Back to basics: diuretics as first-line agents in the treatment of hypertension.

PURPOSE: To compare the safety and efficacy of low-dose diuretics with those of five active first-line therapies for major cardiovascular disease (CVD) endpoints and all-cause mortality. BACKGROUND: Hypertension has an estimated prevalence of 71% in older black Americans, 61% in older Hispanics, and 60% in older white patients. 1 Large trials of patients aged 60 and older have shown that antihypertensive drug therapy reduces stroke, coronary heart disease, CVD, heart failure, and mortality. 2,3 In the last decade there has been an explosion in the number of agents available for treating hypertension. The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure in 1993 and again in 1997 recommended low-dose diuretics and beta-blockers as first-line treatment for patients with uncomplicated hypertension. The recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) addressed first-line therapy. This study was designed to determine whether newer agents are better than low-dose diuretics at reducing the major cardiovascular complications of hypertension. 4 Low-dose diuretics were compared with amlodipine, lisinopril, and doxazosin. Low-dose diuretics and doxazosin had the same blood pressure lowering effect, but the doxazosin arm was terminated early because of a 25% increased risk for major cardiovascular events. This study emphasizes that choice of medication is important because drugs may have actions that enhance or diminish their blood-pressure-lowering effects. This meta-analysis underscores the fact that lowering of blood pressure is not an adequate surrogate for assessing the effect of a drug on other important clinical outcomes. Although choice of an agent may depend on concomitant illnesses, antihypertensive agents used as first-line therapy need to be reassessed. METHODS: Medline searches, previous meta-analyses, and journal reviews from January 1995 through December 2002 were used as data sources. They identified studies designed to evaluate the effects of antihypertensive therapies on the occurrence of cardiovascular morbidity and mortality. The search was not restricted by language. The studies selected were randomized, controlled trials that evaluated major CVD endpoints in hypertensive patients over the course of at least 1 year. Trials that recruited patients with congestive heart failure (CHF) or myocardial infarction (MI) were excluded. The studies in the analysis were confined to those using the six most commonly used antihypertensive classes (diuretics, beta-blockers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and alpha-blockers). First-line treatment was always clearly identified. Treatment had to be unconfounded by other therapy such as smoking cessation and lipid lowering. Outcome measures were coronary heart disease (CHD) and CVD. CHD included fatal and nonfatal MI, stroke, CHF, and fatal CHD. CVD events included CHD, stroke, CHF, and other CVD mortality. Two of the authors extracted data independently, and differences were resolved by consensus. There were 42 trials, which included 192,478 patients followed for an average of 3 to 4 years. Outcomes were assessed using network meta-analyses, which preserves the within trial randomized comparison of each study and combines all available comparisons between treatments. MAIN RESULTS: