Assessed as up to date: 2009/03/31

Background
Sustained elevated blood pressure, unresponsive to lifestyle measures, leads to a critically important clinical question: What class of drug to use first-line? This review answers that question.

Objectives
Primary objective: To quantify the benefits and harms of the major first-line anti-hypertensive drug classes: thiazides, beta-blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, alpha-blockers, and angiotensin II receptor blockers (ARB).

Search strategy
Electronic search of MEDLINE (Jan. 1966-June 2008), EMBASE, CINAHL, the Cochrane clinical trial register, using standard search strategy of the hypertension review group with additional terms.

Selection criteria
Randomized trials of at least one year duration comparing one of 6 major drug classes with a placebo or no treatment. More than 70% of people must have BP >140/90 mmHg at baseline.

Data collection and analysis
The outcomes assessed were mortality, stroke, coronary heart disease (CHD), cardiovascular events (CVS), decrease in systolic and diastolic blood pressure, and withdrawals due to adverse drug effects. Risk ratio (RR) and a fixed effects model were used to combine outcomes across trials.

Main results
Of 57 trials identified, 24 trials with 28 arms, including 58,040 patients met the inclusion criteria.
Thiazides (19 RCTs) reduced mortality (RR 0.89, 95% CI 0.83, 0.96), stroke (RR 0.63, 95% CI 0.57, 0.71), CHD (RR 0.84, 95% CI 0.75, 0.95) and CVS (RR 0.70, 95% CI 0.66, 0.76). Low-dose thiazides (8 RCTs) reduced CHD (RR 0.72, 95% CI 0.61, 0.84), but high-dose thiazides (11 RCTs) did not (RR 1.01, 95% CI 0.85, 1.20).
Beta-blockers (5 RCTs) reduced stroke (RR 0.83, 95% CI 0.72, 0.97) and CVS (RR 0.89, 95% CI 0.81, 0.98) but not CHD (RR 0.90, 95% CI 0.78, 1.03) or mortality (RR 0.96, 95% CI 0.86, 1.07).
ACE inhibitors (3 RCTs) reduced mortality (RR 0.83, 95% CI 0.72-0.95), stroke (RR 0.65, 95% CI 0.52-0.82), CHD (RR 0.81, 95% CI 0.70-0.94) and CVS (RR 0.76, 95% CI 0.67-0.85).
Calcium-channel blocker (1 RCT) reduced stroke (RR 0.58, 95% CI 0.41, 0.84) and CVS (RR 0.71, 95% CI 0.57, 0.87) but not CHD (RR 0.77 95% CI 0.55, 1.09) or mortality (RR 0.86 95% CI 0.68, 1.09). No RCTs were found for ARBs or alpha-blockers.

Authors' conclusions
First-line low-dose thiazides reduce all morbidity and mortality outcomes. First-line ACE inhibitors and calcium channel blockers may be similarly effective but the evidence is less robust. First-line high-dose thiazides and first-line beta-blockers are inferior to first-line low-dose thiazides.

Author(s)
Wright James M, Musini Vijaya M

Thiazides best first choice for hypertension
One of the most important decisions in treating people with elevated blood pressure is what drug class is used first. This decision has enormous consequences in terms of health outcomes and cost. In this review health outcomes resulting from 4 drug classes are summarized. Most of the evidence demonstrated that first-line low-dose thiazides reduce mortality and morbidity (stroke, heart attack and heart failure). No other drug class improved health outcomes better than low-dose thiazides, and beta-blockers and high-dose thiazides were inferior. Low-dose thiazides should be the first choice drug in most patients with elevated blood pressure. Fortunately, thiazides are also very inexpensive.

Implications for practice
Choice of first-line treatment, morbidity and mortality evidence versus placebo or no treatment.

• Most of the available evidence justifying treatment of patients with elevated blood pressure used a thiazide as the first-line drug.
• First-line low-dose thiazides are more effective than first-line high-dose thiazides and first-line beta-blockers.
• Evidence for first-line ACE inhibitors is similar to low-dose thiazides but less robust and ACE inhibitors are more expensive than thiazides.
• Evidence for first-line calcium channel blockers is insufficient.
• There are no RCTs comparing first-line use of other classes of drugs such as angiotensin receptor blockers or alpha blockers.
• Morbidity and mortality benefit depends on the drug class received, not the BP achieved.

Blood pressure measurement.

• Blood pressure must be measured (average of multiple readings) using proper technique with patient non-stimulated and resting for at least five minutes.

Population.

• Moderate evidence for secondary prevention, survivors of TIA, stroke or myocardial infarction age 55 to 80 years, BP ≧ 140/90 mmHg.
• Good evidence for primary prevention adult patients with moderate to severe hypertension, BP ≧ 160/100 mmHg.
• Weak evidence for primary prevention adult patients with mild hypertension BP < 160/100 and ≧140/90 mmHg.
• BP targets are only achieved in about 60% of patients with mild, moderate and severe hypertension treated with stepped care antihypertensive drugs.

Implications for research
At the present time RCT data versus placebo or no treatment is lacking for all classes other than thiazides as first-line treatment. Since we have clear evidence of effectiveness of first-line low dose thiazides in primary prevention patients with blood pressure of ≧ 160/100 mmHg and secondary prevention patients with lower BPs, it would be unethical to do further trials for this population compared to a placebo or untreated control group. Future RCTs in these populations should be done with low-dose first-line thiazides as the comparison group. The benefits and harms of treatment of primary prevention patients with lower blood pressures remains uncertain at the present time. Large trials recruiting primary prevention patients in lower blood pressure categories and using first-line low-dose thiazides compared to placebo are needed.


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