Unraveling the mystery: Have we been treating hypertension incorrectly?

The widely prescribed antihypertensive and diuretic drug chlorthalidone—the guideline-recommended agent for first-line therapy in hypertension—causes more side effects than hydrochlorothiazide, a similarly effective diuretic, according to a recent study published in JAMA Internal Medicine. Specifically, results from this study—the first to compare chlorthalidone and hydrochlorothiazide—showed that chlorthalidone may carry a three-fold greater risk of renal and electrolyte abnormalities, which can lead to kidney problems, abnormal heart rhythms, and type 2 diabetes. 

“In this comparative cohort study of 730,255 individuals from multiple large databases, no difference in association with effectiveness between the [two] drugs was found, but a significantly worse safety profile for chlorthalidone was observed. Recommendations to prefer chlorthalidone to hydrochlorothiazide are not supported by real-world evidence,” wrote the authors, led by George Hripcsak, MD, MS, Department of Biomedical Informatics, Columbia University Medical Center, New York, NY.

Hypertension is a huge problem in the United States. According to the CDC, nearly one-half of adults (45%) have hypertension, now defined as a systolic blood pressure of  ≥ 130 mmHg or a diastolic blood pressure of  ≥ 80 mmHg. Of the 108 million Americans with hypertension, only about 24% have their hypertension under control. In all, 21 million adults with hypertension are recommended lifestyle modifications only by their physicians, and 61 million adults are recommended prescription medications and lifestyle modifications (51%). 

These statistics are even more sobering when you consider that in 2017, hypertension was a primary or contributing cause of death for nearly half a million Americans, totaling almost 1,300 deaths per day. In addition, hypertension costs the United States roughly $131 billion annually.

In its 2017 hypertension guidelines, the American College of Cardiology/American Heart Association recommends thiazide and thiazide-like diuretics as first-line treatment for hypertension. While hydrochlorothiazide is most commonly prescribed, the guidelines specify that chlorthalidone is the preferred choice due to its longer half-life and proven efficacy in reducing cardiovascular disease. There have been no studies, however, comparing the risks and benefits of chlorthalidone with hydrochlorothiazide.

“To our knowledge, there have been no completed large head-to-head randomized clinical trials comparing chlorthalidone and hydrochlorothiazide on cardiovascular effectiveness,” wrote Dr. Hripcsak and colleagues.

To that end, Dr. Hripcsak and fellow researchers conducted the Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) study to compare the efficacy and safety of chlorthalidone with hydrochlorothiazide as first-line treatment for hypertension in real-world practice. They searched three Observational Health Data Sciences and Informatics (OHDSI) databases for both outpatient and inpatient care episodes of patients who were prescribed antihypertensive monotherapy for the first time in the United States and identified 730,225 individuals (mean age: 51.5 years; 61.6% women). In all, 36,918 were prescribed chlorthalidone and 693,337 were prescribed hydrochlorothiazide.

The prespecified primary outcomes of their study included hospitalization for acute myocardial infarction (MI), heart failure (HF), ischemic or hemorrhagic stroke, and a composite outcome for cardiovascular disease that included these three outcomes combined, in addition to sudden cardiac death.

Although researchers found no significant differences in the risks of MI, hospitalized HF, or stroke between the two groups, they did find that chlorthalidone was associated with significantly higher risks of hypokalemia, hyponatremia, acute renal failure, chronic kidney disease, and type 2 diabetes. Chlorthalidone was, however, associated with a significantly lower risk of diagnosed abnormal weight.

For example, in the largest OHDSI database evaluated, the Commercial Claims and Encounters Database, researchers found a significant incidence of hypokalemia in the 14,104 patients treated with chlorthalidone and the 287,390 with hydrochlorothiazide (6.3% vs 1.9%, respectively).

With comparable efficacy found for both chlorthalidone and hydrochlorothiazide—but a significantly worse safety profile for chlorthalidone—clinicians may want to re-think their prescribing for patients with hypertension.

“Chlorthalidone use was associated with a higher rate of electrolyte and renal disorders, with an increase in hypokalemia, hyponatremia, acute renal failure, and chronic kidney disease. Based on the electrolyte findings, chlorthalidone’s association with an increase in rate of type 2 diabetes may be associated with potassium depletion or dehydration. Chlorthalidone’s lower rate of abnormal weight gain may be associated with more effective diuresis,” the authors concluded.