Cochrane for Clinicians
Putting Evidence into Practice
First-Line Treatment for Hypertension
Am Fam Physician. 2010 Jun 1;81(11):1333-1335.
A 53-year-old, otherwise healthy woman presents with persistent hypertension despite lifestyle changes. She saw an advertisement on television about a new hypertension medication and asks about it for treatment.
What class of medications is the best first-line treatment for hypertension?
In comparing the effects of thiazide diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers (CCBs) with placebo, thiazide diuretics lowered mortality and morbidity from stroke, heart attack, and heart failure more than beta blockers.1 ACE inhibitors and CCBs reduced mortality and morbidity as much as thiazide diuretics, but the evidence is less robust. Because the use of thiazide diuretics is supported by a strong body of evidence and no other class of antihypertensive medications has been shown to be better at improving outcomes, they are the first-line drugs for most patients with hypertension. Current evidence does not support using beta blockers as first-line therapy for hypertension. (Strength of Recommendation = A, based on consistent, good-quality patient-oriented evidence)
Background: Sustained elevated blood pressure, unresponsive to lifestyle measures, leads to a critically important clinical question: What class of drug is the best first-line option? This review answers that question.
Objectives: To quantify the benefits and harms of the major first-line antihypertensive drug classes: thiazides, beta blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, alpha blockers, and angiotensin receptor blockers.
Search Strategy: Electronic search of Medline (January 1966 through June 2008), EMBASE, CINAHL, and the Cochrane clinical trial register, using standard search strategy of the hypertension review group with additional terms.
Selection Criteria: Randomized trials of at least one year duration comparing one of six major drug classes with placebo or no treatment. More than 70 percent of participants must have blood pressure greater than 140/90 mm Hg at baseline.
Data Collection and Analysis: The outcomes assessed were mortality, stroke, coronary heart disease (CHD), cardiovascular events, decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. Risk ratio (RR) and a fixed effects model were used to combine outcomes across trials.
Main Results: Of 57 trials identified, 24 trials with 28 arms (n = 58,040) met the inclusion criteria. Thiazides (19 randomized controlled trials [RCTs]) reduced mortality (RR = 0.89; 95% confidence interval [CI], 0.83 to 0.96), stroke (RR = 0.63; 95% CI, 0.57 to 0.71), CHD (RR = 0.84; 95% CI, 0.75 to 0.95), and cardiovascular events (RR = 0.70; 95% CI, 0.66 to 0.76). Low-dose thiazides (eight RCTs) reduced CHD (RR = 0.72; 95% CI, 0.61 to 0.84), but high-dose thiazides (11 RCTs) did not (RR = 1.01; 95% CI, 0.85 to 1.20).
Beta blockers (five RCTs) reduced stroke (RR = 0.83; 95% CI, 0.72 to 0.97) and cardiovascular events (RR = 0.89; 95% CI, 0.81 to 0.98), but not CHD (RR = 0.90; 95% CI, 0.78 to 1.03) or mortality (RR = 0.96; 95% CI, 0.86 to 1.07).
ACE inhibitors (three RCTs) reduced mortality (RR = 0.83; 95% CI, 0.72 to 0.95), stroke (RR = 0.65; 95% CI, 0.52 to 0.82), CHD (RR = 0.81; 95% CI, 0.70 to 0.94), and cardiovascular events (RR = 0.76; 95% CI, 0.67 to 0.85).
Calcium channel blockers (one RCT) reduced stroke (RR = 0.58; 95% CI, 0.41 to 0.84) and cardiovascular events (RR = 0.71; 95% CI, 0.57 to 0.87), but not CHD (RR = 0.77; 95% CI, 0.55 to 1.09) or mortality (RR = 0.86; 95% CI, 0.68 to 1.09).
No RCTs were found for angiotensin receptor blockers or alpha blockers.
Authors’ Conclusions: First-line low-dose thiazides reduce all morbidity and mortality outcomes. ACE inhibitors and calcium channel blockers may be similarly effective, but the evidence is less robust. First-line high-dose thiazides and beta blockers are inferior to first-line low-dose thiazides.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
The choice of hypertension medication should be informed by evidence about its effectiveness in reducing adverse health outcomes, including stroke, myocardial infarction, and mortality. In this Cochrane review, the authors quantified the effectiveness of four classes of antihypertensive medications (i.e., thiazide diuretics, beta blockers, ACE inhibitors, and CCBs) versus placebo in reducing mortality, stroke, coronary heart disease (CHD), and cardiovascular events.1 If taken for five years, thiazide diuretics were highly effective in the secondary prevention of cardiovascular events (absolute risk reduction [ARR] = 5.5 percent; number needed to treat [NNT] = 18). In patients with moderate to severe hypertension (i.e., systolic blood pressure greater than 160 mm Hg), thiazide diuretics were effective in the primary prevention of cardiovascular events (ARR = 5.1 percent; NNT = 20). However, only low-dose thiazide diuretics were effective; high-dose thiazide diuretics were no different than placebo in risk of mortality and cardiovascular events.1
Although there were fewer trials of ACE inhibitors and CCBs as first-line agents, the current evidence suggests that they were also effective in the prevention of cardiovascular events in patients with moderate to severe hypertension, or as secondary prevention (NNT for five years = 18 to 22).1 The effectiveness of antihypertensive medication for primary prevention in patients with mild to moderate hypertension (i.e., systolic blood pressure of 140 to 160 mm Hg) is more modest than in patients with severe hypertension or preexisting CHD. In this situation, 122 patients would need to be treated with thiazide diuretics or 135 patients with beta blockers for five years to prevent one cardiovascular event. Beta blockers did not show any ARR of cardiovascular events for secondary or primary prevention in patients with moderate to severe hypertension.1
Thiazide diuretics and ACE inhibitors significantly reduced the risk of CHD, whereas beta blockers (risk ratio [RR] = 0.90; 95% confidence interval [CI], 0.86 to 1.07) and CCBs (RR = 0.77; 95% CI, 0.55 to 1.09) did not. Beta blockers and CCBs were also no different from placebo in reducing mortality risk. Thiazide diuretics and ACE inhibitors reduced total mortality risk significantly, but this risk reduction was smaller than that of cardiovascular events and stroke.1
Beta blockers did not provide more benefit than other antihypertensives and were generally not tolerated as well. Another Cochrane review, which compared first-line beta blockers with other classes of antihypertensive medications using additional head-to-head randomized controlled trials (RCTs), found that although the stroke risk reduction was statistically significant with beta blockers, the magnitude of the effect was small (ARR over five years = 0.5 percent).2 Patients who took beta blockers were more likely to discontinue treatment because of adverse effects than patients taking thiazide diuretics, ACE inhibitors, or angiotensin receptor blockers. Beta blockers were as well tolerated as CCBs.2
The Cochrane review of first-line antihypertensive medications has a number of limitations, one of which is that it did not address any renal outcomes.1 In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), neither amlodipine (Norvasc) nor lisinopril (Zestril) were found to be superior to chlorthalidone in reducing the rate of developing end-stage renal disease.3 Subsequent analyses of the ALLHAT and other clinical trials have confirmed that alpha blockers, ACE inhibitors, and CCBs were no better than thiazide diuretics as initial therapy for the reduction of cardiovascular or renal risk.4
This Cochrane review did not include any trials in which two first-line antihypertensives were compared with each other without a placebo or untreated control.1 This excludes large RCTs, such as ALLHAT and the Nordic Diltiazem Study.5,6 However, neither of these trials concluded that any class of antihypertensive surpassed thiazide diuretics in reducing morbidity or mortality.5,6 Four out of the five trials of beta blockers included in the Cochrane review used atenolol (Tenormin); therefore, it is not possible to determine whether the relatively poor performance of beta blockers should be attributed to the entire class or to atenolol alone.1 However, there is no evidence supporting the use of beta blockers over other antihypertensives.1,2
The strongest body of evidence indicates that for most patients with hypertension, thiazide diuretics are the best proven first-line treatment in reducing morbidity and mortality. They are particularly effective in the secondary prevention of cardiovascular events in all patients with hypertension, and in the primary prevention of cardiovascular events in patients with moderate to severe hypertension. Current evidence does not support the use of beta blockers, particularly atenolol, as first-line treatment for hypertension. Although there is increasing evidence that ACE inhibitors and possibly CCBs may be equivalent to thiazide diuretics in reducing morbidity and mortality, the relative expense of these medications makes thiazide diuretics a more favorable first-line choice in patients who do not have contraindications for their use.
1. Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database Syst Rev. 2009;(3):CD001841.
2. Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2007;(1):CD002003.
3. Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165(8):936–946.
4. Wright JT Jr, Probstfield JL, Cushman WC, et al.; ALLHAT Collaborative Research Group. ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Arch Intern Med. 2009;169(9):832–842.
5. 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) [published corrections appear in JAMA. 2004;291(18):2196, and JAMA. 2003;289(2):178]. JAMA. 2002;288(23):2981-2997.
6. Hansson L, Hedner T, Lund-Johansen P, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet. 2000;356(9227):359–365.
The Cochrane Abstract in this article is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Bui presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab001841.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
A collection of Cochrane for Clinicians published in AFP is available at http://www.aafp.org/afp/cochrane.
Copyright © 2010 by the American Academy of Family Physicians.
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