Chlorthalidone versus hydrochlorothiazide: maybe it matters after all

At a journal club meeting earlier this week, we discussed a recently published meta-analysis/systemic review comparing chlorthalidone and hydrochlorothiazide (HCTZ) for the reduction of major cardiovascular events in patients with hypertension [1].  Controversy surrounding the widespread use of HCTZ over chlorthalidone seems to be a favorite theme among advocates for evidence-based medicine -- after all, chlorthalidone (rather than HCTZ) was the agent featured in the landmark ALLHAT trial of patients with hypertension, where improvements in cardiovascular endpoints were observed when it was compared to amlodipine and lisinopril -- all at a fraction of the cost [2]. Although the efficacy of chlorthalidone has been extrapolated to HCTZ, use of the latter has become far more widespread, where prescriptions for HCTZ outnumber those for chlorthalidone by as much as 20-fold [1]. This is likely also the result of the minimal cost of HCTZ -- currently included on the Wal-Mart $4 list and other discount programs -- and its inclusion as a combination product with nearly every other antihypertensive on the market. However, as many have suspected for a long time, there may be merit to the use of chlorthalidone over HCTZ, despite the lower cost and convenience of HCTZ.

Because no trial has directly compared chlorthalidone and HCTZ, Roush, et al conducted a retrospective review of nine randomized trials (n > 50,000) as well as drug-adjusted and blood pressure-adjusted meta-analyses comparing these two agents in the management of hypertension.  Compared to HCTZ, chlorthalidone reduced the risk of cardiovascular events by 21% (95% CI 12-28%, p = 0.0001) and risk of heart failure by 23% (95% CI 2-39%, p = 0.032) -- results that were independent of actual blood pressure control. Impressively, the number-needed-to-treat to prevent a single cardiovascular event with chlorthalidone (compared to HCTZ) over a 5-year period was only 27.  The investigators attribute these differences to several possible factors, including effects of chlorthalidone unrelated to its vasodilatory properties, as well as known pharmacokinetic differences between chlorthalidone and HCTZ.

Although there are usually other compelling indications that warrant the use of alternative anti-hypertensives in my patient population (e.g., ACE inhibitors in patients with established coronary artery disease, heart failure, diabetes, or chronic kidney disease), there are some instances where the decision to initiate either chlorthalidone or HCTZ arises (e.g., hypertensive urgency, uncontrolled hypertension on maximum doses of other therapies).  In these scenarios, when cost or pill burden is not an issue, I recommend chlorthalidone over HCTZ, not so much for the academic purity of it but because of its pharmacokinetic advantages. Chlorthalidone has a terminal half-life of over 40 hours -- one of the longest of any anti-hypertensive currently available. Because patients with hypertension rarely "feel" the symptoms of their disease, daily compliance with anti-hypertensive medications can be a significant issue. With such a long terminal half-life, even if a patient remembers to take chlorthalidone every other day, they are likely to derive some anti-hypertensive benefit.

The only drawback with this strategy is cost and pill burden.  Although chlorthalidone is generic and relatively inexpensive, it is not available on any of the retail discount programs (of which I am aware).  The only exception is in a combination product with atenolol, but I usually have reasons for using an alternative beta blocker (e.g., metoprolol, carvedilol, etc), so this is not usually an option.  Moreover, compliance decreases as the number of medications increases, so the limited number of combination products available makes chlorthalidone an entirely separate prescription to fill and another pill to take. 

However, if neither of these issues is the case, it seems that the analysis conducted by Roush, et al, only adds further evidence to support the use of chlorthalidone over HCTZ.

1. Roush GC, Holford TR, Guddati AK. Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events: Systematic Review and Network Meta-Analyses. Hypertension. 2012 Apr 23.
2. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97.