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Circulation. 2008;117:2691-2705
doi: 10.1161/CIRCULATIONAHA.107.709931
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(Circulation. 2008;117:2691-2705.)
© 2008 American Heart Association, Inc.

Controversies in Cardiovascular Medicine

Should β-blockers and diuretics remain as first line therapy for hypertension?

Thiazide-Type Diuretics and β-Adrenergic Blockers as First-Line Drug Treatments for Hypertension

Jeffrey A. Cutler, MD, MPH; Barry R. Davis, MD, PhD

From the National Heart, Lung, and Blood Institute, Bethesda, Md (J.A.C.), and the University of Texas Health Science Center at Houston School of Public Health, Houston, Tex (B.R.D.).

Correspondence to Barry R. Davis, MD, PhD, University of Texas Health Science Center at Houston, School of Public Health, 1200 Herman Pressler St, Suite E801, Houston, TX 77030. E-mail Barry.R.Davis{at}uth.tmc.edu


*    Introduction
up arrowTop
 *Introduction
down arrowTrials of Blood Pressure...
 down arrowThe Continuing Case for...
 down arrowThe Evidence for and...
 down arrowConclusions
 down arrowReferences
 
Systemic arterial hypertension affects 72 million US adults and an additional hundreds of millions of persons worldwide.1,2 Most of these are candidates for pharmacological treatment to reduce risk of cardiovascular disease (CVD) events, based primarily on a very large body of epidemiological and intervention research in humans. Because of this high prevalence and the cardiovascular consequences of untreated or inadequately treated hypertension, the selection of drugs for initial and continuing, long-term treatment has large public health and economic implications. Fortunately, such decisions and the expert recommendations that seek to guide them can call on evidence from 4 decades of randomized multicenter clinical trials evaluating effects of treatment on clinical CVD. We summarize that evidence in this article, in approximate chronological order, and we comment on the related treatment guidelines. We close with some of the major clinical questions yet to be resolved.

Response by Messerli et al p 2705


*    Trials of Blood Pressure Reduction
up arrowTop
 up arrowIntroduction
 *Trials of Blood Pressure...
down arrowThe Continuing Case for...
 down arrowThe Evidence for and...
 down arrowConclusions
 down arrowReferences
 
Before the current era beginning in the early 1990s of emphasis on positive-control trials, which directly compare different drug regimens, there were 3 decades of trials that compared an active regimen with placebo or, in a few cases, "usual care." For most of this period, the mainstay of treatment was generally a thiazide-type diuretic (hereinafter called thiazides) or, to a lesser extent, a β-adrenergic blocker (termed β-blockers). With few exceptions, these trials, especially those with high statistical power and thiazide-based regimens, showed benefit for CVD outcomes.3–8 This evidence, which provided a basis for recommending thiazides or β-blockers as first-step drugs in most editions of US guidelines through 1997,9 needs to continue to be given due weight in practice and practice guidelines.

The largest and most consistent benefits from the earlier trials were for stroke and (where reported) heart failure. Benefits for coronary heart disease (CHD) were less clear, and commentators frequently speculated that potentially adverse metabolic effects—on potassium (for diuretics), lipids, and glucose—of thiazides and β-blockers were related to this shortfall in reducing CHD outcomes. Two reports in the early 1990s reduced concern about the CHD shortfall considerably. A meta-analysis of essentially all randomized antihypertensive treatment trials with clinical events outcomes, placed in an epidemiological context to address the question of what effects would be expected on the basis of risks of various events at different blood pressure (BP) levels, showed that treatment significantly reduced nonfatal myocardial infarction (MI) or CHD death (major CHD) by 14%, which represented approximately two thirds of the epidemiological expectation.10,11 The authors attributed the shortfall to the short duration of treatment in the trials, averaging {approx}2 to 3 years to CHD events, which was a plausible conclusion. Shortly thereafter, the Systolic Hypertension in the Elderly Program (SHEP) reported that a thiazide-based regimen (using low-dose chlorthalidone) not only reduced fatal and nonfatal stroke by 36% but also lowered major CHD by 27%.8

The results of these trials have also provided a basis for guidelines on drug choice through indirect comparisons among trials and groups of trials. Subsequent to SHEP, the similarly designed Systolic Hypertension in Europe (Syst-Eur) trial reported that treatment with a dihydropyridine calcium channel blocker (CCB) as the main drug reduced BP, stroke, and all cardiac events to an extent similar to that in SHEP.12 However, neither the effects on CHD or heart failure were separately statistically significant. For angiotensin-converting enzyme (ACE) inhibitors, there was no large trial focused on hypertension, but several trials reported that these drugs reduced mortality and morbidity in patients with heart failure and/or CHD13–16; the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial showed that enalapril lowered the risk of MI and overt heart failure in patients with reduced ejection fraction.17 The size of the heart failure effect was, however, only 20%, in contrast with the 49% benefit in SHEP.18

These newer trials provided important added justification for earlier recommendations concerning use of CCBs and ACE inhibitors as first-line drugs in treating hypertension in the 1988 Report of the Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.19 However, both JNCV and JNCVI recommended thiazides and β-blockers as preferred initial drugs for antihypertensive treatment.9,20 As in the case of ACE inhibitors, the trials of secondary prevention of heart disease continued to play a large role in the thinking about benefits of β-blockers in hypertension.

Despite all of these factors, that is, the weight of the evidence, the consensus incorporated in JNC recommendations, and the low acquisition costs of several generic agents, the use of thiazides and β-blockers to treat hypertension declined dramatically after 1981–1983 through the early 1990s (Figure 1).21 These trends can be attributed to the following: (1) concerns raised regarding metabolic effects; (2) results of trials that used doses of thiazides much higher than in general use today22; and (3) effective marketing of newer patented drugs, in part based on their effects on intermediate markers of various disease processes. Thiazide dosing issues were eventually addressed on the basis of the dose-response curves for BP effects versus potassium depletion, the SHEP trial results, and, most persuasively, by a meta-analysis that separated use of "low-dose" (actually, low-to-moderate dose) from high-dose thiazides among cardiovascular events trials.23 Nevertheless, it was increasingly recognized that large, direct comparison trials would be needed to provide a solid scientific basis for drug selection. One of the first such trials, and the largest in terms of total study population as well as patients per treatment arm, was the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).


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  		Figure 1. Percentage of drug mentions by class of antihypertensive agent, 1982–1993.21 Data from IMS America.59 Reprinted from Manolio et al,21 with permission. Copyright 1995, American Medical Association.


*    The Continuing Case for Thiazide- Type Diuretics
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 up arrowIntroduction
 up arrowTrials of Blood Pressure...
 *The Continuing Case for...
down arrowThe Evidence for and...
 down arrowConclusions
 down arrowReferences
 
Direct Comparison Trials
ALLHAT: Design and Prespecified Outcomes
ALLHAT was designed to address the issue of which class of drugs should be used for initial therapy for hypertension. It was planned as a practice-based trial to mirror community treatment of hypertension, obtain sufficient patients, and capture the diversity of hypertensive patients (by age, sex, ethnicity, and diabetic status). More specifically, the study was a randomized, double-blind, multicenter clinical trial, designed to determine whether the incidence of CHD is reduced in high-risk patients with hypertension by a CCB (represented by amlodipine), an ACE inhibitor (represented by lisinopril), or an {alpha}-blocker (represented by doxazosin), each compared with diuretic treatment (represented by chlorthalidone).24 The overall findings of the trial showed that CHD risk was not improved for any of the 3 newer agents compared with chlorthalidone25,26 and that total mortality was also similar for the 4 groups (Tables 1 and 2Down).


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  		Table 1. Clinical Outcomes by Antihypertensive Treatment Group25


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  		Table 2. Outcomes in the BP Component of ALLHAT by Treatment Group as of February 15, 200026

However, diuretic-based therapy was superior to {alpha}-blocker–based, ACE inhibitor–based, and CCB-based therapy in preventing 1 or more major forms of CVD, including heart failure and (in some comparisons) stroke.25,26 Results were consistent for all outcomes by age, sex, diabetic status, and ethnicity, except for stroke and combined CVD. For these end points, significant heterogeneity was seen in the lisinopril-chlorthalidone comparison by ethnicity: Black persons assigned to chlorthalidone had a greater reduction in risk for stroke and CVD, in agreement with larger BP differences.

On the basis of these findings, the ALLHAT investigators recommended that diuretics should be the drug of choice for initial hypertension therapy and, because most hypertensive patients require >1 drug, diuretics should generally be part of any antihypertensive regimen. With regard to applicability of these conclusions, although ALLHAT was conducted in high-risk patients to ensure that enough outcome events would occur during the study to detect important treatment differences, its findings (just as those from most trials) can and should be reasonably extrapolated beyond the exact sample in which it was conducted.

BP Differences in ALLHAT
One of the main criticisms of ALLHAT was that its outcome findings (especially the subgroup findings for stroke) could be explained by observed BP differences among treatment groups. The chlorthalidone-based regimen happened to be the most effective in reducing clinical outcomes and, to a small degree, in BP lowering (Figure 2).25


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  		Figure 2. Mean systolic and diastolic BP by year during follow-up.25 Reprinted from Reference 25, with permission. Copyright 2002, American Medical Association.

Meta-regressions of effects of BP differences on trial results27 suggest that they offer a partial explanation, except for heart failure. In ALLHAT, the small differences in achieved mean systolic BP and diastolic BP (<1 mm Hg) between the amlodipine and chlorthalidone groups overall and the lisinopril and chlorthalidone groups in nonblack persons should have had a negligible effect on cardiovascular event rates. In these respective comparisons, the observed rates of heart failure were higher with amlodipine (relative risk [RR]=1.38; 95% CI, 1.25 to 1.52) and lisinopril (RR=1.15; 95% CI, 1.01 to 1.30) than with chlorthalidone.25

Extrapolating Findings to Drugs Within a Class
Could the ALLHAT results be extrapolated to other drugs of the same class? For {alpha}-blockers, ACE inhibitors, and dihydropyridine CCBs, such extrapolation seems reasonable.28 Data from studies using various thiazide-type diuretics (chlorthalidone, hydrochlorothiazide, indapamide, and bendrofluazide) suggest similar benefits among equivalent doses of all thiazide-type diuretics tested in CVD prevention trials against placebo, usual care, or another drug class.5,6,8,29–34 However, a few studies suggest that the longer duration of action of chlorthalidone may provide some advantage in CVD prevention over hydrochorothiazide.22,35

Results From Other Trials
After the ALLHAT results appeared, several other active comparator trials were reported. The Second Australian National Blood Pressure Study (ANBP2), a practice-based open-label trial, was the only other large trial besides ALLHAT to compare diuretic-based (hydrochlorothiazide recommended) with ACE inhibitor–based (enalapril recommended) antihypertensive treatment.34 A total of 6083 participants, aged 65 to 84 years, were treated and followed up for a mean of 4.1 years. The primary end point was a composite of all cardiovascular events (including recurrent events, an unusual design) plus all-cause mortality. Cardiovascular events included major coronary events, stroke and transient ischemic attacks, heart failure (not otherwise defined), acute occlusion of any other major artery, and dissecting or ruptured aortic aneurysm. The results for the primary end point favored the ACE inhibitor group with marginal significance (RR, 0.89; 95% CI, 0.79 to 1.00; P=0.05). The corresponding results with the use of first cardiovascular event had essentially the same RR (P=0.07). The RR for heart failure was 0.85 (95% CI, 0.62 to 1.18; P=0.33). Frohlich36 weighed the supposedly conflicting results of ANBP2 and ALLHAT, suggesting possible explanations such as the patients studied (many more black patients in ALLHAT) and the specific drugs used. Additionally, there were almost 8 times as many cardiovascular events in the 2 comparable arms in ALLHAT as in ANBP2, and only ALLHAT was double blind. ANBP2 used a prospective, randomized, open-label, blinded end point (PROBE) design, increasing the potential for bias in the reporting of events (the rates of some outcomes might have been "expected" to be lower with the ACE inhibitor) even though ANBP2 relied on end point committee–adjudicated outcomes. Doses of agents in ANBP2 were left up to the local investigator and were not reported; thus, it is not possible to assess whether appropriate doses of hydrochlorothiazide were used. Even given the possible biases, however, the results of ANBP2 are consistent with those of ALLHAT if the upper confidence limit for the RR in ANBP2 is compared with the estimates of RR in ALLHAT.37

The International Nifedipine GITS study [Intervention as a Goal in Hypertension Treatment (INSIGHT)] was the other large trial besides ALLHAT to compare diuretic-based (co-amilozide) with CCB-based (nifedipine) antihypertensive treatment on cardiovascular mortality and morbidity in high-risk patients with hypertension.33 It was a randomized, double-blind trial in 6321 patients aged 55 to 80 years with hypertension. Patients had at least 1 additional cardiovascular risk factor and were randomly assigned to nifedipine (30 to 60 mg in a long-acting gastrointestinal-transport system [GITS] formulation) or co-amilozide (hydrochlorothiazide 25 to 50 mg plus amiloride). The primary outcome was cardiovascular death, MI, heart failure, or stroke. Primary outcomes occurred in 200 patients (6.3%) in the nifedipine group and in 182 (5.8%) in the co-amilozide group (RR=1.10; 95% CI, 0.91 to 1.34; P=0.35). The CCB was not superior to the diuretic in preventing cardiovascular morbidity and mortality. Nonfatal heart failure was more common in the CCB arm (RR=2.20; 95% CI, 1.07 to 4.49; P=0.028). There were only 3 fatal heart failure events: 2 in the CCB arm and 1 in the diuretic arm.

Further Details on Heart Failure in ALLHAT
Another major ALLHAT criticism concerned the heart failure findings. Specifically, were the findings real, and could they be explained by withdrawal from antihypertensive medications, such as diuretics and ACE inhibitors, on entry into ALLHAT?

Several articles have addressed these 2 questions in detail.38–41 The reliability of the heart failure diagnosis during the trial was examined in depth via the ALLHAT Heart Failure Validation Study (HFVS).40 This study was designed to validate and elucidate the significance of heart failure events in ALLHAT. This study involved all hospitalized heart failure events and relevant hospital records related to these events. Cardiology fellows, external to ALLHAT and blinded to treatment assignment, centrally abstracted the documentation for each heart failure hospitalization (2778 in 1935 patients; 2 independent reviews per case). ALLHAT and Framingham criteria were assigned by a computer algorithm; the reviewers also rendered a global clinical judgment. Percent agreements with site physician diagnoses were 71%, 80%, and 84% for ALLHAT, Framingham, and reviewers’ judgment, respectively. On the basis of these 3 criteria, RRs (95% CI) for new-onset hospitalized heart failure compared with chlorthalidone were, respectively, 1.46 (1.27 to 1.68), 1.42 (1.25 to 1.62), and 1.45 (1.28 to 1.64) for amlodipine; 1.18 (1.02 to 1.28), 1.13 (0.99 to 1.30), and 1.15 (1.01 to 1.32) for lisinopril (Figure 3); and 1.79 (1.51 to 2.11), 1.71 (1.46 to 2.00), and 1.80 (1.55 to 2.10) for doxazosin.40


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  		Figure 3. Incident hospitalized (Hosp) heart failure (HF) outcomes by antihypertensive treatment group (amlodipine/lisinopril vs chlorthalidone).40 *Prespecified end point of treated, hospitalized, or fatal heart failure. Reprinted from Einhorn et al,40 with permission. Copyright 2007, Elsevier.

Although there was early divergence of the heart failure incidence curves in ALLHAT, it continued after the first year for doxazosin and amlodipine versus chlorthalidone. For lisinopril versus chlorthalidone, the curves also separated early but appeared to converge between years 6 and 7.25 Diagnostic analysis revealed that the proportional hazards assumption of constant relative risk over time was not valid.39 A more appropriate model showed that RRs of amlodipine or lisinopril versus chlorthalidone during year 1 were 2.22 (1.69 to 2.91; P<0.001) and 2.08 (1.58 to 2.74; P<0.001); after year 1, they were 1.22 (1.08 to 1.38; P<0.001) and 0.96 (0.85 to 1.10; P=0.58) (Figure 4).39


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  		Figure 4. Cumulative event rates for hospitalized (Hosp)/fatal heart failure (HF) by treatment group.39

In addition, information about previous medication use was collected on the hospitalized and fatal cases of heart failure as a follow-up to the HFVS.41 When case-only design theory was used to assess interactions,42 the analyses did not support an effect of preentry diuretic use on the observed heart failure differences. However, the addition of second- and third-line drugs ({approx}30% at year 1) probably contributed to the lessening of the divergence starting at 6 to 12 months after randomization. Given these additional examinations, the original conclusions remained the same. Thiazide-type diuretics should be the preferred first-step therapy for prevention of heart failure in high-risk patients with hypertension.

Diabetes in ALLHAT
As noted above, the initial ALLHAT reports showed consistent findings for those in the prespecified subgroups with and without a baseline history of diabetes.25,26 A subsequent report on comparisons among the chlorthalidone, amlodipine, and lisinopril arms utilized baseline fasting glucose levels in addition to history to classify participants into those with diabetes, impaired fasting glucose (110 to 125 mg/dL), and fasting normoglycemia. Results were similar in all 3 subgroups, showing, in particular, the superiority of chlorthalidone for heart failure and the absence of any outcome (including end-stage renal disease) for which another arm was superior.43

Among those without diabetes mellitus (DM) at baseline, the mean fasting glucose was {approx}93.5 mg/dL. Changes in fasting glucose and percentage of incident diabetes mellitus (IDM) at 4 years, although not prespecified outcomes, were +10.8 mg/dL and 11.0% in the chlorthalidone group; +9.3 mg/dL and 9.3% in the amlodipine group, and +6.8 mg/dL and 7.8% in the lisinopril group, respectively.25 It was observed that these and other metabolic differences did not translate into any overall disadvantage for the diuretic arm during the mean follow-up of 4.9 years (range, 4 to 8 years). Nevertheless, further epidemiological-type analyses were conducted to examine the association of glucose changes with CVD and renal outcomes.44 There was no significant association of 2-year fasting glucose change with subsequent events, overall or in the chlorthalidone arm separately. In addition, among those who developed IDM by 2 years compared with those who did not, there was no significant increase in subsequent risk for any major disease outcomes except CHD, eg, the RRs for all CVD combined were 1.04 (95% CI, 0.80 to 1.35) for all arms and 0.96 (0.66 to 1.37) for chlorthalidone; for total mortality, they were 1.31 (0.96 to 1.81) and 1.05 (0.66 to 1.67), respectively. For CHD, the risk associated with IDM was 1.64 (1.15 to 2.33) overall but only 1.46 (0.88 to 2.42) in the chlorthalidone arm (Figure 5).


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  		Figure 5. Cox regression models showing the hazard ratios (95% CIs) associated with IDM during the first 2 years of follow-up on subsequent CVD and renal end points in those without DM at baseline.44 All hazard ratios controlled for treatment group (total cohort), 2-year blood pressure, age, race, sex, smoking status, baseline fasting glucose level, baseline body mass index, 2-year serum potassium level, and atenolol and statin administration at 2 years. NA indicates not applicable (too few events for analysis). Reprinted from Barzilay et al,44 with permission. Copyright 2006, American Medical Association.

Is this tendency for IDM occurring during low/moderate-dose chlorthalidone treatment to impart less risk for adverse clinical events than during other regimens real? If so, what could be the explanation? First, in the only other long-term follow-up data in treated hypertensive patients that are relatively uncontaminated with concomitant drugs, the findings in the SHEP 14-year extended follow-up study showed a similar phenomenon: a contrast between an increased CVD risk associated with IDM in the placebo arm but not in the chlorthalidone arm.45 Second, it must be recognized that in a typical hypertensive population, the great majority of IDM that occurs while taking a thiazide is not drug induced but is due to typical causes of type 2 diabetes and therefore would be expected to carry the same risk as any such occurrence. From ALLHAT data on IDM at 4 years, such a fraction can be estimated as 83%, if it is assumed that the CCB is metabolically neutral.46 If only 1 of 5 cases of IDM in patients prescribed a thiazide is due to the drug but these cases cannot be separated from the majority, the lower risk in such patients would serve to somewhat lower but not eliminate the overall DM-associated risk.

For the reason why thiazide-induced IDM could carry less risk than "naturally occurring" DM, one needs to consider the abundant, but mostly older and often forgotten, literature on potassium depletion and glucose disorders.46,47 To the extent that glucose disorders are due to this mechanism, it is plausible that its natural history is quite different. Furthermore, as pointed out in Reference 46, "In the diuretic-treated patient hypokalemia is likely to be intermittent, due to dietary and drug adherence variation, and potassium-sparing therapeutic intervention [which] may also translate to dysglycemia that is intermittent...and thus confer little risk of diabetic complications."

Network Meta-Analysis
The role of the efficacy of various antihypertensive therapies used as first-line agents in preventing major cardiovascular disease outcomes has been assessed with network meta-analysis.48 This type of analysis combines direct within-trial, between-drug comparisons with indirect evidence from the other trials. The indirect comparisons, which preserve the within-trial randomized findings, were constructed from trials that had 1 treatment in common.

Data were combined from 42 clinical trials that included 192 478 patients randomized to 7 major treatment strategies, including placebo. For all outcomes, low-dose diuretics were superior to placebo (Figure 6): CHD (RR, 0.79; 95% CI, 0.69 to 0.92); congestive heart failure (RR, 0.51; 95% CI, 0.42 to 0.62); stroke (RR, 0.71; 0.63 to 0.81); CVD events (RR, 0.76; 95% CI, 0.69 to 0.83); CVD mortality (RR, 0.81; 95% CI, 0.73 to 0.92); and total mortality (RR, 0.90; 95% CI, 0.84 to 0.96). None of the other first-line treatment strategies—β-blockers, ACE inhibitors, CCBs, {alpha}-blockers, and angiotensin receptor blockers—was significantly better than low-dose diuretics for any outcome. BP changes were similar between comparison treatments. On the basis of this network meta-analysis, the authors concluded that low-dose diuretics were the most effective first-line treatment for preventing the occurrence of CVD morbidity and mortality.


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  		Figure 6. Network meta-analysis of first-line treatment strategies in randomized controlled clinical trials in hypertension.48 Asterisks, placed after the closed parentheses of the 95% CI, indicate that β-blockers (P<0.05), angiotensin-converting enzyme inhibitors (P<0.05), calcium channel blockers (P<0.05), and angiotensin receptor blockers (P<0.05) were significantly better than placebo for outcome. {alpha}-Blockers were not significantly better than placebo for any outcome (P>0.05). Reprinted from Psaty et al,48 with permission. Copyright 2003, American Medical Association. All rights reserved.

JNC7 Recommendations
In 2003, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) issued its recommendations on the basis of the ALLHAT results and other trial evidence that was available at that time.49 Its major conclusions and recommendations were as follows.

In trials comparing thiazide-type diuretics with other classes of antihypertensive agents, they are (1) well tolerated; (2) effective and relatively safe for the management of hypertension despite potential adverse metabolic effects; and (3) unsurpassed in preventing the cardiovascular complications of hypertension. They are also less expensive and underutilized. The doses of thiazide-type diuretics used in successful morbidity trials of low/moderate-dose diuretics should be used (generally the equivalent of 25 to 50 mg of hydrochlorothiazide or 12.5 to 25 mg of chlorthalidone), although therapy may be initiated at lower doses and titrated to these doses if tolerated.

The algorithm for the treatment of hypertensive patients is to begin with lifestyle modification, and if the BP goal is not achieved, thiazide-type diuretics should be used as initial therapy for most patients, either alone or in combination with 1 of the other classes (ACE inhibitors, angiotensin receptor blockers, β-blockers, CCBs) that have also been shown to reduce 1 or more hypertensive complications in randomized controlled outcome trials (Figure 7). Selection of 1 of these other agents as initial therapy is recommended when a diuretic cannot be used or when a compelling indication is present that requires the use of a specific drug. If the initial drug selected is not tolerated or is contraindicated, then a drug from 1 of the other classes proven to reduce cardiovascular events should be substituted. Because most hypertensive patients will require ≥2 antihypertensive medications to achieve their BP goals, addition of a second drug from a different class should be initiated when use of a single agent in adequate doses fails to achieve the goal. It is further recommended that patients with stage 2 hypertension be started on 2 drugs initially, 1 of which should be a thiazide.


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  		Figure 7. JNC7 algorithm for treatment of hypertension.49 SBP indicates systolic BP; DBP, diastolic BP; ACEI, ACE inhibitors; ARB, angiotensin receptor blockers; and BB, β-blockers. Reprinted from Chobanian et al,49 with permission from Lippincott Williams & Wilkins. Copyright 2003, American Heart Association.


*    The Evidence for and Against β-Blockers
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 up arrowIntroduction
 up arrowTrials of Blood Pressure...
 up arrowThe Continuing Case for...
 *The Evidence for and...
down arrowConclusions
 down arrowReferences
 
The British Medical Research Council (BMRC) trial of treatment of mild hypertension was the first clinical events trial with a β-blocker–based arm (propanolol) in addition to a thiazide arm (bendrofluazide).6 Compared with placebo, only the thiazide significantly reduced stroke, likely as a result of the greater BP reduction than with the β-blocker. Both active treatment arms showed reductions in major cardiovascular events. Along with trials that found improved survival in post-MI patients with β-blockers, this experience was sufficient for guidelines to begin recommending thiazides and β-blockers as relatively equivalent alternatives for initiating treatment. This remained the situation through the 1990s, despite publication of results from the BMRC trial of treatment of hypertension in older adults, the β-blocker arm of which showed no significant reduction in either stroke or CHD events compared with placebo.7 In keeping with practice trends, a cardioselective β-blocker, atenolol, was selected in this trial; in this arm, systolic BP was less well controlled for the first year than in the hydrochlorothiazide arm.

Although 1 observer began questioning the role of the class for first-line treatment,50 during the era of direct comparison trials, the arm representing traditional classes of drugs most often offered participating clinicians a choice of thiazides or β-blockers or selected a β-blocker (most commonly, atenolol) as the comparator. Generally, before 2005 there were few differences for major cardiovascular event rates in individual trials between such regimens and those based on newer classes; an exception was the Losartan Intervention For End point reduction in hypertension (LIFE) trial, in which a composite of stroke, MI, and cardiovascular death was 13% (P=0.02) less frequent in the losartan-based than in the atenolol-based group, owing mostly to an advantage for stroke.51 This small disadvantage for the β-blocker in a special study population selected for left ventricular hypertrophy, in the light of numerous trials not showing such a disadvantage, was not sufficient for the JNC7 group to downgrade the role of β-blockers as alternative first-line drugs.49

The balance of evidence changed substantially with the reporting of results of the Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Treatment Arm (ASCOT-BPLA).52 This large open-label trial (PROBE design) compared atenolol-based treatment (bendroflumethiazide as an add-on) with amlodipine-based treatment (perindopril as add-on); it was stopped early because of 11% lower all-cause mortality in the amlodipine group (P=0.02). When the study was terminated early, there was no advantage in this arm for the primary CHD end point (hazard ratio=0.90; P=0.11), and stroke was also significantly reduced, by 23%. This may have been related to the lower mean BP: 2.7/1.9 mm Hg on average, with a greater difference during the first year. Both effects may have in turn been related to the once daily use of atenolol and/or the relatively low dose of the thiazide added to atenolol when needed for BP control.

After the publication of ASCOT, several meta-analyses were produced that led to recommendations unfavorable to β-blockers (while continuing to acknowledge that evidence on non-atenolol β-blockers in a primary prevention setting is scanty).53,54 Although the trials included differed somewhat between the meta-analyses and the Lindholm article did not address heart failure, they both concluded that β-blockers were less effective than other major antihypertensive classes in preventing stroke (Figure 8). Therefore, the recommendations were to delete β-blockers as a first-line antihypertensive treatment, except in cases in which there are compelling indications, mainly for patients with CHD.


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  		Figure 8. Outcome data for all β-blockers vs other antihypertensive treatment.53 CONVINCE indicates Controlled Onset Verapamil Investigation of Cardiovascular End Points; ELSA, European Lacidipine Study on Atherosclerosis; HAPPHY, Heart Attack Primary Prevention in Hypertension; INVEST, International Verapamil-Trandolapril Study; MRC, Medical Research Council; NORDIL, Nordic Diltiazem Study; STOP-2, Swedish Trial in Old Patients With Hypertension; and UKPDS, UK Prospective Diabetes Study. Reprinted from Lindholm et al,53 with permission. Copyright 2005, Elsevier.


*    Conclusions
up arrowTop
 up arrowIntroduction
 up arrowTrials of Blood Pressure...
 up arrowThe Continuing Case for...
 up arrowThe Evidence for and...
 *Conclusions
down arrowReferences
 
We believe that the JNC7 report came to the proper conclusions about thiazides, on the basis of (1) results of the abundant trials aimed at the effect of BP reduction on clinical events comparing thiazide-based regimens with placebo or lesser treated controls; (2) ALLHAT results in the context of the few other trials evaluating thiazide-based treatment versus another class (trials testing a β-blocker and/or thiazide protocol versus another class are not very informative); and (3) the network meta-analysis by Psaty et al48 that summarized all of this evidence. As noted in JNC7, thiazides (1) are well tolerated, better than other classes in the double-blind setting of ALLHAT, in which a heterogeneous patient population was treated in widely diverse clinical settings; (2) are at least as effective as other classes for BP control in most patients, with the possible exception of younger white men55; (3) are unsurpassed in preventing cardiovascular events and improving survival, including an advantage in prevention of heart failure (in the short term versus ACE inhibitors and in the long term versus CCBs); and (4) have very low acquisition costs. Although frequency of their use in antihypertensive regimens has increased substantially since the ALLHAT and JNC7 publications,56 they are still underutilized, and organized efforts to improve performance in this regard are continuing, most impressively in the Department of Veterans Affairs medical system (William Cushman, MD, personal communication, September 20, 2006).

Some commentators have focused on the small increase in IDM associated with thiazide use while virtually ignoring the advantage for heart failure prevention. This seems backward. Regarding diabetes, naturally occurring disease carries appreciable long-term cardiovascular risk, but it is not clear that thiazide-induced cases do, and they are largely preventable or reversible by management of potassium balance. On the other hand, heart failure imparts high functional impact and mortality risk in the short to medium term. It seems that this benefit should be given considerable weight, except in patients known to be at very low risk of heart failure. Thus, the British recommendation to the effect that thiazides and CCBs are equally desirable choices as first-line drugs in older patients seems ill considered.54

As noted above, the role of other major drug classes (ACE inhibitors, angiotensin receptor blockers, β-blockers, and CCBs) in JNC7 is in cases in which a thiazide is not tolerated or contraindicated, which is an infrequent situation; for listed compelling indications; or in combination treatment, which is likely to be required to control BP in most patients. There is no update of JNC guidelines currently available that might have changed the recommendations regarding β-blockers, but British guidelines have placed them as a lesser choice than the other classes except for compelling indications, ie, situations in which there is another indication for their use. This conclusion seems reasonable to us, even though the data are scant for non-atenolol β-blockers and the evidence for benefit in secondary prevention is much stronger for other β-blockers.57 Interestingly, the parallel situation for ACE inhibitors in younger patients (lack of cardiovascular outcome data) did not deter the British report from recommending them as first choice in this demographic group. Once again, the recommendation seems to turn on effects on dysglycemia without really knowing their importance. However, to our knowledge, there is no reassuring evidence regarding associated risks and mechanisms for β-blockers as exists for thiazides.

Additional Research
Although a strong evidence base exists for a consensus on preferred and other acceptable drug classes for initiating antihypertensive pharmacotherapy, there are several other major research questions for ongoing and needed trials, several of which were highlighted in a report from a 2003 National Heart, Lung, and Blood Institute workshop.58 These include the following: (1) What is the optimal second drug class to add to a thiazide? (2) What goal BP, especially systolic, should be sought for minimizing CVD risk? From the evidence on heart failure in ALLHAT and the importance of the condition generally, we believe that heart failure should be included in any composite primary CVD end point for future hypertension treatment trials.


*    Acknowledgments
 
The authors acknowledge the invaluable technical assistance of Sara L. Pressel, MS.

Disclosures

Dr Davis has served as a consultant for Biomarin, GlaxoSmithKline, Proctor & Gamble, and Takeda Pharmaceutical Company Limited. Dr Cutler has no conflicts of interest.


*    References
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 up arrowIntroduction
 up arrowTrials of Blood Pressure...
 up arrowThe Continuing Case for...
 up arrowThe Evidence for and...
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 *References
 

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Response to Cutler and Davis

Franz H. Messerli, MD; Sripal Bangalore, MD, MHA; and Stevo Julius, MD

We are delighted that Drs Cutler and Davis find the conclusion of the British guidelines to remove β-blockers from their first-line status in hypertension "reasonable"—a position we have taken a decade ago. Indeed, one may wonder why β-blockers were ever elevated to that status; ever since the MRC trial, every single study comparing β-blockers with either placebo or other therapy has been negative. Never has a drug class been prescribed so much on the basis of so little evidence. In the United States alone, more than 120 million prescriptions for β-blockers were written in 2007. This means that numerous patients still are exposed to the adverse effects, cost, and inconvenience of a drug class without ever having any benefit. We also agree with our colleagues that, on the basis of the ALLHAT study, "thiazide-type diuretics should be the preferred first-step therapy for prevention of heart failure in high-risk patients with hypertension," although this is true for chlorthalidone only. However, we strongly object to the authors’ suggestion that evidence gained in high-risk patients such as ALLHAT "should be reasonably extrapolated beyond the exact sample in which it was conducted." That this is pure conjecture and that there is no scientific basis for extrapolation has now been documented by ACCOMPLISH, which now relegates the thiazides to third-line therapy. As to the cost of thiazides, the authors’ own recent ALLHAT analysis showed that amlodipine tended to be preferred on the basis of the fact that it provided a (nonsignificantly) greater survival benefit than the other drugs. This analysis is misleading in that it did not even consider the now generic price of these drugs, nor did it assess cost of new-onset diabetes associated with them. On the basis of our meta-analysis, we estimate that β-blockers and diuretics could account for more than 100 000 cases of new-onset diabetes in the United States every year. Recent data on outcome, cost, and adverse events allow us now to assign antihypertensive drugs to their proper place in the therapeutic arsenal; keeping thiazides or β-blockers as first-line therapy seems to us, as Ralph Waldo Emerson said, "a foolish consistency...the hobgoblin of little minds."


*    Footnotes
 
Dr Cutler is a consultant to the National Heart, Lung, and Blood Institute. The opinions expressed in this article are his own and those of Dr Davis and are not necessarily those of the National Heart, Lung, and Blood Institute or the US Department of Health and Human Services, the editors, or the American Heart Association.

This article is Part I of a 2-part article. Part II appears on page 2706.





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