Background
Hypertension is a modifiable cardiovascular risk factor. Although it is established that low-dose thiazides reduce mortality as well as cardiovascular morbidity, the dose-related effect of thiazides in decreasing blood pressure has not been subject to a rigorous systematic review. It is not known whether individual drugs within the thiazide diuretic class differ in their blood pressure-lowering effects and adverse effects.

Objectives
To determine the dose-related decrease in systolic and/or diastolic blood pressure due to thiazide diuretics compared with placebo control in the treatment of patients with primary hypertension. Secondary outcomes included the dose-related adverse events leading to patient withdrawal and adverse biochemical effects on serum potassium, uric acid, creatinine, glucose and lipids.

Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1), Ovid MEDLINE (1946 to February 2014), Ovid EMBASE (1974 to February 2014) and ClinicalTrials.gov.

Selection criteria
We included double-blind, randomized controlled trials (RCTs) comparing fixed-dose thiazide diuretic monotherapy with placebo for a duration of 3 to 12 weeks in the treatment of adult patients with primary hypertension.

Data collection and analysis
Two authors independently screened articles, assessed trial eligibility, extracted data and determined risk of bias. We combined data for continuous variables using a mean difference (MD) and for dichotomous outcomes we calculated the relative risk ratio (RR) with 95% confidence interval (CI).

Main results
We included 60 randomized, double-blind trials that evaluated the dose-related trough blood pressure-lowering efficacy of six different thiazide diuretics in 11,282 participants treated for a mean duration of eight weeks. The mean age of the participants was 55 years and baseline blood pressure was 158/99 mmHg. Adequate blood pressure-lowering efficacy data were available for hydrochlorothiazide, chlorthalidone and indapamide. We judged 54 (90%) included trials to have unclear or high risk of bias, which impacted on our confidence in the results for some of our outcomes.

In 33 trials with a baseline blood pressure of 155/100 mmHg, hydrochlorothiazide lowered blood pressure based on dose, with doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg/day lowering blood pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderate-quality evidence)/2 mmHg (95% CI 1 to 4, moderate-quality evidence), 6 mmHg (95% CI 5 to 7, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence), 8 mmHg (95% CI 7 to 9, high-quality evidence)/3 mmHg (95% CI 3 to 4, high-quality evidence) and 11 mmHg (95% CI 6 to 15, low-quality evidence)/5 mmHg (95% CI 3 to 7, low-quality evidence), respectively.

Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available: bendrofluazide, chlorthalidone, cyclopenthiazide, metolazone or indapamide.

In seven trials with a baseline blood pressure of 163/88 mmHg, chlorthalidone at doses of 12.5 mg to 75 mg/day reduced average blood pressure compared to placebo by 12.0 mmHg (95% CI 10 to 14, low-quality evidence)/4 mmHg (95% CI 3 to 5, low-quality evidence).

In 10 trials with a baseline blood pressure of 161/98 mmHg, indapamide at doses of 1.0 mg to 5.0 mg/day reduced blood pressure compared to placebo by 9 mmHg (95% CI 7 to 10, low-quality evidence)/4 (95% CI 3 to 5, low-quality evidence).

We judged the maximal blood pressure-lowering effect of the different thiazides to be similar. Overall, thiazides reduced average blood pressure compared to placebo by 9 mmHg (95% CI 9 to 10, high-quality evidence)/4 mmHg (95% CI 3 to 4, high-quality evidence).

Thiazides as a class have a greater effect on systolic than on diastolic blood pressure, therefore thiazides lower pulse pressure by 4 mmHg to 6 mmHg, an amount that is greater than the 3 mmHg seen with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors, and the 2 mmHg seen with non-selective beta-blockers. This is based on an informal indirect comparison of results observed in other Cochrane reviews on ACE inhibitors, ARBs and renin inhibitors compared with placebo, which used similar inclusion/exclusion criteria to the present review.

Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides. These effects were dose-related and were least for hydrochlorothiazide. Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides. There is a high risk of bias in the metabolic data. This review does not provide a good assessment of the adverse effects of these drugs because there was a high risk of bias in the reporting of withdrawals due to adverse effects.

Authors' conclusions
This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect. The mean blood pressure-lowering effect over the dose range 6.25 mg, 12.5 mg, 25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure, thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews, which compared these antihypertensive drug classes with placebo and used similar inclusion/exclusion criteria.

Thiazides did not increase withdrawals due to adverse effects in these short-term trials but there is a high risk of bias for that outcome. Thiazides reduced potassium, increased uric acid and increased total cholesterol and triglycerides.

Blood pressure‐lowering efficacy of monotherapy with thiazide diuretics for primary hypertension

Objective Hypertension guidelines recommend initial treatment with a β-blocker or diuretic and adding the other drug where blood pressure is not controlled. We hypothesized that systematic rotation through the major classes of antihypertensive drugs would demonstrate substantial differences in the p

Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs.

Hypertension: which beta-blocker?

Synopsis: Atenolol1 is a β1-selective (cardioselective) adrenoceptor blocking drug without partial agonist or membrane stabilising activity. Its profile of action most closely resembles that of metoprolol which differs only in that it has some membrane stabilising activity. Atenolol has been well studied and is effective in the treatment of hypertension and in the prophylactic management of angina. Its narrow dose response range obviates the need for highly individualised dose titration. In patients with angina its long duration of β-blocking activity allows once daily dosage, whereas other β-blockers, unless in sustained release dosage forms, need to be given in divided doses. Other β-blockers can be given once daily in hypertension, but at present the evidence for effective control with a once daily regimen is more convincing with atenolol. Further studies are needed to clarify any important differences in blood pressure control between the various β-blocking drugs, both in conventional or sustained release dosage forms. As with metoprolol, atenolol is preferable to non-selective β-blockers in patients with asthma or diabetes mellitus. Atenolol has been well tolerated in most patients, its profile of adverse reactions generally resembling that of other β-blocking drugs, although its low lipid solubility and limited penetration into the brain results in a lower incidence of central nervous system effects than seen with propranolol. Atenolol is eliminated virtually entirely as unchanged drug in the urine and dosage needs to be reduced in patients with moderate to severely impaired renal function (glomerular filtration rate less than 30ml/min). There is no need for modification of dosage of atenolol in liver disease.

Atenolol: A Review of its Pharmacological Properties and Therapeutic Efficacy in Angina Pectoris and Hypertension

Clinical pharmacology of the new beta-adrenergic blocking drugs. Part 3. Comparative clinical experience and new therapeutic applications.

The antihypertensive effect of the new beta-blocker, ICI 66,082 was studied in 37 patients with renal or essential hypertension. A daily dose of 75 mg produced a significant antihypertensive effect and a further blood pressure decrease was obtained by increasing the daily dose up to 300 mg; at this treatment level, the antihypertensive effect averaged 29.4/24.0 mm Hg. Increasing the dose from 300 to 600 mg daily did not produce a significant additional blood pressure decrease. Six of the 37 patients retained fluid, producing a loss in the antihypertensive effect. No significant correlation was found between the percentage systolic blood pressure fall and the following parameters determined before therapy: systolic blood pressure and its variability, heart rate (at rest and after stimulation by exercise or isoproterenol), cardiac output and total peripheral resistance, renin concentration (at rest and after stimulation) and urinary excretion of catecholamines and derivates.

Predictive value of various parameters for the antihypertensive effect of the beta blocker ICI 66,082 (1).

Fifty-five patients with mild to moderate, renal or essential hypertension were admitted to a double blind cross-over trial of 18 weeks, involving treatment periods with placebo, the thiazide bendrofluazide (15 mg daily) and the beta blocker atenolol (600 mg daily). Compared to the placebo period (190/117 mm Hg) the hypotensive effect of atenolol (-24/16 mm Hg) was more pronounced than the hypotensive effect of bendrofluazide (-17/6 mm Hg). Arguments in favor of initiating antihypertensive drug therapy with beta blocker were its more powerful hypotensive effect, the quicker onset of its action, less metabolic disturbance, decreased frequency of complaints and patient's preference. On thiazides body weight and the frequency of swollen ankles decreased. Plasma renin concentration was not found to have a strong predicting power for the hypotensive effect of atenolol or bendrofluazide but low renin patients showed a more pronounced blood pressure decrease on bendrofluazide and high renin patients, especially essential hypertensives, on atenolol. While these points can be a guide to therapy today, the preference of one drug over the other must eventually be based on their relative efficacy in decreasing morbidity and mortality from the hypertensive disease.

Missotten A

Papers

Predictive value of various parameters for the antihypertensive effect of the beta blocker ICI 66,082 (1).

Relative value of beta blockers and thiazides for initiating antihypertensive therapy. Beta blockers or thiazides in hypertension.