Skip to main content

Are Current Hypertension Recommendations Supported by Real-World Evidence?

February 19, 2020

Although chlorthalidone is currently the preferred thiazide diuretic for hypertension, researchers sought to understand both the safety and effectiveness of chlorthalidone as well as hydrochlorothiazide as first-line therapies for hypertension in real-world practice. According to the findings, published online in JAMA Internal Medicine, chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide.

“The 2017 American College of Cardiology/American Heart Association hypertension guideline recommends thiazide and thiazidelike diuretics as one of the first-line treatment classes,” explained George Hripcsak, MD, MS, Columbia University Medical Center, and colleagues. “Hydrochlorothiazide is the most commonly prescribed member of the class, but the guideline states that chlorthalidone is preferred on the basis of longer half-life and proven trial reduction of cardiovascular disease.”

In order to compare the effectiveness and safety of both drugs as first-line therapy for hypertension in real-world practice, Dr Hripcsak and colleagues conducted an observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning January 2001 through December 2018. The study authors primarily observed acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. In total, 51 safety outcomes were measured.

The researchers identified 730,225 (mean [SD] age, 51.5 [13.3] years; 450 100 women [61.6%]) for the study. Of those participants, 36 918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693,337 were dispensed or prescribed hydrochlorothiazide and had 3089 composite outcome events.

According to the findings, there were no significant differences observed in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, with a calibrated hazard ratio for the composite cardiovascular outcome of 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85-1.17). Further, participants receiving chlorthalidone were at a higher risk of:

  • hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12);
  • hyponatremia (HR, 1.31; 95% CI, 1.16-1.47);
  • acute renal failure (HR, 1.37; 95% CI, 1.15-1.63);
  • chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42); and
  • type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30).

Finally, the researchers found that the use of chlorthalidone lowered the risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86).

“This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities,” Dr Hripcsak and colleagues concluded.

“These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users was found.”

Of note, Dr Hripcsak and colleagues said that although advanced methods, sensitivity analyses, and diagnostics were used, the possibility of residual confounding and limited length of observation periods warrants the need for further research.  

Julie Gould


Hripcsak G, Suchard MA, Shea S, et al. Comparison of cardiovascular and safety outcomes of chlorthalidone vs hydrochlorothiazide to treat hypertension [published online February 17, 2020]. JAMA Intern Med. doi:10.1001/jamainternmed.2019.7454

Back to Top