Are Chlorthalidone and Hydrochlorothiazide Equivalent Blood‐Pressure‐Lowering Medications?

Abstract

While the majority of participants in clinical trials demonstrate the benefits of the thia-zide-like diuretic, chlorthalidone (CTD),1 hydrochlorothiazide (HCTZ) is prescribed more frequently in the United States.2 Only one large outcome trial, the Multiple Risk Factor Intervention Trial (MRFIT), used both HCTZ and CTD, but no head-to-head comparisons were performed. In MRFIT, after about 5 years patients who received each diuretic as initial therapy were compared against the common "referred care" group. For patients who used CTD as initial therapy, there was a trend indicating lower mortality compared with those using HCTZ. Use of CTD declined after research studies using high doses suggested an increased risk of cardiovascular deaths and a high incidence of hypokalemia.3 A recent review suggests that few differences exist between HCTZ and CTD—thus, they should be considered interchangeable.4 These authors state, however, that there are differences in duration of action and pharmacology between the two agents. Based on these differences, we propose that the same dose of CTD when substituted for HCTZ may result in an additional systolic blood pressure (SBP) reduction and help achieve blood pressure (BP) goals in patients already receiving three or more medications. A consecutive chart review from the Rush University Hypertension Center sought patients with the following inclusion criteria: age over 40 years, not at target BP for medical condition (<140/90 mm Hg and <130/80 mm Hg for those with kidney disease or diabetes), and on a stable antihypertensive regimen that included the same dose of HCTZ for at least 6 months. All patients underwent recording of two sitting BP readings. Nineteen of the 2000 charts (1%) screened met the inclusion criteria. The average of two seated BP readings from the initial visit and the follow-up (after the switch) were analyzed. Following the initial visit, patients were switched from HCTZ to CTD at the same daily dose without any further changes in their antihypertensive regimen. No patients received K+ supplementation before or after the change. Laboratory data for serum K+ and kidney function, as well as clinical data for BP and pulse rates, were recorded at follow-up visits. Patients were also asked about symptoms related to gout at each visit. Seventeen of the 19 patients were taking 25 mg of HCTZ at the index visit; two were taking a dose of 12.5 mg/d (Table). SBP values before and after the diuretic switch are shown for individual patients in the Figure. If two patients are eliminated, i.e., those with baseline SBPs of 220 mm Hg that decreased to 156 mm Hg and 194 mm Hg that decreased to 148 mm Hg, an overall median difference of 4 mm Hg instead of 7 mm Hg in SBP was noted (p=0.052). Six of the 19 who originally had uncontrolled hypertension achieved their individual BP targets after the change in medication. Serum K+ levels from eight of the 19 patients were not significantly different (3.9±0.3 mEq/L on HCTZ vs. 4.0±0.4 mEq/L on CTD). Only one of these patients experienced hypokalemia, i.e., K+=3.0 mEq/L. No patient reported symptoms attributable to gout. The principal finding of these observations is that CTD, at identical daily milligram doses, appears to have greater efficacy in lowering SBP when compared with HCTZ in patients who were uncontrolled on a multidrug regimen that included the latter agent. Moreover, those who were within 10 mm Hg of goal SBP had a higher likelihood of achieving goal BP after the change to CTD; they accounted for eight of the 19 patients who achieved target BP. Lastly, of the eight patients who had K+ data collected, only one patient developed hypokalemia. This is consistent with previously published data for patients receiving CTD and may be, in part, because the majority of patients were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker as part of their regimen. These findings are preliminary observations and subject to many limitations. This was a retrospective, uncontrolled, small observational cohort study, consisting of only 1% of the eligible patients in a single clinic. There was no attempt at randomization between agents, nor to blind the person taking the BP to any recent changes in therapy (including switching from HCTZ to CTD). Additionally, data collection was not preplanned, thus omitting serum K+ measurements in 11 of the 19 patients. Lastly, statistical power is limited due the small cohort size. In spite of these limitations, the results of these observations may help to provide some support for the hypothesis that there are differences in anti-hypertensive efficacy within the class of thiazide diuretics. These data suggest that the longer-acting agent, CTD (typical serum half-life: 45–60 hours), may be useful in helping to achieve BP goal in comparison to the shorter-acting and more commonly used HCTZ (typical serum elimination half-life: 8–15 hours).