Hypertension
Maria G. Tanzi, PharmD
The 2017 American College of Cardiology/American Heart Association guidelines on management of hypertension currently recommend use of thiazide diuretics as first-line agents. In particular, preference is given to chlorthalidone because of its longer half-life and data supporting potential cardiovascular (CV) risk reduction. Recent results from a large observational study published in JAMA Internal Medicine, however, do not support these recommendations.
“We carried out the largest and, we believe, most sophisticated nonrandomized study comparing chlorthalidone and hydrochlorothiazide when used as first-line therapies for hypertension, and we found little difference in effectiveness (preventing heart attacks, strokes, and heart failure) and that chlorthalidone produces more side effects, especially low potassium (almost three times as much) and other electrolyte disorders and kidney problems,” said lead author George Hripcsak, MD, MS, Vivian Beaumont Allen professor and chair of Columbia University’s department of biomedical informatics and director of medical informatics services for New York–Presbyterian Hospital/Columbia Campus.
Analysis
In the large, multicenter cohort study, Hripcsak and colleagues assessed data from three Observational Health Data Sciences and Informatics databases to compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension.
Using data from 730,225 patients from January 2001 through December 2018, the researchers evaluated the primary outcomes of acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite CV disease outcome including all three outcomes as well as sudden cardiac death. In addition, they assessed 51 safety outcomes (e.g., electrolyte disorders, kidney disease, gout). They used large-scale propensity score stratification and negative-control and synthetic positive-control calibration on the databases.
Overall, 693,337 patients were prescribed hydrochlorothiazide, and 36,918 were prescribed chlorthalidone. The mean age for the entire cohort was 51.5 years, and 61.6% were women. No significant differences were observed for any of the primary outcomes for the two diuretics, and use of chlorthalidone was associated with a significantly higher risk of select adverse events. These events included a higher risk of hypokalemia (hazard ratio [HR] 2.72), hyponatremia (1.31), acute renal failure (1.37), chronic kidney disease (1.24), and type 2 diabetes (1.21).
Applicability
Hripcsak noted that diuretics are recognized as among the best drugs to treat hypertension, but there are no randomized studies to help decide which diuretic is best for a patient. Hydrochlorothiazide is the most frequently used agent in the United States, especially since it is available in numerous combination antihypertensive medications (e.g., lisinopril/hydrochlorothiazide). However, chlorthalidone has gained favor in recent years, and its use is rising.
When asked about the applicability of the current results, Hripcsak said, “We believe that if a patient is taking hydrochlorothiazide, our study shows no reason to switch to chlorthalidone at this time. And if the patient is taking chlorthalidone, the physician should be monitoring electrolytes and kidney function carefully.”
Pharmacists can play an integral role in ensuring patients are on appropriate first-line therapies for hypertension and in educating them on potential adverse effects. For thiazide diuretics, counsel patients to take the medication in the morning if the dosing is once daily and to be aware of changes in blood pressure that may cause dizziness. Advise patients to contact their physician if they experience any symptoms of potassium loss, such as excess thirst, tiredness, drowsiness, restlessness, muscle pains or cramps, nausea, vomiting, or increased heart rate or pulse.
Hripcsak indicated that a large randomized study to compare the two drugs is currently in progress and may reveal more information. Although not from a randomized controlled design, the current real-world data suggest that preferences for chlorthalidone as the thiazide “diuretic of choice” to manage hypertension may need to be reevaluated.