The Diuretic Comparison Project (DCP) trial, showing no difference in reduction of clinical events between the thiazide diuretics chlorthalidone and hydrochlorothiazide when used for the treatment of hypertension, has now been published in The New England Journal of Medicine.
The trial was first presented and reported by theheart.org | Medscape Cardiology at last month’s American Heart Association Scientific Sessions 2022.
In the current paper published online December 14, the authors, led by Areef Ishani, MD, Minneapolis Veterans Affairs (VA) Health Care System, Minneapolis, Minnesota, explain that early studies suggested that chlorthalidone was superior to hydrochlorothiazide in patients with hypertension, but more recent observational studies have shown that the two drugs reduced cardiovascular events at a similar rate. Chlorthalidone may be associated with an increased risk of adverse events, including hypokalemia.
They note that in 2020, Part D Medicare expenditures showed that approximately 1.5 million persons received prescriptions for chlorthalidone as compared with 11.5 million who received prescriptions for hydrochlorothiazide, despite guidelines that recommended chlorthalidone as the preferred agent. The discrepancy between guideline recommendation and real-world use is possibly related to the belief that chlorthalidone has a greater risk for adverse effects without clear evidence for differences in cardiovascular outcomes, the authors suggest.
They conducted the current study to directly compare the effect of the two agents on cardiovascular outcomes in patients with hypertension.
The pragmatic DCP trial was carried out within the Veterans Affairs Healthcare System, and randomly assigned 13,523 patients (mean age, 72.5 years) with hypertension who were receiving hydrochlorothiazide at baseline (25 or 50 mg per day) to continue hydrochlorothiazide at their baseline dose or to switch to chlorthalidone (12.5 or 25 mg per day).
The mean baseline systolic blood pressure was 139 mm Hg in both trial groups and did not change substantially during the trial.
Over a median follow-up of 2.4 years, there was no difference in the primary outcome — a composite of MI, stroke, hospitalization for heart failure, urgent coronary revascularization for unstable angina, and non–cancer-related death — between the chlorthalidone group (10.4%) and the hydrochlorothiazide group (10.0%), giving a hazard ratio of 1.04 (95% CI, 0.94 – 1.16; P = .45).
In addition, there were no treatment differences between the two groups in any primary outcome component. Hypokalemia and potassium supplement use were more common in the chlorthalidone group than in the hydrochlorothiazide group.
“Importance Lies in the Design”
In an accompanying editorial, Julie R. Ingelfinger, MD, deputy editor of the New England Journal of Medicine, said the results are not surprising and may not change clinical practice. But she suggests that the importance of the trial lies in its design, which shows that a high-quality pragmatic comparative effectiveness trial can be accomplished in a cost-effective manner within a healthcare system with little disruption in patient care.
Ingelfinger points out several limitations of the trial. These include a lower-than-expected occurrence of primary outcome events, and the stipulation that patients were eligible to participate only if they continued to have hypertension while receiving hydrochlorothiazide.
In addition, 95% of the participants were receiving 25 mg of hydrochlorothiazide and only 5% were receiving 50 mg, which limited comparisons of the dose generally used in practice. Also, only approximately 13% of the patients were receiving hydrochlorothiazide alone for the treatment of hypertension at baseline.
She notes that the DCP is the first head-to-head comparison of hydrochlorothiazide and chlorthalidone in a randomized, prospective outcome trial.
“Without an apparent difference in the hazard ratios for the primary outcome in the two groups over the median follow-up of 2.4 years, results suggest that chlorthalidone therapy remains a good choice for hypertension despite the secondary observation that hypokalemia was more common with chlorthalidone than with hydrochlorothiazide,” Ingelfinger says.
“Although a subgroup analysis suggested that chlorthalidone was better than hydrochlorothiazide for participants with a history of myocardial infarction or stroke, that result may have been by chance,” she adds.
As clinicians generally prefer using hydrochlorothiazide, she suggests that these DCP results will not provide any impetus for change.
“Furthermore, combined therapy and polypills may alter therapy beyond the results of this well-done, highly anticipated trial. Thus, its major effect may be as a model for other pragmatic study programs, which are greatly needed,” she concludes.
This study was s upported by the Veterans Affairs Cooperative Studies Program through a grant to the Diuretic Comparison Project. Ishani reports no relevant financial relationships. Ingelfinger reports book royalties from Springer and from St. Martin’s Press, outside the submitted work, and that she is employed by the New England Journal of Medicine as Deputy Editor.
N Eng J Med. Published online December 14, 2022. Abstract, Editorial
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