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
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
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