaty et al12 conclude that, “Low dose diuretics are the most effective first-line treatment for preventing the occurrence of cardiovascular disease morbidity and mortality,” but their analysis combined HCTZ, chlorthalidone, and other thiazides as either low dose or high dose. Moreover, the low-dose thiazides were often combined with other agents (Table). Table. Outcome Trials of Assumed Low-Dose Thiazide for Initial Therapy of Hypertension Identified by Psaty et al12ReferenceDiuretic Used, mg/dHelgelund5HCTZ, 25 to 50 + triamterene, 50 to 100Amery24HCTZ, 50SHEP Cooperative Research Group9Chlorthalidone, 12.5 to 25.0Medical Research Council Working Party6HCTZ, 25 to 50 + amiloride, 2.5 to 5.0PATS Collaborating Group25Indapamide, 2.5Rosei EA et al26Chlorthalidone, 25National Intervention Cooperative Study in Elderly Hypertension Study Group27Trichlormethiazide, 2Brown MJ et al28HCTZ, 25 to 50 + amiloride, 2.5 to 5.0ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group10Chlorthalidone, 12.5 to 25.0Wing LMH et al29HCTZ, dosage unknownSurprisingly, the first definite evidence for a significant difference in the antihypertensive efficacy of HCTZ and chlorthalidone was published just 5 years ago, in this journal.13 Their review concluded that, “chlorthalidone is about 1.5 to 2.0 times more potent as HCTZ, and the former has a much longer duration of action.” The authors called for a proper comparative trial of the 2 agents in lower doses but noted that, “a randomized trial to prove any differences in outcome will probably never be performed,” because the drugs are generic.Even more surprisingly, the first published trial of the 24-hour ambulatory blood pressure monitoring comparing the 2 drugs appeared only 3 years ago, again in this journal and from the same investigators.14 They found a greater lowering of systolic blood pressure with 25 mg of chlorthalidone than with 50 mg of HCTZ in a crossover trial of 30 stage 1 hypertensives (average baseline office blood pressure: 143/93 mm Hg) with 8-week periods of drug intake and a 4-week washout period between. The daytime ambulatory blood pressure monitoring was a statistically insignificant 3.3-mm Hg mean difference, but the nighttime mean difference was a highly significant 7.1-mm Hg lower blood pressure with chlorthalidone. Of further interest, the falls in serum potassium were similar during the 8-week periods of HCTZ or chlorthalidone intake, averaging 0.5 mEq/L.Meaning of the FactsA number of important facts pertinent to clinical practice can be concluded from currently available data, as described here. Chlorthalidone is the preferable diuretic for initial and subsequent therapy of hypertension, starting with 12.5 mg/d and increasing to ≤25.0 mg/d with or without other antihypertensive drugs.Second, studies comparing other antihypertensive drugs in full doses against 12.5 to 25.0 mg of HCTZ15,16 are as likely to favor the other drug, as seen with comparisons against the inadequate doses of the β-blocker atenolol.17 As Messerli and Bangalore note, “Many pharmaceutical companies tend to go down the path of least resistance, ie, select an antihypertensive drug that can be beaten easily with regard to efficacy and safety.”17 Other reasons for the continued use of HCTZ may be involved.Third, even in low doses, potent diuretics, such as chlorthalidone, can lower serum potassium enough to cause cardiac arrest.18 In view of the strong evidence that small doses of the aldosterone blockers spironolactone and eplerenone can protect vulnerable patients19,20 and significantly reduce blood pressures resistant to ≥3 drugs,21 a logical way to provide maximal antihypertensive efficacy and to prevent hypokalemia might be a combination of chlorthalidone and spironolactone 12.5/25.0 mg/d, although there are no trials in which the 2 drugs were given as combination. Both are inexpensive ($4 for a 30-day supply of each) but unfortunately not available in a single tablet. The 25-mg tablets of generic chlorthalidone can be halved with a pill cutter, and 25-mg doses of spironolactone are available.ConclusionThere seems little reason to follow the advice of those who state that, “The risk/benefit of β-blockers and diuretics preclude their use for first-line therapy in hypertension.”22 β-Blockers without vasodilatory action have likely been proven to be inadequate,23 but appropriate use of diuretics can still be a safe and effective way to treat hypertension.DisclosuresNone.FootnotesCorrespondence to Norman M. Kaplan, 5323 Harry Hines Blvd, Dallas, TX 75390-8586. E-mail [email protected] References 1 Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. JAMA. 1970; 213: 1143–1152.CrossrefMedlineGoogle Scholar2 Kaplan N, Victor R. Treatment of hypertension: drug therapy. In: Kaplan’s Clinical Hypertension. 10th ed. Philadelphia, PA: Lippincott and Wilkins; 2010. In press.Google Scholar3 Hypertension Detection and Follow-Up Program Cooperative Group. Five-year findings of the hypertension detection and follow-up program: I–reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA. 1979; 242: 2562–2571.CrossrefMedlineGoogle Scholar4 Report by the Management Committee. The Australian Therapeutic Trial in Mild Hypertension. Lancet. 1980; 1: 1261–1267.MedlineGoogle Scholar5 Helgeland A. Treatment of mild hypertension: a five year controlled drug trial–The Oslo Study. Am J Med. 1980; 69: 725–732.CrossrefMedlineGoogle Scholar6 Medical Research Council Working Party. Medical research council trial of treatment of hypertension in older adults: principal results. BMJ. 1992; 304: 405–412.CrossrefMedlineGoogle Scholar7 Multiple Risk Factor Intervention Trial Research Group. Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation. 1990; 82: 1616–1628.CrossrefMedlineGoogle Scholar8 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. Hypertension. 2003; 42: 1206–1252.LinkGoogle Scholar9 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991; 265: 3255–3264.CrossrefMedlineGoogle Scholar10 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: 2981–2997.CrossrefMedlineGoogle Scholar11 Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, Kewis CE, Liebson PR. Treatment of Mild Hypertension Study: final results– Treatment of Mild Hypertension Study Research Group. JAMA. 1993; 270: 713–724.CrossrefMedlineGoogle Scholar12 Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, Weiss NS. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003; 289: 2534–2544.CrossrefMedlineGoogle Scholar13 Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone: evidence supporting their interchangeability. Hypertension. 2004; 43: 4–9.LinkGoogle Scholar14 Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, Bergus GR. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006; 47: 352–358.LinkGoogle Scholar15 Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008; 359: 2417–2428.CrossrefMedlineGoogle Scholar16 Schmieder RE, Philipp T, Guerediaga J, Gorostidi M, Smith B, Weissbach N, Maboudian M, Botha J, van Ingen H. Long-term antihypertensive efficacy and safety of the oral direct renin inhibitor aliskiren: a 12-month randomized, double-blind comparator trial with hydrochlorothiazide. Circulation. 2009; 119: 417–425.LinkGoogle Scholar17 Messerli FH, Bangalore S. Antihypertensive efficacy of aliskiren: is hydrochlorothiazide an appropriate benchmark? Circulation. 2009; 119: 371–373.LinkGoogle Scholar18 Siscovick DS, Raghunathan TE, Psaty BM, Koepsell TD, Wicklund KG, Lin X, Cobb L, Rautaharju PM, Copass MK, Wagner EH. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med. 1994; 330: 1852–1857.CrossrefMedlineGoogle Scholar19 Pitt B. Aldosterone blockade in patients with acute myocardial infarction. Circulation. 2003; 107: 2525–2527.LinkGoogle Scholar20 Pitt B, Ahmed A, Love TE, Krum H, Nocolau J, Cardoso JS, Parkhomenko A, Aschermann M, Corbalan R, Solomon H, Shi H, Zannad F. History of hypertension and eplerenone in patients with acute myocardial infarction complicated by heart failure. Hypertension. 2008; 52: 271–278.LinkGoogle Scholar21 Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H, Poulter NR; for the Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007; 49: 839–845.LinkGoogle Scholar22 Messerli FH, Bangalore S, Julius S. Risk/benefit assessment of beta-blockers and diuretics precludes their use for first-line therapy in hypertension. Circulation. 2008; 117: 2706–2715.LinkGoogle Scholar23 Lindholm LH, Carlberg B, Samuelsson O. Should β-blockers remain first choic in the tratmento of primary hypertension? A meta analysis. Lancet. 2005; 366: 1545–1553.CrossrefMedlineGoogle Scholar24 Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R, Forette F, Hamdy R, Joossens JV, Lund-Johansen P, Petrie J, Tuomilehto J, Williams B. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet. 1985; 1: 1349–1354.CrossrefMedlineGoogle Scholar25 PATS Collaborating Group. Post-Stroke Antihypertensive Treatment Study: a preliminary report. Chin Med J (Engl). 1995; 108: 710–717.MedlineGoogle Scholar26 Rosei EA, Dal Palu C, Leonetti G, Magnani B, Pessina A, Zanchetti A, for the VHAS Investigators. Clinical results of the Verapamil in Hypertension and Atherosclosis Study. J Hypertens. 1997; 15: 1337–1344.CrossrefMedlineGoogle Scholar27 National Intervention Cooperative Study in Elderly Hypertension Study Group. Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. Hypertension. 1999; 34: 1129–1133.CrossrefMedlineGoogle Scholar28 Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium channel blocker or diuretic in the international nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000; 356: 366–372.CrossrefMedlineGoogle Scholar29 Wing LMH, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting–enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003; 348: 583–592.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Chekka L, Chapman A, Gums J, Cooper-DeHoff R and Johnson J (2021) Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone, The American Journal of Medicine, 10.1016/j.amjmed.2020.12.015, 134:7, (918-925.e2), Online publication date: 1-Jul-2021. Lang K, Van Iterson E and Laffin L (2020) Contemporary Strategies to Manage High Blood Pressure in Patients with Coexistent Resistant Hypertension and Heart Failure With Reduced Ejection Fraction, Cardiology and Therapy, 10.1007/s40119-020-00203-5, 10:1, (9-25), Online publication date: 1-Jun-2021. Liu C, Liu X, Wang Y, Deng Z, Liu T, Sukhova G, Wojtkiewicz G, Tang R, Zhang J, Achilefu S, Nahrendorf M, Libby P, Wang X and Shi G (2020) Reduced Nhe1 (Na+-H+ Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)–Induced Abdominal Aortic Aneurysms, Hypertension, 76:1, (87-100), Online publication date: 1-Jul-2020. Dineva S, Uzunova K, Pavlova V, Filipova E, Kalinov K and Vekov T (2019) Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide—meta-analysis, Journal of Human Hypertension, 10.1038/s41371-019-0255-2, 33:11, (766-774), Online publication date: 1-Nov-2019. Carnagarin R, Matthews V, Gregory C and Schlaich M (2018) Pharmacotherapeutic strategies for treating hypertension in patients with obesity, Expert Opinion on Pharmacotherapy, 10.1080/14656566.2018.1458092, 19:7, (643-651), Online publication date: 3-May-2018. Gu A, Yue Y and Argulian E (2016) Age Differences in Treatment and Control of Hypertension in US Physician Offices, 2003-2010: A Serial Cross-sectional Study, The American Journal of Medicine, 10.1016/j.amjmed.2015.07.031, 129:1, (50-58.e4), Online publication date: 1-Jan-2016. Cirillo M, Marcarelli F, Mele A, Romano M, Lombardi C and Bilancio G (2014) Parallel-Group 8-Week Study on Chlorthalidone Effects in Hypertensives With Low Kidney Function, Hypertension, 63:4, (692-697), Online publication date: 1-Apr-2014. Okada Y, Jarvis S, Best S, Bivens T, Adams-Huet B, Levine B and Fu Q (2013) Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors, The Journal of Physiology, 10.1113/jphysiol.2013.261362, 591:23, (5913-5922), Online publication date: 1-Dec-2013. Kaplan N (2013) Furosemide for your mother?, Journal of the American Society of Hypertension, 10.1016/j.jash.2013.06.005, 7:6, (507-508), Online publication date: 1-Nov-2013. Gavrilova N and Oganov R (2013) DIURETIC-BASED COMBINATION THERAPY IN PATIENTS WITH ARTERIAL HYPERTENSION: RESULTS OF THE RUSSIAN TRUST STUDY, Cardiovascular Therapy and Prevention, 10.15829/1728-8800-2013-4-62-66, 12:4, (62-66) Kidambi S and Kotchen T (2013) Treatment of Hypertension in Obese Patients, American Journal of Cardiovascular Drugs, 10.1007/s40256-013-0008-5, 13:3, (163-175), Online publication date: 1-Jun-2013. Germino F (2012) Which Diuretic Is the Preferred Agent for Treating Essential Hypertension: Hydrochlorothiazide or Chlorthalidone?, Current Cardiology Reports, 10.1007/s11886-012-0307-5, 14:6, (673-677), Online publication date: 1-Dec-2012. Hughes A, Peterzan M, Chaturvedi N and Hardy R (2012) Response to Potency of Office Blood Pressure From Hydrochlorothiazide and Chlorthalidone Fails to Explain Cardiovascular Events, Hypertension, 60:3, (e23-e23), Online publication date: 1-Sep-2012.Roush G, Holford T and Guddati A (2012) Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events, Hypertension, 59:6, (1110-1117), Online publication date: 1-Jun-2012.Peterzan M, Hardy R, Chaturvedi N and Hughes A (2012) Meta-Analysis of Dose-Response Relationships for Hydrochlorothiazide, Chlorthalidone, and Bendroflumethiazide on Blood Pressure, Serum Potassium, and Urate, Hypertension, 59:6, (1104-1109), Online publication date: 1-Jun-2012.Kaplan N (2011) Chlorthalidone Versus Hydrochlorothiazide, Hypertension, 58:6, (994-995), Online publication date: 1-Dec-2011. Ernst M and Mann S (2011) Diuretics in the Treatment of Hypertension, Seminars in Nephrology, 10.1016/j.semnephrol.2011.09.004, 31:6, (495-502), Online publication date: 1-Nov-2011. Okpechi I and Rayner B (2011) Impact of recent landmark clinical trials on hypertension treatment, Clinical Investigation, 10.4155/cli.11.97, 1:8, (1141-1154), Online publication date: 1-Aug-2011. Martinez-Martin F, Rodriguez-Rosas H, Peiro-Martinez I, Soriano-Perera P, Pedrianes-Martin P and Comi-Diaz C (2010) Olmesartan/amlodipine vs olmesartan/hydrochlorothiazide in hypertensive patients with metabolic syndrome: the OLAS study, Journal of Human Hypertension, 10.1038/jhh.2010.104, 25:6, (346-353), Online publication date: 1-Jun-2011. Dorsch M, Gillespie B, Erickson S, Bleske B and Weder A (2011) Chlorthalidone Reduces Cardiovascular Events Compared With Hydrochlorothiazide, Hypertension, 57:4, (689-694), Online publication date: 1-Apr-2011. Al Badarin F, Abuannadi M, Lavie C and O'Keefe J (2011) Evidence-Based Diuretic Therapy for Improving Cardiovascular Prognosis in Systemic Hypertension, The American Journal of Cardiology, 10.1016/j.amjcard.2010.12.016, 107:8, (1178-1184), Online publication date: 1-Apr-2011. Brook R and Weder A (2011) Initial hypertension treatment: one combination fits most?, Journal of the American Society of Hypertension, 10.1016/j.jash.2011.01.002, 5:2, (66-75), Online publication date: 1-Mar-2011. Ernst M and Lund B (2010) Renewed Interest in Chlorthalidone: Evidence From the Veterans Health Administration, The Journal of Clinical Hypertension, 10.1111/j.1751-7176.2010.00373.x, 12:12, (927-934), Online publication date: 1-Dec-2010. Gaciong Z and Symonides B (2010) Hypertension 2010: what was new for the cardiologist?, Expert Opinion on Pharmacotherapy, 10.1517/14656566.2010.513972, 11:16, (2579-2597), Online publication date: 1-Nov-2010. Kurtz T (2010) Chlorthalidone: Don’t Call It “Thiazide-Like” Anymore, Hypertension, 56:3, (335-337), Online publication date: 1-Sep-2010. Ernst M, Carter B, Zheng S and Grimm R (2010) Meta-Analysis of Dose-Response Characteristics of Hydrochlorothiazide and Chlorthalidone: Effects on Systolic Blood Pressure and Potassium, American Journal of Hypertension, 10.1038/ajh.2010.1, 23:4, (440-446), Online publication date: 1-Apr-2010. Armanini D and Fiore C (2009) Choice of Diuretic Therapy and Reconsideration for Aldosterone Receptors Blockers, Hypertension, 55:1, (e5-e5), Online publication date: 1-Jan-2010. November 2009Vol 54, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/HYPERTENSIONAHA.109.135061PMID: 19752290 Manuscript receivedApril 23, 2009Manuscript acceptedAugust 19, 2009Originally publishedSeptember 14, 2009Manuscript revisedMay 13, 2009 PDF download Advertisement SubjectsClinical StudiesPharmacologyPrimary PreventionTreatment