- Jennifer Middleton, MD, MPH
Even though hydrochlorothiazide (HCTZ) was the 10th most commonly prescribed drug in the US in 2010, an FPIN Help Desk Answers article in the current issue of AFP argues in favor of chlorthalidone over HCTZ, as does a 2008 AFP editorial. Although some studies have found HCTZ and chlorthalidone's effects on cardiovascular mortality to be equivalent, some studies have found chlorthalidone to be more effective.
The AFP FPIN Help Desk article reviews two systematic reviews and one randomized controlled trial (RCT) comparing HCTZ and chlorthalidone for reduction of coronary heart disease (CHD) events. The first systematic review and the RCT both showed greater blood pressure lowering with chlorthalidone compared with HCTZ, but neither measured cardiovascular outcomes. The second systematic review included a network analysis comparing outcomes from studies that used chlorthalidone to studies that used HCTZ. Those researchers found that the number needed to treat (NNT) with chlorthalidone instead of HCTZ to prevent 1 additional cardiovascular death over 5 years was 27.
Some cohort studies have found chlorthalidone non-inferior to – and potentially more hazardous than – HCTZ. A 2013 prospective cohort study conducted in Canada found no difference in cardiovascular outcomes but a higher risk of hospitalization for hypokalemia; interestingly, patients on chlorthalidone were more likely to be on a beta-blocker than those on HCTZ because of a combination pill on the Canadian formulary. A retrospective cohort study reviewed by AFP in 2013 found equivalent outcomes between patients treated with chlorthalidone versus those treated with HCTZ.
These cohort studies showing equivalence between chlorthalidone and HCTZ, along with concern for more hypokalemia with chlorthalidone, may explain why HCTZ is the diuretic of choice in treating hypertension in the US. In the level of evidence hierarchy, cohort studies sit below randomized controlled trials (RCTs) and systematic reviews because they are more prone to bias. On the flip side, however, cohort studies can sometimes provide better information about "real life" conditions; in an RCT, participants follow strict protocols, but in cohort studies, we can measure the effect of interventions as they play out in practice.
So, overall, some cohort studies have found HCTZ and chlorthalidone to be equivalent, but some RCTs and systematic reviews have found differently. Some studies have shown increased hypokalemia with chlorthalidone use, but several large hypertension treatment trials, including the 2015 SPRINT, preferentially used chlorthalidone in their treatment protocols. If you’d like to read more, there’s an AFP By Topic on Hypertension.
When the evidence base is conflicting, it can be challenging to decide what to do in practice. How do you decide which diuretic to prescribe for patients with hypertension?