Proceedings of the Fourth Genoa Meeting on Hypertension, Diabetes, and Renal Diseases
Thiazide Diuretics in the Treatment of Hypertension: An Update
Antonio Salvetti and
Lorenzo Ghiadoni
Department of Internal Medicine, University of Pisa, Pisa, Italy
Address correspondence to: Prof. Antonio Salvetti, Department of Internal Medicine, University of Pisa, Via Roma 67, 56127 Pisa, Italy. Phone/Fax: +39-050-553407; a.salvetti{at}med.unipi.it
Thiazide diuretics were the first tolerated efficient antihypertensivedrugs that significantly reduced cardiovascular morbidity andmortality in placebo-controlled clinical studies. Although thesedrugs today still are considered a fundamental therapeutic toolfor the treatment of hypertensive patients, the following considerationsshould be taken into account. Although there are some indicationsthat chlorthalidone can offer additional advantages as comparedwith other compounds, a recent meta-analysis of placebo-controlledtrials suggested that the beneficial effects of thiazide diureticscould be a class effect. Thiazide diuretics must be used atappropriate and/or optimal doses to achieve the optimal antihypertensiveeffect with the smallest occurrence of side effects, includingalterations in glucose and lipid profiles and hypokalemia. Moreover,because thiazide diuretics can increase the incidence of new-onsetdiabetes, especially when combined with blockers, caution isadvised in using these drugs above all in patients who are athigh risk for developing diabetes, in whom thiazide diureticsshould be used at the lowest active dose and possibly in combinationwith drugs that block the renin-angiotensin system. Finally,the current debate on whether thiazide diuretics are the first-choicedrug for most patients with uncomplicated hypertension, as statedin the Seventh Joint National Committee Report, or are includedin the major classes of antihypertensive agents that are suitablefor initiation and maintenance of therapy, as reported in theEuropean Society of Hypertension–European Society of CardiologyGuidelines, derives from different interpretations of controlledclinical trial data on drug class comparison and of cost-benefitanalyses. However, considering that the benefit of antihypertensivedrugs seems to be due principally to BP lowering per se withoutdefinitive evidence of the superiority of a particular drugclass and that there is no cost-benefit analysis showing thesuperiority of thiazide diuretics, it is believed that thesedrugs should not be considered as the only first-choice drugbut included among first-choice drugs.
Since the discovery of thiazide diuretics in 1957, which forthe first time offered the possibility of efficiently reducingBP, these drugs have represented a fundamental tool for thetreatment of hypertension. Moreover, placebo-controlled clinicalstudies have documented clearly the benefit of thiazide diuretics,either given alone or combined with blockers, in reducing cardiovascular(CV) morbidity and mortality (1), a benefit similar to thatachieved with other antihypertensive drug classes, such as angiotensin-convertingenzyme (ACE) inhibitors and calcium antagonists (2). In thisarticle, we review topics concerning the role of thiazide diureticsin the treatment of hypertension.
This debate first was raised by data from the Multiple RiskFactor Intervention Trial (3), which aimed to examine specialintervention and usual care groups. The data indicated thatcoronary heart disease (CHD) and total mortality trends wereless favorable at clinics where special intervention cliniciansfavored hydrochlorothiazide over chlorthalidone. This led toa protocol change with the recommendation that all patientsswitch from hydrochlorothiazide to chlorthalidone at a maximumdose from 100 to 50 mg/d, which subsequently led to a more favorabletrend in CHD and total mortality (3). Although these resultssuggested a beneficial effect of chlorthalidone as comparedwith hydrochlorothiazide, such conclusions are not robust, especiallyconsidering that they are based on a post hoc subgroup analysis.Furthermore, the data are based on a group identifier (clinic)rather than individual patient treatments, and the beneficialeffect of the change in treatment could be due to reductionin the chlorthalidone dose (4).
The debate has been reinforced further by the data from twolarge, controlled, clinical studies on drug class comparison.Whereas in the Antihypertensive and Lipid-Lowering Treatmentto Prevent Heart Attack Trial (ALLHAT) (5) chlorthalidone ascompared with lisinopril-based treatment showed no inferiorityfor primary outcomes (CHD mortality and nonfatal myocardialinfarction) and a superiority for stroke and heart failure (HF)prevention, the Second Australian National Blood Pressure trial(ANBP2) (6) indicated a marginal superiority of enalapril versushydrochlorothiazide-based treatment on primary end points (allCV [first and recurrent] plus all-cause mortality) with no substantialdifference for stroke and HF. Although these conflicting resultscould be dependent on the specific thiazide diuretic used, thereare other likely explanations, such as samples studied, trialdesign, and type of statistical analysis (4). Finally, a recentmeta-analysis of placebo-controlled trials that used chlorthalidoneor other thiazide-like diuretics indicated that major healthoutcomes did not differ between two treatments, a finding thatsuggests that the beneficial effects of thiazide diuretics couldbe a class effect (7).
The relevance of dosage choice of thiazide diuretics can beevaluated considering both the effect of different diuretictherapy doses on CV mortality and morbidity and the dose-responsecurve in terms of antihypertensive efficacy and metabolic effects.With regard to the first issue, a meta-analysis of clinicalstudies indicated that low-dose (12.5 to 25 mg/d chlorthalidoneor hydrochlorothiazide) and high-dose (50 mg/d or more of bothdrugs) diuretic therapy lowered BP to a similar degree and exerteda similar benefit in reducing stroke, congestive HF, CV, andtotal mortality, but only low-dose diuretic therapy significantlyreduced CHD incidence (8). The concept of a high dose of diuretictherapy should be replaced by that of optimal dose, which derivesfrom studies that evaluated the dose-response curve of thiazidediuretics, as recently reviewed (9).
Data obtained with chlorthalidone so far indicate that the plateauof the dose-response antihypertensive curve is reached witha daily dose of 25 mg and that increasing the dosage does notincrease the BP-lowering effect but further increases the occurrenceof negative metabolic effects, principally hypokalemia (10,11).Data obtained with hydrochlorothiazide, the most widely usedthiazide diuretic in clinical practice, are less certain andsuggest that the plateau of the dose-response BP-lowering curveis reached with the dose of 50 mg/d, whereas negative metaboliceffects, principally hypokalemia, occur in a dose-dependentmanner with a dose up to 100 mg/d (9,12). Therefore it seemsrational to recommend that diuretic treatment with chlorthalidoneshould start with 6.25 mg in the elderly and 12.5 mg in youngerpatients, with a maximum dose of 25 mg/d, whereas the startingdoses of hydrochlorothiazide should be 12.5 mg in the elderlyand 25 mg in younger patients, with a maximum dose of 50 mg/d(9). Moreover the decision to increase the dosage of these drugsto achieve BP control should be weighed against the occurrenceof negative metabolic effects.
Metabolic effects that can have a negative impact on CV riskprofile include alterations in lipids, hypokalemia, impairmentof glucose metabolism, and, therefore, the occurrence of type2 diabetes (13). Although changes in lipid profile, characterizedby an increase in total and LDL cholesterol and decrease inHDL cholesterol, have been reported to be modest and transient(13), data from ALLHAT (5) indicate that the increase in totalcholesterol is detectable up to 4 yr of follow-up.
Hypokalemia, which as already stated is a dose-dependent phenomenon,can worsen the patient’s prognosis because it can increasethe risk for sudden death (14) and CV events among diuretic-treatedhypertensive patients (15) and could abolish the benefit oftreatment in elderly patients with isolated systolic hypertension(16). Furthermore, hypokalemia can impair glucose metabolismby reducing insulin secretion and insulin sensitivity (13).
Data from controlled clinical trials, recently reviewed (17),indicate that the incidence of new-onset diabetes (NOD) is lowerin patients who are treated with drugs that block the renin-angiotensinsystem (RAS), such as ACE inhibitors and angiotensin receptorblockers, as compared with those who are treated with conventionaltherapy, i.e., thiazide diuretics alone and above all combinedwith blockers.
These findings prompted the debate on whether this differencein the incidence of NOD is due to the beneficial effects ofRAS-blocking drugs or, conversely, to the negative action ofconventional therapy on glucose metabolism. This second hypothesisseems to be a rational explanation for the following considerations.Incidence of NOD also is reduced in patients who receive calciumantagonists, drugs that are believed to be neutral on glucosemetabolism, when compared with conventional therapy (17). Alongitudinal observational study showed that given similar fastingblood glucose values, low-dose thiazide diuretic treatment furtherincreased the incidence of NOD (18). In the International VerapamilSR-Trandolapril Study (INVEST) (19), the addition of hydrochlorothiazidedose-dependently increased the risk for NOD not only in patientswho received atenolol but also in those who were treated withverapamil. Similarly, in the Valsartan Antihypertensive Long-termUse Evaluation (VALUE) Trial (20), the greater incidence ofNOD in the amlodipine arm can be explained tentatively by thegreater occurrence of hypokalemia induced by the associationof hydrochlorothiazide. Finally, the Antihypertensive Treatmentand Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE)Study (21) showed that in 1 yr of follow-up of previously untreatedhypertensive patients, treatment with hydrochlorothiazide frequentlyassociated with atenolol impaired glucose metabolism, whereastreatment with candesartan frequently associated with felodipinewas neutral. Considering that NOD has a bad prognostic significancebecause it increases the incidence of CV events in hypertensivediuretic users even when BP is well controlled (22) and givesthe same CV risk as pre-existing diabetes in treated hypertensivepatients (18), caution is advised in using thiazide diuretics,especially when combined with blockers, above all in patientswho are at high risk for developing diabetes, such as thosewith genetic (familial or ethnic) predisposition, obesity, fastingglucose intolerance, and/or the metabolic syndrome. Particularlyin these patients, thiazide diuretics should be used at thelowest active dose with close monitoring of metabolic parametersand possibly in combination with RAS-blocking drugs.
Are Thiazide Diuretics the First-Choice Drug or One of the First-Choice Drugs?
The debate on whether thiazide diuretics are the first-choicedrug, as recommended by the Seventh Joint National Committee(JNC-7) Report (23), or are among first-choice drugs, as recommendedby European Society of Hypertension–European Society ofCardiology (ESH-ESC) Guidelines (24), is principally based ondifferent interpretations of controlled clinical trials andsecondly on drug cost considerations.
The JNC-7 Report (23) recommendation arose from the two-foldrecognition that thiazide-type diuretics have been the basisof antihypertensive therapy in most outcome trials and thatin these trials, including the recently published ALLHAT (5,25),diuretics have been virtually unsurpassed in preventing theCV complications of hypertension. Moreover, diuretics can beuseful in achieving BP control as well as enhancing the antihypertensiveefficacy of multidrug regimens, and they are more affordablethan other antihypertensive agents. These recommendations needto be evaluated according to these lines of reasoning.
The strengths and limitations of ALLHAT already have been commentedon (26) and can be summarized as follows. The main strengthof this study is that with regard to primary outcomes (coronarymortality and nonfatal myocardial infarction), chlorthalidone-basedtreatment was equally as effective as treatment that was basedon amlodipine or lisinopril or doxazosin, and with regard tosome secondary end points such as prevention of stroke, it wassuperior when compared with doxazosin and lisinopril. It wasalso more effective in prevention of morbidity—but notmortality—from congestive HF when compared with the otherthree treatments (5,25). However, the difference with regardto stroke could be due to a difference in systolic BP (26).In contrast, the difference with regard to congestive HF mightbe explained by poor accuracy and/or difficulty in diagnosis;alternatively, withdrawal of previous diuretic therapy may haveunmasked congestive HF symptoms in patients with left ventriculardysfunction (26). Therefore, ALLHAT confirmed and strengthenedthe clinical relevance of thiazide diuretics in the treatmentof hypertension but did not prove the superiority of these drugs.This conclusion is in agreement with an expanded analysis ofthe ALLHAT data presented at the American Society of HypertensionMeeting 2004 (27), which suggests the following interpretations:
The superiority of chlorthalidone versus lisinopril was detectablein black but not in white patients. Therefore, it would be reasonableto state that whereas diuretics remain the preferred first-linedrugs for black patients, ACE inhibitors and diuretics couldbe regarded as coequal recommendations for initiating therapyin white patients.
The primary coronary end point was notdifferent for amlodipinecompared with the other two drugs,and the other major end pointsof stroke and all-cause mortalitytended slightly in its favor.Therefore, for many patients,the excellent antihypertensiveefficacy and tolerability ofcalcium antagonists continue tomake them a popular and appropriatechoice.
The nonsuperiority of a particular drug class, beyond BP reduction,is also supported by the following considerations:
Placebo-controlledclinical studies have shown that the benefitof antihypertensivetherapy in preventing CV events with diureticsalone or combinedwith a blocker (1) is similar to that achievedwith ACE inhibitorsand calcium antagonists (2). Such a findingsuggests that thisbenefit is due to BP lowering per se (1,2).
Meta-analysesof controlled clinical studies, including thoseon drug classcomparison, indicate that reduction in CV morbidityand mortalityrates depends BP reduction and that larger reductionsin BPproduce larger reductions in risk for major CV events(2,28,29).
These conclusions are supported further by data from the VALUETrial (30), which indicate that early (within 6 mo) controlof systolic BP (<140 mmHg) can significantly reduce the incidenceof CV events in high-risk hypertensive patients.
The overall data given above do not point to a greater benefitof a particular drug class, beyond reduction in BP values, whichis actually the more likely explanation of the benefit of antihypertensivetherapy. In this setting, thiazide-like diuretics can be viewedas efficient but not as superior to other antihypertensive drugs.Therefore, their preferential choice should be based principallyon drug cost and, in particular, whether they are really lessexpensive.
Certainly thiazide-like diuretics are less expensive than newertypes of antihypertensive agents and therefore are favored interms of cost minimization (4), but cost is not the sole consideration,and further cost–benefit analyses, announced by the ALLHATauthors although not performed so far (4), are awaited. We believethat their analysis also should take into account the adversemetabolic effects of thiazide diuretics, consisting of an increasein cholesterol levels, blood glucose, NOD, and hypokalemia (4,5).Although these metabolic effects did not translate into a greaterfrequency of CV events in the relatively short-term follow-upof ALLHAT (5), they could have a major impact on cost–benefitanalyses because in the long term, they can reduce the benefitof treatment and increase the cost owing to the need for furtherpharmacologic therapy that is designed to treat the metabolicabnormalities (26).
The last point to be taken into account is that choice of antihypertensivedrugs should be based on additional considerations, as follows.First, efficacy in reducing BP and tolerability, the latteralso including metabolic effects, must be evaluated in individualpatients. Second, as shown in Table 1, the presence of associatedclinical conditions with compelling indications (23), subclinicaltarget organ damage (24), and other associated (but not causallyrelated to hypertension) clinical conditions can indicate thechoice of a particular antihypertensive drug class not necessarilyincluding thiazide diuretics. Finally, a combination of twoor more drugs, not always including diuretics, is needed inthe majority of hypertensive patients to achieve goal BP (24).Above all, these last considerations could indicate that thedebate on the first-choice drug class probably has been overemphasized(24).
The answer to the question of whether thiazide diuretics arethe first-choice drug for treatment of hypertension is two-fold:No, if the diuretic is the only first-choice drug; yes, if thediuretic is one of the first-choice drugs.
Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH: Blood pressure, stroke, and coronary heart disease. Part 2: Short-term reductions in blood pressure: Overview of randomised drug trials in their epidemiological context.
Lancet 335
: 827
–838, 1990[CrossRef][Medline]
Turnbull F: Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials.
Lancet 362
: 1527
–1535, 2003[CrossRef][Medline]
Multiple Risk Factor Intervention Trial Research Group: Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial.
Circulation 82
: 1616
–1628, 1990[Abstract/Free Full Text]
Davis BR, Furberg CD, Wright JT Jr, Cutler JA, Whelton P: ALLHAT Collaborative Research Group: ALLHAT: Setting the record straight.
Ann Intern Med 141
: 39
–46, 2004[Abstract/Free Full Text]
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: 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 288
: 2981
–2997, 2002[Abstract/Free Full Text]
Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, Johnston CI, McNeil JJ, Macdonald GJ, Marley JE, Morgan TO, West MJ: A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly.
N Engl J Med 348
: 583
–592, 2003[Abstract/Free Full Text]
Psaty BM, Lumley T, Furberg CD: Meta-analysis of health outcomes of chlorthalidone-based vs nonchlorthalidone-based low-dose diuretic therapies.
JAMA 292
: 43
–44, 2004[Free Full Text]
Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, Lemaitre RN, Wagner EH, Furberg CD: Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis.
JAMA 277
: 739
–745, 2004
Carter BL, Ernst ME, Cohen JD: Hydrochlorothiazide versus chlorthalidone: Evidence supporting their interchangeability.
Hypertension 43
: 4
–9, 2004[Abstract/Free Full Text]
Materson BJ, Oster JR, Michael UF, Bolton SM, Burton ZC, Stambaugh JE, Morledge J: Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose.
Clin Pharmacol Ther 24
: 192
–198, 1978[Medline]
Salvetti A, Pedrinelli R, Bartolomei G, Cagianelli MA, Cinotti G, Innocenti P, Loni C, Saba G, Saba P, Papi L: Plasma renin activity does not predict the antihypertensive efficacy of chlorthalidone.
Eur J Clin Pharmacol 33
: 221
–226, 1987[CrossRef][Medline]
Materson BJ, Cushman WC, Goldstein G, Reda DJ, Freis ED, Ramirez EA, Talmers FN, White TJ, Nunn S, Chapman RH: Treatment of hypertension in the elderly: I. Blood pressure and clinical changes. Results of a Department of Veterans Affairs Cooperative Study.
Hypertension 15
: 348
–360, 1990[Abstract/Free Full Text]
Tuck ML: Metabolic considerations in hypertension.
Am J Hypertens 3
: 355S
–365S, 1990[Medline]
Grobbee DE, Hoes AW: Non-potassium-sparing diuretics and risk of sudden cardiac death.
J Hypertens 13
: 1539
–1545, 1995[Medline]
Cohen HW, Madhavan S, Alderman MH: High and low serum potassium associated with cardiovascular events in diuretic-treated patients.
J Hypertens 19
: 1315
–1323, 2001[CrossRef][Medline]
Franse LV, Pahor M, Di Bari M, Shorr RI, Wan JY, Somes GW, Applegate WB: Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP).
J Hypertens 18
: 1149
–1154, 2000[CrossRef][Medline]
Pepine CJ, Cooper-Dehoff RM: Cardiovascular therapies and risk for development of diabetes.
J Am Coll Cardiol 44
: 509
–512, 2004[Abstract/Free Full Text]
Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, Norgiolini S, Bracco C, Porcellati C: Adverse prognostic significance of new diabetes in treated hypertensive subjects.
Hypertension 43
: 963
–969, 2004[Abstract/Free Full Text]
Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW: A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial.
JAMA 290
: 2805
–2816, 2003[Abstract/Free Full Text]
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The VALUE randomised trial.
Lancet 363
: 2022
–2031, 2004[CrossRef][Medline]
Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O: Metabolic outcome during 1 year in newly detected hypertensives: Results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study).
J Hypertens 21
: 1563
–1574, 2003[CrossRef][Medline]
Alderman MH, Cohen H, Madhavan S: Diabetes and cardiovascular events in hypertensive patients.
Hypertension 33
: 1130
–1134, 1999[Abstract/Free Full Text]
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.
JAMA 289
: 2560
–2572, 2003[Abstract/Free Full Text]
European Society of Hypertension-European Society of Cardiology Guidelines Committee: 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension.
J Hypertens 21
: 1011
–1153, 2003[CrossRef][Medline]
The ALLHAT: Officers and coordinators for the ALLHAT Collaborative Research Group: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group.
JAMA 283
: 1967
–1975, 2000[Abstract/Free Full Text]
Salvetti A, Ghiadoni L: Guidelines for antihypertensive treatment: An update after the ALLHAT study.
J Am Soc Nephrol 15[Suppl]
: S51
–S54, 2004[Abstract/Free Full Text]
Weber MA: New results and analyses expand and modify key interpretations of the ALLHAT Trial.
Rev Cardiovasc Med 5
: 164
–169, 2004
Staessen JA, Wang JG, Thijs L: Cardiovascular prevention and blood pressure reduction: A quantitative overview updated until 1 March 2003.
J Hypertens 21
: 1055
–1076, 2003[CrossRef][Medline]
Lawes CM, Bennett DA, Feigin VL, Rodgers A: Blood pressure and stroke: An overview of published reviews.
Stroke 35
: 776
–785, 2004[Abstract/Free Full Text]
Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L, Hua T, Laragh JH, McInnes GT, Mitchell L, Plat F, Schork MA, Smith B, Zanchetti A: Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.
Lancet 363
: 2049
–2051, 2004[CrossRef][Medline]
This article has been cited by other articles:
F. Zannad, P. Bousquet, and L. Monassier CHAPTER 11 Clinical Pharmacology of Cardiovascular Drugs
ESC Textbook of Cardiovascular Medicine,
January 1, 2009;
2(1):
med-9780199566990-chapter - med-9780199566990-chapter.
[Abstract][Full Text][PDF]
Top
Abstract
Introduction
blockers, caution is advised in using these drugs above all in patients who are at high risk for developing diabetes, in whom thiazide diuretics should be used at the lowest active dose and possibly in combination with drugs that block the renin-angiotensin system. Finally, the current debate on whether thiazide diuretics are the first-choice drug for most patients with uncomplicated hypertension, as stated in the Seventh Joint National Committee Report, or are included in the major classes of antihypertensive agents that are suitable for initiation and maintenance of therapy, as reported in the European Society of Hypertension–European Society of Cardiology Guidelines, derives from different interpretations of controlled clinical trial data on drug class comparison and of cost-benefit analyses. However, considering that the benefit of antihypertensive drugs seems to be due principally to BP lowering per se without definitive evidence of the superiority of a particular drug class and that there is no cost-benefit analysis showing the superiority of thiazide diuretics, it is believed that these drugs should not be considered as the only first-choice drug but included among first-choice drugs. 
