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Review |

Health Outcomes Associated With Various Antihypertensive Therapies Used as First-Line Agents:  A Network Meta-analysis FREE

Bruce M. Psaty, MD, PhD; Thomas Lumley, PhD; Curt D. Furberg, MD, PhD; Gina Schellenbaum; Marco Pahor, MD; Michael H. Alderman, MD; Noel S. Weiss, MD, DrPH
[+] Author Affiliations

Author Affiliations: Departments of Medicine (Dr Psaty), Epidemiology (Drs Psaty and Weiss and Ms Schellenbaum), Health Services (Drs Psaty), and Biostatistics (Dr Lumley), Cardiovascular Health Research Unit, University of Washington, Seattle; Departments of Public Health Sciences (Dr Furberg) and Medicine (Dr Pahor), Wake Forest University Health Sciences, Winston-Salem, NC; and Department of Epidemiology and Social Medicine (Dr Alderman), Albert Einstein College of Medicine, Bronx, NY.


JAMA. 2003;289(19):2534-2544. doi:10.1001/jama.289.19.2534.
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Context Establishing relative benefit or harm from specific antihypertensive agents is limited by the complex array of studies that compare treatments. Network meta-analysis combines direct and indirect evidence to better define risk or benefit.

Objective To summarize the available clinical trial evidence concerning the safety and efficacy of various antihypertensive therapies used as first-line agents and evaluated in terms of major cardiovascular disease end points and all-cause mortality.

Data Sources and Study Selection We used previous meta-analyses, MEDLINE searches, and journal reviews from January 1995 through December 2002. We identified long-term randomized controlled trials that assessed major cardiovascular disease end points as an outcome. Eligible studies included both those with placebo-treated or untreated controls and those with actively treated controls.

Data Extraction Network meta-analysis was used to combine 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 one treatment in common.

Data Synthesis 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: coronary heart disease (CHD; RR, 0.79; 95% confidence interval [CI], 0.69-0.92); congestive heart failure (CHF; RR, 0.51; 95% CI, 0.42-0.62); stroke (RR, 0.71; 0.63-0.81); cardiovascular disease events (RR, 0.76; 95% CI, 0.69-0.83); cardiovascular disease mortality (RR, 0.81; 95% CI, 0.73-0.92); and total mortality (RR, 0.90; 95% CI, 0.84-0.96). None of the first-line treatment strategies–β-blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), α-blockers, and angiotensin receptor blockers–was significantly better than low-dose diuretics for any outcome. Compared with CCBs, low-dose diuretics were associated with reduced risks of cardiovascular disease events (RR, 0.94; 95% CI, 0.89-1.00) and CHF (RR, 0.74; 95% CI, 0.67-0.81). Compared with ACE inhibitors, low-dose diuretics were associated with reduced risks of CHF (RR, 0.88; 95% CI, 0.80-0.96), cardiovascular disease events (RR, 0.94; 95% CI, 0.89-1.00), and stroke (RR, 0.86; 0.77-0.97). Compared with β-blockers, low-dose diuretics were associated with a reduced risk of cardiovascular disease events (RR, 0.89; 95% CI, 0.80-0.98). Compared with α-blockers, low-dose diuretics were associated with reduced risks of CHF (RR, 0.51; 95% CI, 0.43-0.60) and cardiovascular disease events (RR, 0.84; 95% CI, 0.75-0.93). Blood pressure changes were similar between comparison treatments.

Conclusions Low-dose diuretics are the most effective first-line treatment for preventing the occurrence of cardiovascular disease morbidity and mortality. Clinical practice and treatment guidelines should reflect this evidence, and future trials should use low-dose diuretics as the standard for clinically useful comparisons.

Figures in this Article

In 1993 and again in 1997, the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure recommended low-dose diuretics and β-blockers as first-line treatment for patients with uncomplicated hypertension.1,2 This recommendation reflected the wealth of clinical trial evidence about the health benefits associated with low-dose diuretics and β-blockers.38 The early trials of diuretics and β-blockers had generally randomized patients with high blood pressure to active therapy or to placebo. Early answers were clearest for patients with the highest level of blood pressure.4,5 These studies answered the question of whether several specific antihypertensive treatments improved health outcomes.

Clear evidence of health benefits associated with diuretics and β-blockers precluded further long-term placebo-controlled trials. Thus, the recent large long-term trials have evaluated one active treatment against another active treatment in terms of their ability to prevent cardiovascular events.915 In these active-treatment comparison trials, participants in each treatment group have been randomized to receive one of a variety of first-line agents, including not only diuretics and β-blockers, but also α-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). These comparative trials address the question of which first-line treatment regimen is optimal.

As this history suggests, the clinical trials in hypertension have provided a patchwork of evidence about the health benefits of antihypertensive agents. Some trials used placebo or untreated controls, and others used active-treatment comparison groups. Among the latter, the choice of the treatment and comparison therapies has varied from one trial to the next. Several approaches to the synthesis of these complex data are possible.3,16,17 The Blood Pressure Trialists, for instance, conducted a prospective series of mini–meta-analyses, but this method left many "unresolved issues"17(p1963) due to multiple comparisons and low power.18 In this study, we used a new technique, called network meta-analysis,19 to synthesize the available evidence from placebo-controlled and comparative trials in a single meta-analysis. In addition to updating our previous meta-analysis of low-dose diuretics,3 the primary aim was to compare low-dose diuretics with each of the other 5 active first-line therapies evaluated in large long-term trials in terms of major health outcomes.

Using MEDLINE searches, previous meta-analyses,3,16,17,2024 and journal reviews from January 1995 through December 2002, we identified studies designed to evaluate the effects of antihypertensive therapies on the occurrence of myocardial infarction and stroke. For randomized trials, a MEDLINE search was used to identify randomized clinical trials designed to evaluate the effects of antihypertensive therapies on the occurrence of cardiovascular morbidity and mortality. To update the literature search conducted for a previous meta-analysis,3 the search strategy for 1995 to 2002 was based on the search terms cerebrovascular disorders or cerebrovascular disorder or heart diseases or heart disease and antihypertensive agents (therapeutic use) or hypertension (drug therapy). All available English and non-English abstracts were reviewed (n = 1097), and the full text was consulted as necessary to clarify eligibility status. We limited attention to the 6 most commonly used antihypertensive classes (diuretics, β-blockers, CCBs, ACE inhibitors, ARBs, and α-blockers).

To be eligible for inclusion, studies had to be randomized controlled trials that evaluated major cardiovascular disease end points in hypertensive patients over the course of at least 1 year. Trials that recruited patients who had congestive heart failure (CHF) or who had a myocardial infarction were not eligible. The treatment had to be unconfounded by other therapies, such as smoking cessation or lipid-lowering, but factorial design trials such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)12,15 were eligible. Trials published since 1995 had to have a minimum of 400 person-years of observation. Open randomized trials that used an untreated control group were included,25,26 but we excluded nonrandomized studies,27 nonfactorial multiple risk factor intervention trials,28,29 trials using first-line agents other than the 6 noted above,30,31 and trials that used a placebo group plus other antihypertensive therapies to reduce blood pressure to the same target level as the active treatment.3234

All eligible trials415,25,26,3571 are listed in Table 1a with data on number of events by randomized group. Data for one trial69 were finalized after the search was completed.68 Data were abstracted independently by 2 of the authors (B.M.P. and G.S.), and differences were resolved by consensus.

Table Graphic Jump LocationTable 1a. Cardiovascular Events and Outcomes by Randomized Treatment

Coronary heart disease (CHD) included fatal and nonfatal myocardial infarction and CHD death; stroke, fatal and nonfatal stroke; and CHF, fatal and nonfatal CHF. Cardiovascular disease events included CHD, stroke, CHF, and other cardiovascular disease mortality. While the definition of end points varied slightly among the trials, the end point definitions and methods of classification were identical across treatment groups within each trial. For all comparisons, this meta-analysis aggregates these in-trial comparisons across studies.

Each arm of the trials was classified according to its primary treatment strategy. While most studies used more than 1 drug in a treated group, the agents were usually applied in a stepped-care approach so that the first-line therapy was clearly identified. The primary treatment strategies of interest in this meta-analysis were (1) placebo, untreated, or usual care; (2) low-dose diuretic therapy, which generally started with the equivalent of 12.5 to 25 mg per day of chlorthalidone or hydrochlorothiazide; (3) β-blocker therapy; (4) ACE inhibitors; (5) ARBs; (6) CCBs; and (7) α-blockers. High-dose diuretic therapy was defined as starting doses greater than or equal to the equivalent of 50 mg of chlorthalidone or hydrochlorothiazide and titrating upward72; diuretic dosages were unstated in 2 studies,25,35 but were assigned to the high-dose diuretic group. While high-dose diuretics were included in the standard meta-analysis73 that compared any therapy with no therapy, this treatment strategy is not presented as part of the network meta-analysis since high-dose diuretic therapy is no longer used or recommended for the treatment of high blood pressure. None of the CCBs was a short-acting drug or formulation.

For the main analysis, the logarithm of the relative risk (RR) for each trial and its SE were calculated and used in a network meta-analysis.19 Network meta-analysis preserves the within-trial randomized comparison of each study and, at the same time, combines all available comparisons between treatments. These comparisons included both the direct within-trial comparisons between 2 treatment strategies and the indirect comparisons constructed from 2 trials that have 1 treatment in common. By way of illustration, the Intervention as a Goal in Hypertension Treatment (INSIGHT)9 trial provided a direct within-trial comparison of diuretics and CCBs for stroke (RR of 1.11 in favor of CCBs) and for CHF (RR of 0.46 in favor of diuretics). Systolic Hypertension in the Elderly Program (SHEP)45 and Systolic Hypertension in Europe Trial (SYST-EUR),53 both placebo-controlled trials, used diuretics and CCBs as active treatment. Therefore, the RRs from these 2 placebo-controlled trials can be used to provide estimates of the RR for the indirect comparison between diuretic and CCBs. For the outcome of stroke, multiplying the RR for diuretics vs placebo in SHEP times the RR for placebo vs CCBs in SYST-EUR yielded an indirect comparison of 0.65 × 1.69 = 1.10 in favor of the CCB, which was almost identical to the direct estimate of 1.11 from INSIGHT. For the outcome of CHF, the indirect comparison produced an RR of 0.70 (in favor of diuretics; from 0.53 × 1.33) compared with the direct estimate of 0.46 from INSIGHT. Other indirect comparisons can be computed with 2 or more intermediate treatments rather than the placebo-treatment arm used in this example. Network meta-analysis combines all available direct and indirect comparisons.

As Bucher et al74 have shown, indirect estimates can be combined in large samples if there is no interaction between the treatment effects and the populations or major subgroups in a trial. This requirement for combining similar effect estimates across trials also holds for standard meta-analyses. Indirect estimates cannot simply be assumed to be reliable. The reliability of treatment effects is assessed by computing the differences between various comparisons of the same 2 treatments. The variance of these differences over and above what would be expected from sampling error within each trial is expressed as a variance estimate called the "incoherence" of the network of trials. In the example used in the previous paragraph, the direct and indirect RRs for CHF (0.46 vs 0.71) were more incoherent or heterogeneous than the direct and indirect RRs for stroke (1.11 vs 1.10). Incoherence is a property of the fitted model, and it is incorporated in inferences in a similar way to the heterogeneity estimate in a standard random-effects meta-analysis.73 When the incoherence is small or moderate, it is used to increase the SE of the estimated treatment differences and to reduce the weight given to indirect comparisons. When the incoherence is sufficiently large, combining the trials may not be appropriate.

These computations were performed by fitting a linear mixed model to the log RRs from each trial with a random effect specific to each pair of treatments. Weights were used to avoid double counting of trials, such as ALLHAT,15 that had 3 or more arms. The single line of R source code required to estimate each model appears in Figure 4 of the network meta-analysis methods article by Lumley.19 Each of the 6 main analyses modeled a single outcome as a function of the various first-line treatment strategies. A similar random-effects linear mixed model was used to evaluate blood pressure differences between treatments, and the inverse of the sample size was used for the weights. Because the estimated incoherence for each meta-analysis was small, the incoherence had only a small effect on the width of the confidence intervals (CIs).

Our primary hypothesis involved low-dose diuretics, which are currently recommended as the first-line therapy.1 The RRs that are less than 1.0 indicate that low-dose diuretic therapy is superior to the comparison treatment strategy. We evaluated 2 alternative approaches to handling trials that included both diuretics and β-blockers in a single treatment group.10,13,14,47 In one approach, the 2-drug category was included as a separate treatment, and in the other, the trials were weighted according to the allocation of 68% to β-blockers and 32% to diuretics.75 Since the 2 approaches yielded almost identical estimates of the associations for placebo and β-blockers, we decided to present the simpler model in this article. We also evaluated alternative models that included separate categories for the dihydropyridine CCBs and the nondihydropyridine CCBs. With RRs of less than 1.0 indicating that nondihydropyridines were superior to dihydropyridines, the RRs were 1.12 (95% CI, 0.86-1.46) for CHD; 0.96 (95% CI, 0.76-1.21) for stroke; 0.96 (95% CI, 0.75-1.21) for heart failure; 0.94 (95% CI, 0.81-1.09) for cardiovascular disease events; 0.87 (95% CI, 0.71-1.06) for cardiovascular disease mortality; and 0.93 (95% CI, 0.74-1.09) for total mortality. Since there were no significant differences between the 2 subclasses, the CCBs were presented as a single treatment strategy.

The 42 trials from the United States, Europe, Scandinavia, Australia, Japan, and China included a total of 192 478 patients followed up for an average of 3 to 4 years. The high-dose diuretic trials, generally completed in the 1970s and 1980s, were followed by trials that used low-dose diuretics. Trials completed in the last decade were usually larger than the early trials, and some of them recruited special populations, including individuals with diabetes,56,58,60,66,67 older adults,41,42,45,53 those with a history of cerebrovascular disease,25,50,65 and blacks with renal disease.62,63 Some details about individual trials are provided in Table 1 and in previous meta-analyses.3,16,17,2024 ALLHAT,15 which has not been part of a previous meta-analysis, included 33 357 participants aged 55 years or older with at least 1 other CHD risk factor (mean follow-up was 4.9 years).

The standard meta-analysis of any drug treatment vs no treatment, which omits all active-control trials, appears in Table 2. Compared with placebo, an untreated control group, or usual care, any active treatment was associated with important reductions in the risk of all major outcomes. Combining all types of active treatments in this analysis involved the unevaluated assumption that all treatments had a similar effect. For the outcomes of stroke and major cardiovascular events, there was significant heterogeneity, which may be the result of important differences between drug classes.

Table Graphic Jump LocationTable 2. Fixed and Random Effects Meta-analysis Comparing any Antihypertensive Drug Treatment vs No Treatment for Each Outcome*

For the network meta-analysis, we first conducted an analysis that excluded ALLHAT,15 the largest comparative trial and the mixed β-blocker diuretic trials.10,13,14,47,70Table 3 summarizes 3 independent sets of RRs that compare low-dose diuretics with CCBs or ACE inhibitors: the ALLHAT results; the direct comparisons between trials9,52,55,61,69 other than ALLHAT; and indirect comparisons between the trials other than ALLHAT. For the comparison between diuretic and ACE inhibitor, the 1 remaining direct comparison trial was the Second Australian National Blood Pressure study.69 Depending on the outcome, the indirect comparisons used information from 14 to 24 trials or pairs of trial arms (Figure 1); and the indirect comparisons included paths that passed through placebo, low-dose diuretics, β-blockers, and CCBs. For 5 of the 6 outcomes, the point estimates for the indirect meta-analysis of diuretics and ACE inhibitors were closer to those of ALLHAT than the direct estimates from the Second Australian National Blood Pressure Study. For all outcomes and for both drug comparisons, the point estimates from the 3 sources of data were generally similar. Neither the direct nor the indirect estimates differed from ALLHAT in a systematic way across outcomes. The similarity among estimates suggests that combining data from the 3 sources is reasonable and appropriate.

Table Graphic Jump LocationTable 3. ALLHAT vs Meta-analysis* of the Other Direct and Indirect Evidence Comparisons of Calcium Channel Blockers and Angiotensin-Converting Enzyme Inhibitors With Low-Dose Diuretics
Figure 1. Network Meta-analysis of First-Line Antihypertensive Drug Treatments
Graphic Jump Location
Each first-line drug treatment is a node in the network. The links between the nodes are trials or pairs of trial arms. The numbers along the link lines indicate the number of trials or pairs of trial arms for that link in the network. Reference numbers indicate the trials contributing to each link. A trial such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial12,15 (ALLHAT) with multiple arms appears along several links (diuretics-angiotensin-converting enzyme (ACE) inhibitors, diuretics-calcium channel blockers (CCBs), ACE inhibitors-CCBs, and diuretics-α-blockers). High-dose diuretic trials were excluded.

Figure 2 was constructed from the network meta-analyses to highlight treatment comparisons for all major end points. In Figure 2A, low-dose diuretic therapy was compared with placebo. The RRs were significantly less than 1.0 for all 6 outcomes: CHD (RR, 0.79; 95% CI, 0.69-0.92); CHF (RR, 0.51; 95% CI, 0.42-0.62); stroke (RR, 0.71; 0.63 -0.81); cardiovascular disease events (RR, 0.76; 95% CI, 0.69-0.83); cardiovascular disease mortality (RR, 0.81; 95% CI, 0.73-0.92); and total mortality (RR, 0.90; 95% CI, 0.84-0.96).

Figure 2. Network Meta-analysis of First-Line Treatment Strategies in Randomized Controlled Clinical Trials in Hypertension
Graphic Jump Location
Asterisks, placed after the closed parentheses of the 95% CI, indicate that β-blockers (P<.05), angiotensin-converting enzyme inhibitors (P<.05), calcium channel blockers (P<.05), and angiotensin-receptor blockers (P<.05) were significantly better than placebo for that outcome. α-Blockers were not significantly better than placebo for any outcome (P>.05). CHD indicates coronary heart disease; CHF, congestive heart failure; CI, confidence interval; CVD, cardiovascular disease; and RR, relative risk.

Figure 2B compares the performance of β-blockers with low-dose diuretics. For all outcomes, low-dose diuretics were associated with a lower point estimate for events than β-blockers, but the findings were significant only for the incidence of cardiovascular disease events (RR, 0.89; 95% CI, 0.80-0.98). For some outcomes, (marked by asterisks), β-blockers were significantly better than placebo. For cardiovascular disease events, specifically, the RR was 0.85 (95% CI, 0.78-0.94). The product (0.76) of these 2 RRs (0.85 × 0.89) represents the RR for low-dose diuretics vs placebo (Figure 2A).

In Figure 2C, low-dose diuretics were associated with a significantly lower risk of CHF (RR, 0.88; 95% CI, 0.80-0.96), stroke (RR, 0.86; 95% CI, 0.77-0.97), and cardiovascular disease events (RR, 0.94; 95% CI, 0.89-1.00) than ACE inhibitors. In Figure 2D, low-dose diuretics were associated with significantly lower risks of CHF (RR, 0.74; 95% CI, 0.67-0.81) and cardiovascular disease events (RR, 0.94; 95% CI, 0.89-1.00) than CCBs. For the other outcomes in Figure 2C and Figure 2D, the differences did not achieve conventional levels of significance (P<.05). Again, asterisks in these figures indicate that the drug class differs significantly from placebo for that outcome.

Only 3 trials evaluated ARBs, and in Figure 2E, all the CIs for RRs comparing ARBs and low-dose diuretics included the null. The comparison of α-blockers and low-dose diuretics (Figure 2F) was based on data from ALLHAT.12

The estimates of incoherence for each outcome in this network meta-analysis were small (Table 4). For instance, the differences between the direct and the indirect comparisons of drugs in this meta-analysis inflated the width of the 95% CI by about 0.5% for CHD and by about 5% for cardiovascular disease mortality. While low-dose diuretics were often associated with slightly lower mean levels of blood pressure than other classes of antihypertensive drugs (Table 5), none of the differences was significant.

Table Graphic Jump LocationTable 5. Change in Systolic and Diastolic Blood Pressures for Each Drug Class Compared With Low-Dose Diuretics*

In this network meta-analysis, we combined clinical trial data from 42 studies that included 192 478 patients randomized to 7 major treatment strategies. For all outcomes, the network meta-analysis confirmed that low-dose diuretics were superior to placebo. While several other treatment strategies were significantly better than placebo for some end points, none of the other first-line treatment strategies–β-blockers, ACE inhibitors, CCBs, α-blockers, and ARBs–was significantly better than low-dose diuretics for any major cardiovascular disease outcome. In 8 of the 30 between-drug comparisons, however, low-dose diuretics were significantly better than other treatments for the prevention of cardiovascular disease health outcomes. Among nonsignificant between-drug comparisons, 13 favored low-dose diuretics, 5 favored other therapies, and 4 were indifferent. This network meta-analysis provides compelling evidence that low-dose diuretics are the most effective first-line treatment for preventing the occurrence of cardiovascular disease morbidity and mortality.

β-blockers have long been identified as another preferred first-line treatment for hypertension. In this network meta-analysis, similar to our previous article,3 β-blockers were superior to placebo for the prevention of stroke, CHF, cardiovascular disease events, and total mortality. At the same time, β-blockers were inferior to low-dose diuretics for all outcomes, significantly so for cardiovascular disease events. For uncomplicated hypertension, β-blockers should be considered a second-line antihypertensive agent.

There are no large long-term trials evaluating the optimal second-line antihypertensive therapy, which could include ACE inhibitors, CCBs, and ARBs, as well as β-blockers. In addition to information about the health outcomes in hypertension trials, many investigators use the findings about major cardiovascular benefits from other large long-terms trials to recommend the use of specific drugs for compelling indications.1,76 β-blockers have been particularly effective in patients with coronary disease7779 or heart failure,80,81 and many guidelines recommend them over CCBs as first-line therapy for improving health outcomes in secondary-prevention settings.8286 Like β-blockers, ACE inhibitors have also proven to be a robust therapy, effective in a number of secondary-prevention settings, including coronary disease87,88 and heart failure.89 ACE inhibitors, which may be preferred in special populations such as those with diabetes,90 are also superior to amlodipine in blacks with renal disease.62

Based exclusively on indirect comparisons, there were no significant differences between low-dose diuretics and ARBs. However, the number of ARB trials was small, and this analysis lacked power. The uncertainty occasioned by the small number of ARB trials is reflected in the wide CIs in Figure 2E.

In this meta-analysis (Table 5) and in several of the comparative trials, including ALLHAT,15 the various treatment strategies were associated with slightly different amounts of blood-pressure lowering. The RRs estimated for the outcomes in this meta-analysis preserved the within-trial comparisons of the treatment strategies just as they were implemented and without adjustment for any in-trial blood pressure differences that may have occurred. In ALLHAT,15 adjustment for in-trial blood pressure had minor effects on the estimated RRs. While differences in outcomes in this network meta-analysis may reflect differences in achieved levels of blood pressure, the blood pressure differences were generally small (Table 5). Epidemiological evidence from the Framingham Heart Study91 suggests that adjustment for the 2.4-mm Hg difference in systolic blood pressure between low-dose diuretics and CCBs (Table 5) would have increased the RR for heart failure in Figure 2D only slightly–from 0.74 to about 0.77.

Previous traditional meta-analyses have been constrained by the evolving configuration of the trial designs. With standard techniques of meta-analysis, comparisons of diuretics or β-blockers with placebo were possible.3 Comparisons of CCBs to all other active therapies were also possible.16 Alternatively, it was possible to use various subsets of the trials to evaluate each major type of within-trial comparisons as the Blood Pressure Lowering Treatment Trialists did in their prospective series of mini–meta-analyses.17 All these traditional approaches to meta-analysis ignore part of the available data.

Network meta-analysis incorporates both the direct and indirect comparisons between treatments. In this study, the direct and indirect comparisons were similar (Table 3). Recent empirical evidence suggests the validity of indirect comparisons for a number of conditions and interventions.92 In a series of 44 meta-analyses that permitted comparisons between direct and indirect results, the number of significant differences (n = 3) was only slightly higher than the number expected by chance alone (n = 2.2). Song et al92 conclude that the validity of indirect comparisons depends on the internal validity and the similarity of the evaluated trials, including similarity in dose.

Like heterogeneity in traditional random-effects models of meta-analysis, incoherence is used to quantify variation among estimates and is incorporated into the estimation of the CI. Although the estimated incoherence of the final models in this network meta-analysis was low (Table 4), additional methodological and empirical work needs to be done to evaluate the direct and indirect comparisons across a number of types of interventions. Traditional limitations of meta-analyses due to variations in the treatment regimens, in populations or major subgroups within trials, and in the conduct of the trials also apply to this network meta-analysis.

As investigators gain experience with the use of indirect comparisons74,92 and with the technique of network meta-analysis,19 it may be possible to forego some placebo-controlled trials in selected therapeutic areas. In the presence of compelling evidence of the effect of one drug against placebo, comparative trials with a second agent can provide indirect estimates of its effect against placebo.74,92 This principle is the same as the requirement for good anchoring trials before launching equivalence trials.93,94

While an occasional hypertensive patient cannot take diuretics because of an allergy or an intolerable adverse effect,95 low-dose diuretics were significantly better than other therapies in reducing the occurrence of cardiovascular disease health outcomes for 8 of the 30 between-drug comparisons. In this network meta-analysis, the most effective drug was also the least expensive. Thus, cost-effectiveness analyses are not required.

Based on extensive clinical trial evidence, meta-analysis, and network meta-analysis, low-dose diuretics are the treatment of first choice for patients with uncomplicated hypertension who need pharmacological therapy. Moreover, low-dose diuretics should serve as the active-treatment control arm of future superiority or equivalence trials in patients with hypertension. Trials evaluating the optimal second-line treatment strategy may be appropriate. Until then, recommendations about the best second-line therapies should be based, when possible, on evidence from large long-term outcome trials mounted for other compelling indications such as coronary disease and heart failure.76

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Mulrow CD, Cornell JA, Herrera CR, Kadri A, Farnett L, Aguilar C. Hypertension in the elderly: implications and generalizability of randomized trials.  JAMA.1994;272:1932-1938.
Hebert PR, Moser M, Mayer J, Glynn RJ, Hennekens CH. Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease.  Arch Intern Med.1993;153:578-581.
Cutler JA, Psaty BM, MacMahon S, Furberg CD. Public health issues in hypertension control: what has been learned from clinical trials. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press; 1995:253-279.
Carter AB. Hypotensive therapy in stroke survivors.  Lancet.1970;1:485-489.
Hegeland A. Treatment of mild hypertension: a five-year controlled drug trial: the Oslo Study.  Am J Med.1980;69:725-732.
Liu L, Wang JG, Gong L.  et al.  Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension.  J Hypertens.1998;16:1823-1829.
Multiple Risk Factor Intervention Trial Research Group.  Multiple Risk Factor Intervention Trial: risk factor changes and mortality results.  JAMA.1982;248:1465-1477.
Miettinen TA, Huttunen JK, Naukkarinen V.  et al.  Multifactorial primary prevention of cardiovascular diseases in middle-aged men: risk factor changes, incidence and mortality.  JAMA.1985;254:2097-2102.
Wolff FW, Lindeman RD. Effects of treatment in hypertension: results of a controlled study.  J Chronic Dis.1966;19:227-240.
Sprackling ME, Mitchell JRA, Short AH, Watt G. Blood pressure reduction in the elderly: a randomised controlled trial of methyldopa.  BMJ.1981;283:1151-1153.
The IPPPSH Collaborative Group.  Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH).  J Hypertens.1985;3:379-392.
SCOPE Trial Investigators.  Primary results of SCOPE. Presented at: International Society of Hypertension; June 27, 2002; Prague, Czech Republic.
Hansson L, Lithell H, Skoog I.  et al.  Study on Cognition and Prognosis in the Elderly (SCOPE).  Blood Press.1999;8:177-183.
Barraclough M, Joy MD, MacGregor GA.  et al.  Control of moderately raised blood pressure: report of a co-operative randomized controlled trial.  BMJ.1973;3:434-436.
Hypertension-Stroke Cooperative Study Group.  Effect of antihypertensive treatment on stroke recurrence.  JAMA.1974;229:409-418.
Smith WM. Treatment of mild hypertension: results of a ten-year intervention trial.  Circ Res.1977;40(5 suppl 1):I98-I105.
Perry Jr HM, Goldman AI, Lavin MA.  et al.  Evaluation of drug treatment in mild hypertension: VA-NHLBI feasibility study.  Ann N Y Acad Sci.1978;304:267-288.
 The Australian therapeutic trial in mild hypertension: report by the Management Committee  Lancet.1980;1:1261-1267.
Kuramoto K, Matsushita S, Kuwajima I, Murakami M. Prospective study on the treatment of mild hypertension in the aged.  Jpn Heart J.1981;22:75-85.
Amery A, Birkenhager W, Brixko P.  et al.  Mortality and morbidity from the European Working Party on High Blood Pressure in the Elderly trial.  Lancet.1985;1:1349-1354.
Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care.  BMJ.1986;293:1145-1151.
Wilhelmsen L, Berglund G, Elmfeldt D.  et al.  Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial.  J Hypertens.1987;5:561-572.
Perry Jr MH, Smith WM, McDonald RH.  et al.  Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) pilot study.  Stroke.1989;20:4-13.
SHEP Cooperative Research Group.  Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP).  JAMA.1991;265:3255-3264.
Kostis JB, Davis BR, Cutler J.  et al.  Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension.  JAMA.1997;278:212-216.
Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension).  Lancet.1991;338:1281-1285.
Medical Research Council Working Party.  Medical Research Council trial of treatment of hypertension in older adults: principal results.  BMJ.1992;304:405-412.
The Dutch TIA Trial Study Group.  Trial of secondary prevention with atenolol after transient ischemic attack or nondisabling ischemic stroke.  Stroke.1993;24:543-548.
PATS Collaborating Group.  Post-Stroke Antihypertensive Treatment Study: a preliminary report.  Chin Med J (Engl).1995;108:710-717.
Eriksson S, Olofsson BO, Wester PO.for the TEST study group.  Atenolol in secondary prevention after stroke.  Cerebrovasc Dis.1995;5:21-25.
Borhani NO, Mercuri M, Borhani PA.  et al.  Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): a randomized controlled trial.  JAMA.1996;276:785-791.
Staessen JA, Fagard R, Thijs L.  et al. , for the Systolic Hypertension in Europe Trial Investigators.  Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.  Lancet.1997;350:757-764.
Staessen JA, Thijs L, Birkenhager WH, Bulpitt CJ, Fagard R. Update on the Systolic Hypertension in Europe (SYST-EUR) Trial.  Hypertension.1999;33:1476-1477.
Rosei EA, Dal Palu C, Leonetti G.  et al. , for the VHAS Investigators.  Clinical results of the Verapamil in Hypertension and Atherosclerosis Study.  J Hypertens.1997;15:1337-1344.
Estacio RO, Jeffers BW, Hiatt MR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.  N Engl J Med.1998;338:645-652.
Schrier RW, Estacio RO. Additional follow-up from the ABCD trial in patients with type 2 diabetes and hypertension.  N Engl J Med.2000;343:1969.
Tatti P, Pahor M, Byington RP.  et al.  Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) in patients with hypertension and non-insulin dependent diabetes mellitus.  Diabetes Care.1998;21:597-603.
UK Prospective Diabetes Study Group.  Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.  BMJ.1998;317:703-713.
UK Prospective Diabetes Study Group.  Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39.  BMJ.1998;317:713-720.
National Intervention Cooperative Study in Elderly Hypertensives Study Group.  Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives.  Hypertension.1999;34:1129-1133.
Agodoa LY, Appel L, Bakris GL.  et al.  Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis.  JAMA.2001;285:2719-2728.
Wright Jr JT, Bakris G, Green T.  et al.  Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.  JAMA.2002;288:2421-2431.
Wright J.for the AASK Study Group Investigators.  The African-American Study of Kidney Disease and Hypertension. Presented at: American Society of Hypertension; May 18, 2002; New York, NY.
PROGRESS Collaborative Group.  Randomised trial of perindopril-based blood pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack.  Lancet.2001;358:1033-1041.
Parving HH, Lehnert H, Brochner-Mortensen J.  et al. , for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study.  The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.  N Engl J Med.2001;345:870-878.
Lewis EJ, Hunsicker LG, Clarke WR.  et al.  Renoprotective effect of angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.  N Engl J Med.2001;345:851-860.
The ANBP2 Investigators.  Primary results of the Australian National Blood Pressure 2 Trial. Presented at: International Society of Hypertension; June 23-27, 2002; Prague, Czech Republic.
Wing LMH, Reid CM, Ryan P.  et al. for the Second Australian National Blood Pressure Study Group.  A comparison of outomces with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly.  N Engl J Med.2003;348:583-592.
Black HR, Grimm J RH, Hansson L.  et al.  Controlled Onset Verapamil Investigation of Cardiovascular Endpoints: CONVINCE primary results. Presented at: American Society of Hypertension; May 18, 2002; New York, NY.
Zanchetti Z, Bond G, Hennig M.  et al.  Calcium antagonist lacidipine slows down progression of asymptomatic caroitd atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA): a randomized, double-blind, long-term trial.  Circulation.2002;106:2422-2427.
Sewester CS, Dombek CE, Olin BR, Scott JA, Hebel SK, Novak KK, eds . Drug Facts and Comparisons. St Louis, Mo: Wolters Kluwer Co; 1996.
Berlin JA, Laird NM, Sacks HS, Chalmers TC. A comparison of statistical methods for combining event rates from clinical trials.  Stat Med.1989;8:141-151.
Bucher HC, Guyatt GH, Griffith LE, Walter SD. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials.  J Clin Epidemiol.1997;50:683-691.
Ekbom T, Dahlof B, Hansson L, Lindholm SH, Schersten B, Wester PO. Antihypertensive efficacy and side effects of three betα-blockers and a diuretic in elderly hypertensives: a report from the STOP-Hypertension study.  J Hypertens.1992;10:1525-1530.
Alderman MH, Furberg CD, Kostis JB.  et al.  Hypertension guidelines: criteria that might make them more clinically useful.  Am J Hypertens.2002;15:917-923.
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Heidenreich PA, McDonald KM, Hastie T.  et al.  Meta-analysis of trials comparing β-blockers, calcium antagonists, and nitrates for stable angina.  JAMA.1999;281:1927-1936.
Heidenreich PA, Lee TT, Massie BM. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials.  J Am Coll Cardiol.1997;30:27-34.
Lechat P, Packer M, Chalon S, Cucherat M, Arab T, Boissel JP. Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials.  Circulation.1998;98:1184-1191.
Task Force on the Management of Stable Angina Pectoris.  Management of stable angina pectoris: recommendations of the Task Force of the European Society of Cardiology.  Eur Heart J.1997;18:394-413.
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Ryan TJ, Antman EM, Brooks NH.  et al.  1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations.  Circulation.1999;100:1016-1030.
Braunwald E, Antman EM, Beasley JW.  et al.  ACC/AHA guidelines for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction: executive summary and recommendations.  Circulation.2000;102:1193-1209.
Williams SV, Fihn SD, Gibbons RJ. Guidelines for the management of patients with chronic stable angina: diagnosis and risk stratification.  Ann Intern Med.2001;135:530-547.
The Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med.2000;342:145-153.
Flather MD, Yusuf S, Kober L.  et al. , for the ACE-Inhibitor Myocardial Infarction Collaborative Group.  Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients.  Lancet.2000;355:1575-1581.
Garg R, Yusuf S.for the Collaborative Group on ACE Inhibitor Trials.  Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure.  JAMA.1995;273:1450-1456.
Pahor M, Psaty BM, Alderman MH, Applegate WB, Williamson JD, Furberg CD. Therapeutic benefits of ACE inhibitors and other antihypertensive drugs in patients with type 2 diabetes.  Diabetes Care.2000;23:888-892.
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Blackwelder WC, Chang MA. Sample size graphs for "proving the null hypothesis".  Control Clin Trials.1984;5:97-105.
Neaton JD, Grimm Jr RH, Prineas RJ.  et al. , for the Treatment of Mild Hypertension Research Group.  Treatment of Mild Hypertension Study (TOMHS): final results.  JAMA.1993;270:713-724.

Figures

Figure 1. Network Meta-analysis of First-Line Antihypertensive Drug Treatments
Graphic Jump Location
Each first-line drug treatment is a node in the network. The links between the nodes are trials or pairs of trial arms. The numbers along the link lines indicate the number of trials or pairs of trial arms for that link in the network. Reference numbers indicate the trials contributing to each link. A trial such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial12,15 (ALLHAT) with multiple arms appears along several links (diuretics-angiotensin-converting enzyme (ACE) inhibitors, diuretics-calcium channel blockers (CCBs), ACE inhibitors-CCBs, and diuretics-α-blockers). High-dose diuretic trials were excluded.
Figure 2. Network Meta-analysis of First-Line Treatment Strategies in Randomized Controlled Clinical Trials in Hypertension
Graphic Jump Location
Asterisks, placed after the closed parentheses of the 95% CI, indicate that β-blockers (P<.05), angiotensin-converting enzyme inhibitors (P<.05), calcium channel blockers (P<.05), and angiotensin-receptor blockers (P<.05) were significantly better than placebo for that outcome. α-Blockers were not significantly better than placebo for any outcome (P>.05). CHD indicates coronary heart disease; CHF, congestive heart failure; CI, confidence interval; CVD, cardiovascular disease; and RR, relative risk.

Tables

Table Graphic Jump LocationTable 1a. Cardiovascular Events and Outcomes by Randomized Treatment
Table Graphic Jump LocationTable 2. Fixed and Random Effects Meta-analysis Comparing any Antihypertensive Drug Treatment vs No Treatment for Each Outcome*
Table Graphic Jump LocationTable 3. ALLHAT vs Meta-analysis* of the Other Direct and Indirect Evidence Comparisons of Calcium Channel Blockers and Angiotensin-Converting Enzyme Inhibitors With Low-Dose Diuretics
Table Graphic Jump LocationTable 5. Change in Systolic and Diastolic Blood Pressures for Each Drug Class Compared With Low-Dose Diuretics*

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Collins R, Peto R, MacMahon S.  et al.  Blood pressure, stroke, and coronary heart disease, part 2: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiologic context.  Lancet.1990;335:827-838.
Mulrow CD, Cornell JA, Herrera CR, Kadri A, Farnett L, Aguilar C. Hypertension in the elderly: implications and generalizability of randomized trials.  JAMA.1994;272:1932-1938.
Hebert PR, Moser M, Mayer J, Glynn RJ, Hennekens CH. Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease.  Arch Intern Med.1993;153:578-581.
Cutler JA, Psaty BM, MacMahon S, Furberg CD. Public health issues in hypertension control: what has been learned from clinical trials. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York, NY: Raven Press; 1995:253-279.
Carter AB. Hypotensive therapy in stroke survivors.  Lancet.1970;1:485-489.
Hegeland A. Treatment of mild hypertension: a five-year controlled drug trial: the Oslo Study.  Am J Med.1980;69:725-732.
Liu L, Wang JG, Gong L.  et al.  Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension.  J Hypertens.1998;16:1823-1829.
Multiple Risk Factor Intervention Trial Research Group.  Multiple Risk Factor Intervention Trial: risk factor changes and mortality results.  JAMA.1982;248:1465-1477.
Miettinen TA, Huttunen JK, Naukkarinen V.  et al.  Multifactorial primary prevention of cardiovascular diseases in middle-aged men: risk factor changes, incidence and mortality.  JAMA.1985;254:2097-2102.
Wolff FW, Lindeman RD. Effects of treatment in hypertension: results of a controlled study.  J Chronic Dis.1966;19:227-240.
Sprackling ME, Mitchell JRA, Short AH, Watt G. Blood pressure reduction in the elderly: a randomised controlled trial of methyldopa.  BMJ.1981;283:1151-1153.
The IPPPSH Collaborative Group.  Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH).  J Hypertens.1985;3:379-392.
SCOPE Trial Investigators.  Primary results of SCOPE. Presented at: International Society of Hypertension; June 27, 2002; Prague, Czech Republic.
Hansson L, Lithell H, Skoog I.  et al.  Study on Cognition and Prognosis in the Elderly (SCOPE).  Blood Press.1999;8:177-183.
Barraclough M, Joy MD, MacGregor GA.  et al.  Control of moderately raised blood pressure: report of a co-operative randomized controlled trial.  BMJ.1973;3:434-436.
Hypertension-Stroke Cooperative Study Group.  Effect of antihypertensive treatment on stroke recurrence.  JAMA.1974;229:409-418.
Smith WM. Treatment of mild hypertension: results of a ten-year intervention trial.  Circ Res.1977;40(5 suppl 1):I98-I105.
Perry Jr HM, Goldman AI, Lavin MA.  et al.  Evaluation of drug treatment in mild hypertension: VA-NHLBI feasibility study.  Ann N Y Acad Sci.1978;304:267-288.
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Kuramoto K, Matsushita S, Kuwajima I, Murakami M. Prospective study on the treatment of mild hypertension in the aged.  Jpn Heart J.1981;22:75-85.
Amery A, Birkenhager W, Brixko P.  et al.  Mortality and morbidity from the European Working Party on High Blood Pressure in the Elderly trial.  Lancet.1985;1:1349-1354.
Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care.  BMJ.1986;293:1145-1151.
Wilhelmsen L, Berglund G, Elmfeldt D.  et al.  Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial.  J Hypertens.1987;5:561-572.
Perry Jr MH, Smith WM, McDonald RH.  et al.  Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) pilot study.  Stroke.1989;20:4-13.
SHEP Cooperative Research Group.  Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP).  JAMA.1991;265:3255-3264.
Kostis JB, Davis BR, Cutler J.  et al.  Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension.  JAMA.1997;278:212-216.
Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension).  Lancet.1991;338:1281-1285.
Medical Research Council Working Party.  Medical Research Council trial of treatment of hypertension in older adults: principal results.  BMJ.1992;304:405-412.
The Dutch TIA Trial Study Group.  Trial of secondary prevention with atenolol after transient ischemic attack or nondisabling ischemic stroke.  Stroke.1993;24:543-548.
PATS Collaborating Group.  Post-Stroke Antihypertensive Treatment Study: a preliminary report.  Chin Med J (Engl).1995;108:710-717.
Eriksson S, Olofsson BO, Wester PO.for the TEST study group.  Atenolol in secondary prevention after stroke.  Cerebrovasc Dis.1995;5:21-25.
Borhani NO, Mercuri M, Borhani PA.  et al.  Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS): a randomized controlled trial.  JAMA.1996;276:785-791.
Staessen JA, Fagard R, Thijs L.  et al. , for the Systolic Hypertension in Europe Trial Investigators.  Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.  Lancet.1997;350:757-764.
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