Chlorthalidone Versus Hydrochlorothiazide
2011; Lippincott Williams & Wilkins; Volume: 58; Issue: 6 Linguagem: Inglês
10.1161/hypertensionaha.111.183525
ISSN1524-4563
Autores Tópico(s)Sodium Intake and Health
ResumoHomeHypertensionVol. 58, No. 6Chlorthalidone Versus Hydrochlorothiazide Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBChlorthalidone Versus HydrochlorothiazideA Tale of Tortoises and a Hare Norman M. Kaplan Norman M. KaplanNorman M. Kaplan From the Hypertension Division, Department of Internal Medicine, Southwestern Medical School, University of Texas, Dallas, TX. Originally published24 Oct 2011https://doi.org/10.1161/HYPERTENSIONAHA.111.183525Hypertension. 2011;58:994–995Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 See related article, pp 1001–1007Chlorthalidone (CTD) is the best diuretic for the treatment of hypertension, both in blood pressure–lowering efficacy and, most importantly, in prevention of hypertension-related morbidity and mortality. Despite this fact, hydrochlorothiazide (HCTZ) has been and continues to be by far the most frequently prescribed diuretic in the United States.1 Even among patients with resistant hypertension, where a more potent diuretic is especially needed, CTD is chosen in only 3% of patients.2 There are numerous possible reasons for this flagrant failure of evidence-based medicine. I will refer to the Aesop tale of "The Tortoise and the Hare" as my way of explaining the paradox. In this reference, physicians are the tortoises, whereas a pharmaceutical company is the hare; here, unlike in the original, the hare easily wins the race.The 2 diuretics were approved for the treatment of hypertension within a year of each other, HCTZ in 1959 and CTD in 1960. Soon thereafter, small trials documented the equal efficacy of CTD in much smaller doses in lowering blood pressure compared with HCTZ3 or other thiazides.4 A few years later, the Multiple Risk Factor Intervention Trial (MRFIT) was begun, and the designers offered the 15 participating clinics the choice of using either HCTZ or CTD; 9 chose HCTZ and 6 chose CTD.5 After some 4 years, the MRFIT policy advisory board recommended that all of the participants be given CTD, because the trend of mortality was unfavorable in the HCTZ clinics compared with favorable trends in the CTD clinics.5The wisdom of this decision in favor of CTD was soon validated in 3 large controlled outcome trials, the Systolic Hypertension in the Elderly Program in 1991,6 the Verapamil in Hypertension and Atherosclerosis Study in 1997,7 and, most decisively, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial in 2002.8 In these 3 large outcome trials, CTD provided excellent protection against heart attacks and strokes. Meanwhile, no decreases in morbidity or mortality were seen in multiple trials using HCTZ.9Nonetheless, the machinations of the hare who owned the patent for HCTZ were immediately brought into play as soon as the drug had been approved. When the Veterans' Administration Cooperative Studies on the Treatment of Hypertension were begun in 1964, HCTZ was made available and used in both the initial study on severe hypertension10 and the second one on less severe disease,11 along with reserpine and hydralazine. With this extra boost in awareness and the strengths of the largest pharmaceutical sales force in the world pushing its acceptance, HCTZ soon outsold CTD, then marketed by a smaller Swiss-based company. Moreover, HCTZ was quickly added in combination with antihypertensive drugs from every other class except calcium channel blockers, ending up in ≥28 combination tablets. Meanwhile, after its initial success, the use of CTD progressively fell, and it was combined with only 3 other antihypertensive agents.The well-conditioned hare pushed its patented product as fast and as hard as possible. And the tortoises, US practitioners, soon accepted its superiority, and, by 2010, HCTZ was the choice in >95% of oral diuretic prescriptions.1,2Meanwhile, starting in 2004, investigators, most from the Carver College of Medicine at the University of Iowa, began publishing a series of careful comparisons of the antihypertensive effects of the 2 drugs, having noted that, even in prestigious textbooks of pharmacology, the 2 drugs were considered to be equivalent and interchangeable.12 They13–15 and others using 24-hour ambulatory monitoring16 have shown the longer and stronger efficacy of CTD over HCTZ.Soon thereafter, using a retrospective cohort analysis of the MRFIT data, the clear proof of a greater reduction in heart attacks and strokes with CTD than with HCTZ was shown.17 Adding to this evidence, the Iowa group joined by other investigators presents, in this issue of this journal, further evidence for the superior antihypertensive efficacy of CTD over HCTZ using the greater regression of electrocardiographic left ventricular hypertrophy seen in those on CTD in the MRFIT.18 As they conclude, "Our findings on left ventricular hypertrophy support the idea that greater blood pressure reduction with CTD than HCTZ may have lead to differences in mortality observed in MRFIT."So what have the tortoises done in view of the conclusive evidence of the superiority of CTD over HCTZ, with the 2 now costing the same, 30 tablets for $4.00, and with no significant differences in adverse effects between the two? As expected from tortoises, they have moved exceedingly slow, as documented in references1 and.2 Now that pharmaceutical representatives are no longer promoting HCTZ, perhaps more publications and talks by nonbiased speakers will help, along with the likely impending introduction of the first "modern" drug, an angiotensin receptor blocker, in combination with CTD.19Hopefully, we tortoises will overtake the hare, but, meanwhile, millions of hypertensive patients have been given a less effective drug that almost certainly did not protect them as well as CTD would have. The patients are neither tortoises nor hares, but they have been the unwitting recipients of a flagrant failure of evidence-based medicine.It should be noted that the British National Institute for Health and Clinical Excellence has recently published new guidelines on preferred drugs for treatment of hypertension, in which diuretics have been demoted from first choice to third choice for the majority of patients.20 One wonders, could awareness of the ability of CTD to reduce mortality as well as drugs from any other class have prevented the National Institute for Health and Clinical Excellence from denying the use of the correct diuretic from its preferred location? Surely, the British are now willing to accept hard evidence from their unruly and disloyal former colony.One last issue: should the pharmaceutical company be faulted for its aggressive marketing of its patented HCTZ even if it was known to be an inferior drug? The answer would be "no" in keeping with the capitalistic economic model that Milton Friedman would have applauded. But what if, as has been repeatedly done, the larger pharmaceutical company bought the patent from the original patent holder soon after the evidence that CTD was the better drug became known and then marketed it as aggressively as they did HCTZ? Might their profits have been just as great and many millions more hypertensive patients provided better control of their hypertension?DisclosuresNone.FootnotesThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Correspondence to Norman M. Kaplan, University of Texas, Southwestern Medical School, Department of Internal Medicine, Hypertension Division, 5323 Harry Hines Blvd, Dallas, TX 75390. E-mail norman.kaplan@utsouthwestern.eduReferences1. Ernst ME, Lund BC. Renewed interest in chlorthalidone: evidence from the Veterans Health Administration. J Clin Hypertens. 2010; 12:927–934.CrossrefGoogle Scholar2. Hanselin MR, Saseen JJ, Allen RR, Marrs JC, Nair KV. Description of antihypertensive use in patients with resistant hypertension prescribed four or more agents. Hypertension. 2011; 58:1008–1013.LinkGoogle Scholar3. Bowlus WE, Langford HG. A comparison of the antihypertensive effect of chlorthalidone and hydrochlorothiazide. Clin Pharmacol Ther. 1964; 5:708–711.CrossrefMedlineGoogle Scholar4. Cranston WI, Juel-Jensen BE, Semmence AM, Handfield Jones RPC, Forbes JA, Mutch LMM. Effects of oral diuretics on raised arterial pressure. Lancet. 1963; 2:966–970.CrossrefMedlineGoogle Scholar5. Multiple Risk Factor Intervention Trial Research Group. Mortality after 10 ½ years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation. 1990; 82:1616–1628.CrossrefMedlineGoogle Scholar6. 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 Scholar7. 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 Atherosclerosis Study. J Hypertens. 1997; 15:1337–1344.CrossrefMedlineGoogle Scholar8. 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 Antihypetensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981–2997.CrossrefMedlineGoogle Scholar9. Kaplan NM. The choice of thiazide diuretics: why chlorthalidone may replace hydrochlorothiazide. Hypertension. 2009; 54:951–953.LinkGoogle Scholar10. Veterans Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA. 1967; 202:1028–1034.CrossrefMedlineGoogle Scholar11. Veterans Cooperative Study Group on Antihypertensive Agents. Effects on morbidity of treatment in hypertension: II–results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970; 213:1143–1152.CrossrefMedlineGoogle Scholar12. Jackson EK. Diuretics. In: , Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's the Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006:737–770.Google Scholar13. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlothalidone: Evidence supporting their interchangeability. Hypertension. 2004; 43:4–9.LinkGoogle Scholar14. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJG, 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. Ernst ME, Carter BL, Zheng S, Grimm RH. Meta-analysis of dose-response characteristics of hydrochlorothiazide and chlorthalidone: effects on systolic blood pressure and potassium. Am J Hypertens. 2010; 23:440–446.CrossrefMedlineGoogle Scholar16. Messerli FH, Makani H, Benjo A, Romero J, Alviar C, Bangalore S. Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring. Am J Cardiol. 2011; 57:590–600.CrossrefGoogle Scholar17. Dorsch MP, Gillespie BW, Erickson SR, Bleske BE, Weder AB. Chlorthalidone reduces cardiovascular events compared with hydrochlorothiazide: a retrospective cohort analysis. Hypertension. 2011; 57:689–694.LinkGoogle Scholar18. Ernst ME, Neaton JD, Grimm RH, Collins G, Thomas W, Soliman EZ, Prineas RJ, for the Multiple Risk Factor Intervention Trial Research Group. Long-term effects of chlorthalidone versus hydrochlorothiazide on electrocardiographic left ventricular hypertrophy in the Multiple Risk Factor Intervention Trial. Hypertension. 2011; 58:1001–1007.LinkGoogle Scholar19. Bakris G, White WB, Weber MA, Sica D, Perez A, Cao C, Kupfer S. Results of a double-blind randomized study comparing chlorthalidone and hydrochlorothiazide combined with the new angiotensin receptor blocker azilsartan medoxomil in primary hypertension [abstract]. J Clin Hypertens. 2010; 12:530.Google Scholar20. Krause T, Lovibond K, Caulfield M, McCormack T, Williams B, on behalf of the Guideline Development Group. Management of hypertension: summary of NICE guidance. BMJ. 2011; 343:d4891–d4898.CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Verdecchia P, Cavallini C and Angeli F (2022) Advances in the Treatment Strategies in Hypertension: Present and Future, Journal of Cardiovascular Development and Disease, 10.3390/jcdd9030072, 9:3, (72) Martins V, Ziegelmann P, Helal L, Ferrari F, Lucca M, Fuchs S and Fuchs F (2022) Thiazide diuretics alone or in combination with a potassium-sparing diuretic on blood pressure-lowering in patients with primary hypertension: protocol for a systematic review and network meta-analysis, Systematic Reviews, 10.1186/s13643-022-01890-y, 11:1 Pareek A, Ram C, Agarwala R and Mehta R (2020) Indian guidelines on hypertension-IV (2019): need to differentiate thiazide-like diuretics, Journal of Human Hypertension, 10.1038/s41371-020-00412-4, 34:12, (841-842), Online publication date: 1-Dec-2020. Townsend R, DiPette D, Luft F, Weinberger M and Ram V (2020) Norman M. Kaplan, Hypertension, 76:2, (291-293), Online publication date: 1-Aug-2020. Martins V, Helal L, Ferrari F, Bottino L, Fuchs S and Fuchs F (2019) 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, Trials, 10.1186/s13063-019-3909-z, 20:1, Online publication date: 1-Dec-2019. Slíva J (2018) The current position of hydrochlorothiazide among thiazide and thiazide-like diuretics, Vnitřní lékařství, 10.36290/vnl.2018.013, 64:1, (83-85), Online publication date: 1-Jan-2018. Elias M and Torres R (2017) Delayed Response to Antihypertension Medication, Hypertension, 70:1, (30-31), Online publication date: 1-Jul-2017.Dhruva S, Huang C, Spatz E, Coppi A, Warner F, Li S, Lin H, Xu X, Furberg C, Davis B, Pressel S, Coifman R and Krumholz H (2017) Heterogeneity in Early Responses in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), Hypertension, 70:1, (94-102), Online publication date: 1-Jul-2017. Roush G, Ernst M, Kostis J, Kaur R and Sica D (2015) Not Just Chlorthalidone: Evidence-Based, Single Tablet, Diuretic Alternatives to Hydrochlorothiazide for Hypertension, Current Hypertension Reports, 10.1007/s11906-015-0540-6, 17:4, Online publication date: 1-Apr-2015. Saseen J, Ghushchyan V and Nair K (2014) Comparing Clinical Effectiveness and Drug Toxicity With Hydrochlorothiazide and Chlorthalidone Using Two Potency Ratios in a Managed Care Population, The Journal of Clinical Hypertension, 10.1111/jch.12453, 17:2, (134-140), Online publication date: 1-Feb-2015. de Simone G, Izzo R and Verdecchia P (2013) Are Observational Studies More Informative Than Randomized Controlled Trials in Hypertension?, Hypertension, 62:3, (463-469), Online publication date: 1-Sep-2013. Kaplan N, Cooper O and Victor R (2013) Hypertension Therapy Essential Cardiology, 10.1007/978-1-4614-6705-2_32, (561-575), . 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. Dudenbostel T and Glasser S (2012) Effects of Antihypertensive Drugs on Arterial Stiffness, Cardiology in Review, 10.1097/CRD.0b013e31825d0a44, 20:5, (259-263), Online publication date: 1-Sep-2012. December 2011Vol 58, Issue 6 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.111.183525PMID: 22025371 Originally publishedOctober 24, 2011 PDF download Advertisement SubjectsClinical StudiesEthics and PolicyPharmacology
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