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

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
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.

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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.

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