Therapeutics

Review: First-line low-dose thiazides and ACE inhibitors reduce mortality and morbidity in adults with hypertension
Clinical impact ratings: F C Question
What are the relative benefits of major first-line antihypertensive drug classes?

Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database Syst Rev. 2009;(3):CD001841.

Source of funding: Canadian Institutes of Health Research. For correspondence: Dr J.M. Wright, University of British Columbia, Vancouver, BC, Canada. E-mail jim.wright@ti.ubc.ca.

Review scope
Included studies compared major antihypertensive drug classes with placebo or no treatment and included > 70% of patients with baseline resting blood pressure 140 mm Hg systolic or 90 mm Hg diastolic who had taken the drug class for > 1 year. Outcomes included mortality, stroke, and coronary heart disease.

Commentary
Despite abundant evidence of benefit, low-dose thiazides remain underutilized as first-line agents for control of hypertension. In 2000, thiazides accounted for 25% of antihypertensive prescriptions in the UK, 16% in the USA, and 6% in Norway; these rates all lagged behind those of prescriptions for ACE inhibitors and calcium-channel blockers (1). In part, prescribing trends and practice reflect the findings of highly publicized trials and guidelines. With the publication of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (2), which provided unequivocal evidence of the benefits of thiazides, rates of thiazide prescriptions for hypertension increased in the US Veterans Administration from 32% in 2000 to 42% in 2006 (3). In addition, thiazides are the lowest-priced class of antihypertensive medications. If they were universally used as the first-choice drug for management of uncomplicated hypertension, potential savings in the USA alone could be > US$1 billion per year (4). The systematic review by Wright and colleagues nicely summarizes the evidence of first-line therapy with the most widely used classes of antihypertensive medications. Despite widespread use in routine clinical practice, -blockers and calcium-channel blockers simply do not have the data supporting their use as first-line agents to improve mortality or coronary heart disease outcomes. These data will inform the next revisions of clinical practice guidelines, and for most patients with hypertension, treatment initiation should begin with thiazides or ACE inhibitors. Nirav R. Shah, MD, MPH Gbenga Ogedegbe, MD, MPH, MS New York University School of Medicine New York, New York, USA
References 1. Fretheim A, Oxman AD. International variation in prescribing antihypertensive drugs: its extent and possible explanations. BMC Health Serv Res. 2005;5:21. 2. 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;288:2981-97. 3. Furmaga EM, Cunningham FE, Cushman WC, et al. National utilization of antihypertensive medications from 2000 to 2006 in the Veterans Health Administration: focus on thiazide diuretics. J Clin Hypertens (Greenwich). 2008;10:770-8. 4. Fretheim A, Aaserud M, Oxman AD. The potential savings of using thiazides as the first choice antihypertensive drug: cost-minimisation analysis. BMC Health Serv Res. 2003;3:18.

Review methods
MEDLINE, EMBASE/Excerpta Medica, CINAHL, Cochrane Clinical Trial Register, and WHO-ISH Collaboration Register (all to June 2008), and reference lists were searched for randomized controlled trials. 24 trials (n = 58 040, mean age 62 y) met the selection criteria. Thiazides were evaluated in 19 trials (n = 39 713), -blockers in 5 (n = 19 313), angiotensin-converting enzyme (ACE) inhibitors in 3 (n = 6002), and calcium-channel blockers in 1 (n = 4695). Low-dose thiazide was defined as the equivalent of { 50 mg/d}* of hydrochlorothiazide. No eligible studies evaluated -adrenergic blockers or angiotensin-receptor blockers.

Main results
The main results are in the Table.

Conclusion
In adults with hypertension, low-dose thiazides have the most evidence for cardiovascular benefit followed by angiotensinconverting enzyme inhibitors.
* Information provided by author. First-line antihypertensive drug classes vs control in hypertension
Drug class
Thiazide (low-dose) Thiazide (high-dose) -blockers

Outcomes Number of Weighted RRR (95% CI) trials (n) event rates
Mortality Stroke CHD Mortality Stroke Mortality Stroke CHD 8 (19 874) 8 (19 874) 7 (19 022) 11 (19 839) 11 (19 839) 5 (19 313) 5 (19 313) 5 (19 313) 3 (6002) 3 (6002) 2 (5145) 1 (4695) 1 (4695) 1 (4695) 11 (19 839) 9.8% vs 11% 4.2% vs 6.2% 2.8% vs 3.9% 2.8% vs 3.1% 0.9% vs 1.9% 5.9% vs 6.2% 2.8% vs 3.4% 4.0% vs 4.4% 11% vs 14% 3.9% vs 6.0% 11% vs 14% 5.1% vs 6.0% 2.0% vs 3.4% 2.4% vs 3.1% 2.7% vs 2.7% 11% (3 to 18) 32% (23 to 40) 28% (16 to 39)

NNT (CI)
83 (51 to 304) 51 (41 to 71) 92 (66 to 161)

10% (5 to 24) Not significant 53% (39 to 63) 100 (84 to 135) 4% (7 to 14) Not significant 17% (3 to 28) 17% (5 to 28) 35% (18 to 48) 19% (6 to 30) 42% (16 to 59) 174 (106 to 981) 44 (27 to 148) 48 (35 to 93) 39 (25 to 124) 71 (50 to 184) 10% (3 to 22) Not significant

ACE inhibitors

Mortality Stroke CHD

CCBs

Mortality Stroke CHD

14% (9 to 32) Not significant 23% (9 to 45) Not significant

RRI (CI)
Thiazide (high-dose) CHD

NNH (CI)

1% (15 to 20) Not significant

ACE = angiotensin-converting enzyme; CCB = calcium-channel blocker; CHD = coronary heart disease; other abbreviations defined in Glossary. RRR, RRI, NNT, NNH, and CI calculated from data in article using a fixed-effect model.

JC1-4

2010 American College of Physicians

19 January 2010 | ACP Journal Club | Volume 152 Number 1