Low-dose thiazide diuretics (eg, hydrochlorothiazide 12.5 to 25 mg/d) are the best first-line pharmacotherapy for treating uncomplicated hypertension(strength of recommendation [SOR]: A, based on randomized trials [RCTs] and 1 meta-analysis). Alternate first-line agents include angiotensinconverting enzyme (ACE) inhibitors, beta blockers, and calcium channel blockers (SOR: A, based on RCTs)

Russell, Roger G.

Saseen, Joseph J.

Turner, Chad

University of Missouri: MOspace

C L I N I C A L  I N Q U I R I E SMARCH 2005 / VOL 54, NO 3 · The Journal of Family Practice 281C O N T I N U E D9. Mandell LA, Marrie TJ, Grossman RF, Chow AW, HylandRH. Canadian Guidelines for the Initial Management ofCommunity-acquired pneumonia: An Evidence-BasedUpdate by the Canadian Infectious Diseases Society andthe Canadian Thoracic Society. Clin Infect Dis 2000;31:383–421.10. Niederman MS, Mandell LA, Anqueto A, et al. Guidelinesfor the management of adults with community-acquiredpneumonia. Diagnosis, assessment of severity, antimicro-bial therapy and prevention. Am J Respir Crit Care Med2001; 163:1730–1754. What is the best regimen for newly diagnosedhypertension?■ EVIDENCE-BASED ANSWERLow-dose thiazide diuretics (eg, hydrochloroth-iazide 12.5 to 25 mg/d) are the best first-line phar-macotherapy for treating uncomplicated hyperten-sion (strength of recommendation [SOR]: A, basedon randomized trials [RCTs] and 1 meta-analysis).Alternate first-line agents include angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and calcium channel blockers (SOR: A,based on RCTs).■ EVIDENCE SUMMARYThree landmark placebo-controlled studies haveestablished that thiazide diuretic–based treat-ment reduces morbidity and mortality amongpatients with hypertension.1–3 Based on thesedata, thiazide diuretic therapy is considered the gold-standard treatment for uncomplicated hypertension.Several other clinical trials have subsequentlycompared the effect of thiazide diuretics withthat of other antihypertensive agents (beta-block-ers, calcium channel blockers, and alpha-block-ers) on patient-oriented outcomes. These wereanalyzed in a recent meta-analysis of 42 clinicaltrials that included 192,478 patients randomizedto 7 treatment strategies including placebo.4Results from the largest antihypertensive clinicaltrial, the Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial (ALL-HAT), were included in this meta-analysis.5Comparative results are depicted in the Table.Although these data showed no differencesbetween drug therapies in total and cardiovascu-lar disease mortality, low-dose diuretics reducedcertain cardio-vascular endpoints (ie, heart fail-ure, stroke, cardiovascular disease events) morethan other drug therapies. Angiotensin receptor blockers (ARBs) havenot been compared with thiazide diuretics in atrial. Two long-term trials have compared an ARBto other types of drug therapy: losartan vsatenolol in the Losartan Intervention forEndpoint Reduction (LIFE) trial,6 and valsartanvs amlodipine in the Valsartan AntihypertensiveLong-term Use Evaluation (VALUE) trial.7 In theLIFE trial, the primary composite endpoint of car-diovascular death, myocardial infarction, andstroke was less with losartan than atenolol (23.8vs 27.9 events per 1000 patient-years, losartanand atenolol, respectively; number needed totreat=243 people-years, P=.021).6 However, inthe VALUE trial, the primary endpoint of time tocardiac event was not different between valsar-tan and amlodipine (25.5 vs 24.7 events per 1000patient-years, valsartan and amlodipine, respec-tively; P=.49).7■ RECOMMENDATIONS FROM OTHERSThe Seventh Report of the Joint NationalCommittee (JNC7) recommended thiazide diuret-ics as preferred initial agents in uncomplicatedhypertension.8 The European Society of Hyper-tension/European Society Cardiology recom-mended either a diuretic, beta-blocker, calciumchannel blocker, ACE inhibitor, or ARB for initialtherapy stating that blood pressure control to rec-ommended values via any agent is more impor-tant than the type of agent used.9 Both guidelinesidentified other antihypertensives that may beused in addition to or in place of thiazide diuret-ics for compelling indications, such as heart fail-ure, diabetes, high-risk cardiovascular disease,chronic kidney disease, post-myocardial infarc-tion, and secondary stroke prevention.C L I N I C A L  I N Q U I R I E S282 MARCH 2005 / VOL 54, NO 3 · The Journal of Family PracticeFirst-line treatments for hypertensionRelative risk (95% CI) of outcomeLow-dose CVD Totaldiuretic vs CHD CHF Stroke CVD events mortality mortalityBeta-blocker 0.87 0.83 0.90 0.89* 0.93 0.99(0.74–1.03) (0.68–1.01) (0.76–1.06) (0.80–0.98) (0.81–1.07) (0.91–1.07)ACE inhibitor 1.00 0.88* 0.86* 0.94 0.93 1.00 (0.88–1.14) (0.80–0.96) (0.77–0.97) (0.89–1.00) (0.85–1.02) (0.95–1.05)Calcium 0.89 0.74* 1.02 0.94 0.95 1.03 channel blocker (0.76–1.01) (0.67–0.81) (0.91–1.14) (0.89–1.00) (0.87–1.04) (0.98–1.08)Alpha-blocker 0.99 0.51* 0.85 0.84* 1.00 0.98 (0.75–1.31) (0.43–0.60) (0.66–1.10) (0.75–0.93) (0.75–1.34) (0.88–1.10)*Denotes statistically significant difference favoring low-dose diuretics (P<.05).CI, confidence interval; CHD, congestive heart disease; CVD, cardiovascular disease; ACE, angiotensin-converting enzyme.Source: Psaty BM, Lumley T, Furberg CD, et al, JAMA 2003.4TA B L E■ CLINICAL COMMENTARYThiazide diuretics: first or second agentfor patients with hypertensionSkeptics argue that other antihypertensives areequal to thiazides. However, thiazides are theleast expensive agents (1-year hydrochloroth-iazide 25 mg/d is <$25.00). This aspect of thera-py supports thiazides as first-line pharmacother-apy. The debate of which agent to use first maybe moot considering most hypertensive patientsrequire 2 or more drugs to achieve a systolicblood pressure goal of <140 mm Hg. In addition,the JNC7 recommended starting with 2 agents forpatients far from their blood pressure goal (eg,systolic blood pressure ≥160 mm Hg). Therefore,even if a thiazide is not the initial agent (becauseof preference or other compelling indications) itshould be the second agent for most patients. Joseph J. Saseen, PharmD, FCCP, Chad Turner,MD, University of Colorado Health Sciences Center, Denver;Roger G. Russell, MLS, AHIP, Laupus HealthSciences Library, East Carolina University, Greenville, NC REFERENCES1. Prevention of stroke by antihypertensive drug treatmentin older persons with isolated systolic hypertension. Finalresults of the Systolic Hypertension in the ElderlyProgram (SHEP). SHEP Cooperative Research Group.JAMA 1991; 265:3255–3264.2. Medical Research Council trial of treatment of hyperten-sion in older adults: principal results. MRC Working Party.BMJ 1992; 304:405–412.3. Dahlof B, Lindholm LH, Hansson L, Schersten B, EkbomT, Wester PO. Morbidity and mortality in the Swedish Trialin Old Patients with Hypertension (STOP-Hypertension).Lancet 1991; 338:1281–1285.4. Psaty BM, Lumley T, Furberg CD, et al. Health outcomesassociated with various antihypertensive therapies usedas first-line agents: a network meta-analysis. JAMA 2003;289:2534–2544.5. ALLHAT Officers and Coordinators for the ALLHATCollaborative Research Group. The Antihypertensive andLipid-Lowering Treatment to Prevent Heart Attack Trial.Major outcomes in high-risk hypertensive patients ran-domized to angiotensin-converting enzyme inhibitor or cal-cium channel blocker vs diuretic: The Antihypertensiveand Lipid-Lowering Treatment to Prevent Heart AttackTrial (ALLHAT). JAMA 2002; 288:2981–2997. 6. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascularmorbidity and mortality in the Losartan Intervention ForEndpoint reduction in hypertension study (LIFE): a ran-domised trial against atenolol. Lancet 2002; 359:995–1003.7. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hyper-tensive patients at high cardiovascular risk treated withregimens based on valsartan or amlodipine: the VALUErandomised trial. Lancet 2004; 363:2022–2031.8. Chobanian AV, Bakris GL, Black HR, et al. Seventh reportof the Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure.Hypertension 2003; 42:1206–1252.9. European Society of Hypertension—European Society ofCardiology Guidelines Committee. 2003 European Societyof Hypertension-European Society of Cardiology guide-lines for the management of arterial hypertension. J Hypertens 2003; 21:1011–1053. 

What is the best regimen for newly diagnosed hypertension?

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