Abstract-Hydrochlorothiazide (HCTZ) is widely used for hypertension, and prescriptions for HCTZ outnumber those for chlorthalidone (CTDN) by Ͼ20-fold in 2 recent surveys. Some have recently expressed a preference for CTDN. However, head-to-head trials testing the effect of the 2 drugs on cardiovascular events (CVEs) are lacking. We conducted a systematic review of randomized trials in which 1 arm was based on either HCTZ or CTDN followed by 2 types of network meta-analyses, a drug-adjusted analysis and an office systolic blood pressure-adjusted analysis. Nine trials were identified: 3 based on HCTZ and 6 based on CTDN. In the drug-adjusted analysis (nϭ50 946), the percentage of risk reduction in congestive heart failure for CTDN versus HCTZ was 23 (95% CI, 2-39; Pϭ0.032); and in all CVEs was 21 (95% CI, 12-28; PϽ0.0001). In the office systolic blood pressure-adjusted analysis (nϭ78 350), the percentage of risk reduction in CVEs for CTDN versus HCTZ was 18 (95% CI, Pϭ0.024). When the reduction in office systolic blood pressure was identical in the 2 arms, the risk for CVEs in HCTZ arms was 19% higher than in its nondiuretic comparator arms (Pϭ0.021). Relative to HCTZ, the number needed to treat with CTDN to prevent 1 CVE over 5 years was 27. In conclusion, CTDN is superior to HCTZ in preventing cardiovascular events. This cannot be attributed entirely to the lesser effect of HCTZ on office systolic blood pressure but may be attributed to the pleomorphic effects of alternative medications or to the short duration of action of HCTZ. Pharmaceutical preparations of the 2 drugs differ. HCTZ is available in 12.5-mg and 25.0-mg tablets and in 19 combination tablets, whereas CTDN is commonly available only in an unscored 25-mg tablet, an excessive dose in many patients, and in only 3 combination tablets, including atenolol, clonidine, and azilsartan. In light of the practical features of HCTZ, 2 there were 134 million prescriptions (solo or as a combination tablet) in 2007. 3 HCTZ is the 10th most commonly prescribed drug in the United States, with 48 million solo prescriptions annually from 2006 through 2010. 4 In 2 recent surveys, one in the United States and the other in Germany, HCTZ prescriptions outnumbered those for CTDN by Ͼ20-fold. 5,6 In the last several years, some have compared the drugs pharmacologically and have recommended CTDN rather than HCTZ. 3,[7][8][9][10][11][12] Two recent reanalyses of Multiple Risk Factor Intervention Trial (MRFIT) data have found CTDN to be superior to HCTZ in reducing cardiovascular events (CVEs) 13 and left ventricular hypertrophy. 14 However, no randomized, controlled trials have compared the 2 medications head to head with respect to CVEs. To examine whether 1 drug was superior over the other in reducing CVEs, we undertook a systematic review of randomized, controlled trials with either HCTZ or CTDN as the step 1 agent and then conducted 2 different types of network analyses.
MethodsPreferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines were followed th...