Low-dose diuretics, low-dose beta blockers, or low-dose combined still recommended
3-2 HEALTH OUTCOMES ASSOCIATED WITH ANTIHYPERTENSIVE THERAPIES USED AS FIRST-LINE AGENTS:
A Systematic review and meta-analysis The 1988 guidelines (JNC-IV) recommended diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium channel blockers (CCB) as first-line agents. In 1993, based on long-term clinical trials, JNV-V reversed this position and recommended low-dose diuretics and beta-blockers as first choice agents unless they are contraindicated or unacceptable, or unless there are special indications for other agents.
The recommendation has been controversial. ACE inhibitors and CCBs are widely used as initial therapy for hypertension.
This review selected studies that evaluated antihypertensive therapies in terms of their ability to prevent stroke and myocardial infarction. (Ie, major disease end points rather than surrogate end-points such as reduction of BP.) Even a well-designed surrogate end point trial may give misleading results from the standpoint of important health outcomes.
Conclusion: Low-dose diuretics and low-dose beta-blockers are recommended as first-line therapy.

STUDY
1. Literature search 1980-95 selected long-term studies that assessed major disease end points as an outcome. In terms of the scientific evidence regarding health outcomes, which antihypertensive therapies qualify to be used routinely and widely as first-line antihypertensive agents?

RESULTS
1. Diuretics and beta-blockers have been evaluated in 18 long-term randomized trials. (Over 45,000 patients; average follow-up-5 years).

2. Relative risks compared with placebo:

3. Although CCBs and ACE inhibitors reduce BP, the clinical trial evidence in terms of health outcomes is meager. (No long-term, randomized clinical trials have been designed to evaluate major disease end points as the primary outcome.) For several short-acting dihydropyridine CCBs, the available evidence suggests the possibility of harm.
4. Whether the long-acting formulations and the nondihydropyridine calcium channel blockers are safe and prevent major cardiovascular events in patients with hypertension remains untested and therefore unknown.

DISCUSSION

1. Nondihydropyridine calcium channel blockers (CCBs) have been advocated for use in patients with coronary disease. Calcium-channel blocking agents have not been shown to reduce mortality after acute MI. It is the consensus of a committee of the American College of Cardiology (1996) that CCBs are still used too frequently in patients with acute MI. Beta- blocking agents are a more appropriate choice across the broad spectrum of patients. The evidence of benefit for for beta-blockers is more extensive and compelling.
2. The purpose of therapy is to reduce complications of untreated hypertension. As a result many patients must receive long-term therapy so that a few may avoid or delay cardiovascular events.
3. Inexpensive diuretics and beta-blockers have been proven to be both safe and effective in long-term, randomized clinical trials. "Recent studies have also given us a new appreciation for the importance of low-dose diuretic therapy for the prevention of coronary disease as well as stroke in patients with hypertension."
4. The clinical rationale for withholding safe, effective, and proven therapies must be compelling.

CONCLUSION
"Until the results of large long-term clinical trials evaluating the effects of calcium channel blockers and ACE inhibitors of cardiovascular disease incidence are completed, the available scientific evidence provides strong support for the current national guidelines, which recommend diuretics and beta-blockers as first-line agents and low-dose therapy for all antihypertensive agents."
JAMA March 5, 1997; 277 Review article, first author from Univ. Of Washington, Seattle

Comment:
This review was written by some of the same investigators who ran up a red flag concerning short-acting CCBs.
Many randomized controlled trials use surrogate end points (eg. BP, cholesterol, body mass index). This data is not conclusive. RTJ

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