Chlorthalidone Demonstrates No Greater Effectiveness Than Hydrochlorothiazide in a Large, Pragmatic Clinical Trial

AUTHOR: 
Michael J. Bloch, MD
Associate Professor, University of Nevada School of Medicine
Medical Director, Renown Vascular Care, Renown Institute for Heart and Vascular Health
President, Blue Spruce Medical Consultants, PLLC

CITATION:
Bloch MJ. Chlorthalidone Demonstrates No Greater Effectiveness Than Hydrochlorothiazide in a Large, Pragmatic Clinical Trial. Consultant360. Published online February 14, 2023.

For decades, thiazide and thiazide-type diuretics have been a mainstay in the treatment of hypertension. In fact, a large proportion of the data that originally supported the pharmacologic therapy of hypertension was produced from studies using thiazide-type diuretics. While hydrochlorothiazide (HCTZ) is the most commonly utilized thiazide-type diuretic, it has rarely been utilized in large-scale randomized clinical trials, which often use chlorthalidone (CTD). This distinction is important since CTD has a longer half-life and requires a lower dosage to reach the same blood pressure-lowering effect as compared to HCTZ.  There remains debate as to whether or not CTD should be the preferred agent in the contemporary management of hypertension.

The 2017 American College of Cardiology/American Heart Association Guideline for the Prevention, Detection, Evaluation, and Management of High BP in Adults suggests that thiazides are a preferred class of antihypertensive medication in most patients with hypertension.¹  While both HCTZ and CTD are listed as alternatives in these guidelines, the authors highlight that “CTD is the preferred agent on the basis of prolonged half-life and proven trial reduction of cardiovascular (CV) events." 

Yet, despite these data and recommendations, in the United States, the use of HCTZ far outpaces that of CTD. This discrepancy is certainly due in part to the widespread availability of HCTZ, both as a stand-alone medication and as a fixed-dose combination (FDC) but also likely due at least in part to concerns regarding hypokalemia and other potential adverse effects of CTD. 

The Chlorthalidone vs Hydrochlorothiazide for Hypertension – Cardiovascular Events trial was designed to determine whether CTD is superior to HCTZ in preventing major CV events in a relatively “real-world” setting.²  In this pragmatic, open-label, clinical trial, Veterans Administration (VA) patients who were 65 years of age or older and who were prescribed HCTZ as a stand-alone tablet at doses of 25 or 50 mg daily were randomized to remain on HCTZ or to switch to CTD 12.5 or 25 mg daily. Importantly, patients who were taking HCTZ as part of a FDC were excluded. Neither patients nor providers were blinded to the treatment assignment. The primary endpoint was a composite of nonfatal myocardial infarction, stroke, heart failure requiring hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety, including the incidence of hypokalemia and hospitalization with hypokalemia, was also assessed. 

A total of 13,523 patients were randomly assigned; the mean age at randomization was 72 years, and an overwhelming number of patients were male (97%); approximately 11% of patients had a history of myocardial infarction (MI) or stroke. Baseline systolic BP was 139 mmHg and did not change significantly over the course of the trial in either group. After a mean follow-up of 2.4 years, there was no significant difference in the incidence of the primary endpoint between the CTD group (10.4%) and the HCTZ group (10.0%). There were no significant differences in any component of the primary endpoint. Interestingly, in the subgroup of patients with a history of MI or stroke at baseline, there was a modest decrease in the primary endpoint in the CTD group compared to the HCTZ group. The incidence of hypokalemia (6.0% vs 4.4%) and hospitalization for hypokalemia was higher with CTD than HCTZ. 

This trial is subject to several important limitations. First, since all included patients were on HCTZ at baseline, the results actually showed the effect of switching from HCTZ to CTD rather than choosing one drug or the other as initial therapy. Second, the trial was limited to patients older than 65 years of age and were almost exclusively men; whether these results would be similar in younger patients or in women remains an open question. Third, neither patients nor providers were blinded to treatment allocation and pre-existing biases regarding the use of CTD could have influenced results. Fourth, this was not a study of patients with resistant hypertension, where CTD may still offer a benefit. Finally, this trial is of relatively short duration (< 3 years); whether longer-term follow-up would have led to a difference in outcomes remains unknown. The hypothesis-generating finding that patients with a history of MI or stroke seemed to benefit from change to CTD is intriguing in this regard. 

Despite these limitations, this is one of the few large-scale prospective studies that directly compared the impact of CTD vs HCTZ on CV events at comparable doses. These findings need to be replicated in studies that include younger patients, more women, those with previous CV disease or resistant hypertension, and those naïve to previous thiazide therapy. However, pending further studies, these results should make clinicians much more comfortable in their current prescribing habits favoring HCTZ over CTD. 

The pragmatic nature of this clinical trial is also deserving of mention. Most large-scale prospective, randomized, clinical trials make use of a highly resourced delivery team of investigators and study coordinators who work in parallel with a patient’s usual care team. Study medications are usually dispensed directly from the study team, and both patients and investigators are blinded to treatment allocation. This traditional approach decreases the potential for bias but may jeopardize real-world applicability and certainly increases the cost of research. In contrast, this trial, comparing HCTZ with CTD, was fully embedded within each patient’s usual care team at the VA. As such, not only was the cost of the trial significantly decreased, but we were able to see a more-complete picture of real-world effectiveness than a more-traditional study design. As medical information systems continue to develop and delivery systems become more robust, we will likely see a shift in many of our landmark clinical trials to a more pragmatic study design. 

References:

1.    Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Hypertension. 2018;71(6):e13-e115. doi:10.1161/HYP.0000000000000065

2.    Ishani A, Cushman WC, Leatherman SM, et al; Diuretic Comparison Project Writing Group. Chlorthalidone vs. hydrochlorothiazide for hypertension-cardiovascular events. N Engl J Med. 2022;387(26):2401-2410. doi:10.1056/NEJMoa2212270