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N Engl J Med 2022 Dec 29;387(26):2401-2410. doi: 10.1056/NEJMoa2212270. Epub 2022 Dec 14.
Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events
Areef Ishani, William C Cushman, Sarah M Leatherman, Robert A Lew, Patricia Woods, Peter A Glassman, Addison A Taylor, Cynthia Hau, Alison Klint, Grant D Huang, Mary T Brophy, Louis D Fiore, Ryan E Ferguson; Diuretic Comparison Project Writing Group
PMID: 36516076
Introduction
Eighty years ago, the only available diuretics were intravenous or intramuscular mercurial agents. But they were notorious for their untoward reactions, which included fatal anuria from tubular necrosis. Then in 1950, acetazolamide, the carbonic anhydrase inhibitor, was discovered. It increases diuresis by increasing the urinary loss of sodium, potassium, and water, along with bicarbonate. Although it was a welcome change, its action was limited, and once metabolic acidosis had occurred, its effect would be self-limiting (Earley LE, 1964). (Of course, ADVOR changed all that).
Next up was chlorthalidone, the thiazide-like, sulfonamide-derived diuretic, first approved by the Food and Drug Administration (FDA) in 1960. It quickly became the go-to diuretic for treating hypertension and was heavily used for the next 20 years. And just when the physicians thought they had found the perfect diuretic, another came along, hydrochlorothiazide (HCTZ), discovered in 1959 but FDA approved only in 1977. Although HCTZ is currently prescribed more often than chlorthalidone for hypertension, passion for chlorthalidone remains strong. So, is it the physician's passion or the intricacies of pharmacokinetics that make chlorthalidone seem superior to HCTZ?
HCTZ has a half-life of 6-9 hours (single dose) or 8-15 hours (long-term), HCTZ has a quick onset of action, reaching peak levels within 4-6 hours. Its antihypertensive effects are longer in patients with higher baseline blood pressure, but there is also a dose-related risk of hypokalemia. Bendroflumethiazide is another commonly used thiazide with similar properties. On the other hand, chlorthalidone is considered a ‘thiazide-like’ diuretic, with peak levels reached 2-6 hours after oral administration. Its half-life is a lengthy 40 hours (single dose) or 45-60 hours (long-term), with a large degree of interindividual variability. Chlorthalidone is approximately 1.5 to 2 times more potent than HCTZ to dose. After oral intake, chlorthalidone rapidly accumulates in red blood cells, after which it is slowly released, explaining the prolonged duration of action. Indapamide is slightly less long-acting than chlorthalidone, but grouped in the same ‘thiazide-like’ class.
Pharmacokinetic and Pharmacodynamic: HCTZ vs Chlorthalidone (adapted by Carter BL et al, 2004)
So, what about clinical evidence? Is chlorthalidone really better than HCTZ or is it all just a myth? Well, the answer is not that simple. The clinical evidence on these two thiazide diuretics is a mixed bag. Most of the trials which support the CV benefit of ‘thiazides’ have actually been with ‘thiazide-like’ diuretics, i.e. chlorthalidone or indapamide (MRFIT, SHEP, ALLHAT trial, HYVET, SPRINT). Observational studies suggest chlorthalidone compared to HCTZ may increase the risk of cardiovascular events and adverse effects (Dhalla IA et al, 2013, Hripcsak G, et al, 2020, Edwards C, et al, 2021). The BP lowering is more potent and longer with chlorthalidone (Ernst ME et al, 2006, Bakris GL et al, 2012) but does that translate into a clinical benefit? In the absence of direct head:head comparison, a network meta-analysis suggested chlorthalidone is superior (Roush et al, Hypertension 2012). But that is an indirect comparison - we do need a direct comparison to clear the air.
The purpose of this Diuretics Comparison Project (DCP) trial was to determine if swapping to chlorthalidone was a better option than continuing HCTZ in preventing cardiovascular problems in older patients with hypertension who were previously taking HCTZ.
The Study
Methods
The trial was a multicenter, pragmatic, open-label, embed to healthcare system trial. Individuals more than 65 years old were recruited from the Department of Veterans Affairs health system who were receiving HCTZ 25 mg or 50mg at the baseline.
Intervention
Patients were randomized to continue HCTZ or switch to chlorthalidone 12.5mg or 25 mg. Patients who were on blood pressure combo-pills which contained HCTZ were excluded. Thus, the conversion from HCTZ to chlorthalidone was 2:1.
Pragmatic design
It was quite a large and extremely pragmatic trial carried out within the framework of the VA point-of-care program; the score on the basis of eight PRECIS-2 (Pragmatic–Explanatory Continuum Indicator Summary) criteria (with each criterion scored on a scale from 1 to 5, with higher scores indicating greater pragmatism) was 37 out of 40. What does that mean in English? Participants were chosen on very broad inclusion criteria as mentioned above. They were identified on the basis of screening the VA electronic health record (EHR) and mailed the inform consent. They were contacted by phone, and an ‘oral’ consent was taken. After randomization, the intervention was delivered by the VA pharmacists. All outcomes were recorded through the VA EHR system.
Figure S2. PRECIS-2 Figure and Scoring
Outcomes
The primary outcome was a first occurrence of a composite outcome of a nonfatal cardiovascular disease event or non–cancer-related death, assessed in a time-to-event analysis. Non-fatal cardiovascular disease events were nonfatal myocardial infarction, stroke, hospitalization for heart failure, or urgent coronary revascularization for unstable angina.
Secondary outcomes were the individual components of the primary outcome. Safety outcomes included electrolyte abnormalities, hospitalizations, and acute kidney injury.
Patients were followed until they withdrew from the trial or died, or until the end of the trial. Follow-up continued beyond the time that the primary-outcome event occurred in order to determine secondary, safety, and recurrent outcomes.
Statistical analysis
It was calculated that 1055 primary-outcome events would provide the trial with 90% power to detect a 17.5% lower hazard for the primary outcome in the chlorthalidone group supposing a 3% annual incidence of the primary outcome in the HCTZ group. Primary analyses were performed with the use of unadjusted log-rank tests according to VA health care system. Secondary analyses and analysis of the time to hospitalization for hypokalemia were performed with the use of a competing-risk model and adjusted Cox proportional-hazards models. Pre-specified subgroup analyses were conducted with the use of baseline demographic and clinical data which includes race, age, blood pressure, eGFR, presence or absence of diabetes, history of myocardial infarction or stroke, and median systolic blood pressure. A planned interim analysis of the primary hypothesis was performed after 500 primary-outcome events had occurred.
Funding
This trial was funded by the Veterans Affairs Cooperative Study Program.
Results
72 VA health care systems from 537 locations were included in the trial between June 2016 and October 2021.16,595 patients consented to participate, and 13,523 underwent randomization, out of which 6756 were assigned to the chlorthalidone group and 6767 to the HCTZ group.
Fig S1: Flow of patients in the trial
The baseline characteristics of the study population is as follows Table 1 from Ishani A, et al, 2023
The mean age of the population was 72 years. 97% of the study group were men, 15% were Black and around 11% had history of stroke or myocardial infarction. Most patients (94.5%) of the study group were on HCTZ 25 mg once daily at baseline. About 20% could be considered to have resistant hypertension given the use of 4 or more BP lowering medications. The average SBP was 139 mm Hg and the median number of antihypertensive medications for control of blood pressure was 2.6.
The median follow period was 2.4 years. The median average daily dose throughout the trial, after factoring in concordance, was 12.3 mg in the chlorthalidone group and 23 mg in the HCTZ group. 15.4% of the chlorthalidone group were switched back to treatment with HCTZ, and 3.8% who had been assigned to continue treatment with HCTZ were switched to chlorthalidone.
Systolic blood pressure readings in both groups remained unchanged and comparable between arms.
Figure 1 from Ishani et al
Primary Outcome
The primary composite outcome occurred in 10.4% in the chlorthalidone group in comparison to 10.0% in the HCTZ group (P=0.45). Annual event rate was 4.5 % in chlorthalidone and 4.3% in HCTZ cohort.
Figure 2 from Ishani A, et al, 2023
There was also no significant difference between the individual components of the primary outcomes between the two groups.
Table 2 from Ishani A, et al, 2023
Within the subgroup analysis, patients with history of MI or stroke in the chlorthalidone group appeared to have lower incidence of primary outcome in comparison to HCTZ group (HR 0.73, 95% CI 0.57-0.94), whereas patients in chlorthalidone group without history of MI or stroke had slightly higher incidence of primary outcome (HR 1.12, 95% CI 1.00-1.26), which the authors term as a ‘qualitative interaction’.
Figure 3 from Ishani A, et al, 2023
Safety outcomes
Hospitalization from any cause remained similar between the two groups. Patients on chlorthalidone had more monitoring for hypokalemia, and incidence of hospitalizations for hypokalemia was higher in the chlorthalidone group (HR 1.35; 95% CI, 1.00 to 1.82). Follow up serum potassium levels less than 3.1 mmol/L were also higher in the chlorthalidone group when compared to HCTZ group (P<0.001). Prescriptions for potassium supplements were issued more often to patients in the chlorthalidone group than to those in the HCTZ group.
Between the two groups there were no differences in rates of hyponatremia, AKI, new onset diabetes, or gout.
Discussion
For years, nephrologists have held onto the notion that switching to chlorthalidone as the superior diuretic, a belief so deeply ingrained that switching to it was almost like a rite of passage. They've paraded it as the epitome of smart and clever medical practice. We recently also discussed the utility of using chlorthalidone deep into CKD.
But now, the DCP trial results have come to challenge this long-standing dogma, and nephrologists are left with a burning question: was their unwavering trust in chlorthalidone all for nothing?
There is an issue with generalizability - given that this VA trial mostly had older men. The authors explicit tabulate these in this table. But unless one can make a biologically plausible scenario of why chlorthalidone should work in younger men, or in women, this issue is a non-issue.
Table S1 from Ishani et al
What about the dose conversion? Is 2:1 conversion the right one? A meta-analysis revealed that 8.6 mg of chlorthalidone and 26.4 mg of HCTZ (so ~ 3:1) were needed to decrease systolic blood pressure by 10 mmHg (Peterzan MA et al, Hypertension 2013), but that much greater BP reduction could be achieved at higher doses of each. Should higher doses of chlorthalidone been used - especially given there seemed to be no SBP difference achieved? Difficult to say - but also one should consider higher doses of chlorthalidone would likely cause a higher proportion of adverse events.
The results from the DCP trial do leave us with mixed feelings. While there was no significant difference in the primary composite outcome between the two treatments, a subgroup analysis hinted at interaction between treatment and prior heart attack or stroke history. However, we must be careful in over-interpreting small subgroup results within larger, overall negative trials. Some will point to the the unique pleiotropic effects of thiazide-like diuretics on platelets and the vasculature (Woodman R, et al, 2010), and chlorthalidone’s direct vascular relaxant effects by opening calcium-activated potassium channels, and its inhibition of carbonic anhydrase can alter the channel's pH-activated action. (Roush GC, et al, 2013). However, it is fairly difficult to envisage an obvious mechanism by which chlorthalidone can prevent events in patients with previous stroke or MI but at the same time is inferior in preventing a first event - it may just be a chance finding, or serves only as a starting point for future hypothesis generation at best. It would also have been interesting to see a subgroup based on number of BP lowering medications - since it is more often that we switch from HCTZ to chlorthalidone in the setting of uncontrolled or resistant hypertension.
The results of the study indicate that chlorthalidone therapy is clearly linked to a higher rate of hospitalizations and cases of laboratory-identified hypokalemia. This may be due to the heightened vigilance of healthcare providers and patients, who were closely monitoring potassium levels because of swapping to a new medication - but is also consistent with the higher potency of chlorthalidone and the observational literature. Those in the chlorthalidone group were more likely to switch back to HCTZ, but this is to be expected when the starting population of the study were all selected as already tolerating on HCTZ, especially in open-label study.
DCP must be praised for its novel approach compared to traditional RCTs. The study utilized the electronic health record (EHR) to identify eligible patients and a centralized process that was integrated into standard care. The consent process involved calling both patients and their clinicians. By embedding randomization into routine clinical care, it becomes possible to quickly gather data, and the trial had an impressive recruitment rate of 100 patients/week, including more than 4000 providers and 13,500 patients at 537 clinics.
The results of the trial do cast a shadow of doubt over the myth of chlorthalidone's superiority, leaving us in a state of bewilderment, questioning what they thought they knew. Will this be the end of the chlorthalidone myth or will we cling onto their cherished beliefs?
Conclusion
Despite the promising potential of chlorthalidone, this study found no significant difference in major cardiovascular outcomes or non-cancer-related deaths between patients taking hydrochlorothiazide and those swapped to instead take chlorthalidone. It will be intriguing to see which aspects of DCP results will be supported or refuted by the 50,000 patient cluster-randomized EVIDENCE trial (Rogers et al, Trials, 2021) comparing the short-acting bendroflumethiazide with the longer-acting thiazide-like indapamide in Scotland.
Summary prepared by
Priyadarshini John, Nephrologist,
Hyderabad, India
Cristina Popa, MD,
Department of Internal Medicine-Nephrology,
University of Medicine and Pharmacy
"Grigore T Popa", Iași, Romania
NSMC Interns, Class of 2022
Reviewed by Jamie Willows and Swapnil Hiremath
Featured image credit: Artificial Intelligence directed by Evan Zeitler