Thiazide diuretics are underused in the treatment of hypertension, despite their proven superiority.^1,2 The most common thiazide used in the United States is hydrochlorothiazide (HCTZ) at a dose of 12.5 to 25 mg per day. Chlorthalidone (Thalitone; brand available as 15-mg tablet only) is a thiazide-like diuretic that is used infrequently, even though it is available as a generic, is inexpensive, and has been used as the prototype diuretic in most of the randomized controlled clinical trials during the past three decades that established the effectiveness and superiority of thiazides or thiazide-like diuretics for the treatment of hypertension. Chlorthalidone was used in the landmark SHEP study³at a dose of 12.5 to 25 mg daily, and the large Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT)¹ used a similar dose for it. In the Multiple Risk Factor Intervention Trial (MRFIT), centers that used chlorthalidone had better mortality outcomes than centers that used HCTZ.⁴

Is HCTZ at a dose of 12.5 to 25 mg per day equipotent to a daily dose of 12.5 to 25 mg of chlorthalidone? Studies conducted in the 1970s showed that 50 mg of chlorthalidone once daily was equivalent to 50 mg of HCTZ twice daily.^5,6 The half-life of chlorthalidone is much longer than that of HCTZ (24 to 55 versus 2.5 hours, respectively).⁷ A recent crossover trial that used 24-hour ambulatory blood pressure monitoring confirmed this higher potency of chlorthalidone and helped bring the issue back to life⁸ ; in this study, not only did 25 mg of chlorthalidone daily lower blood pressure as well or better than 50 mg of HCTZ daily, but the nighttime dipping of systolic blood pressure was more pronounced with chlorthalidone than with HCTZ (14 versus 6 mm Hg, respectively).⁸

A network meta-analysis of three trials that compared the effects of HCTZ or chlorthalidone with placebo in the treatment of hypertension found that the beneficial effects of HCTZ were qualitatively comparable with those of chlorthalidone regarding most cardiovascular outcomes (congestive heart failure was not included in the analysis because of a lack of data on this outcome in two of the studies). For the studies in this analysis that used HCTZ, 25 to 50 mg per day was combined with a potassium-sparing diuretic (i.e., amiloride [Midamor] or triamterene [Dyrenium]).^9,10 Therefore, a dose of 12.5 to 25 mg of HCTZ per day is not proven to have the same beneficial effect as chlorthalidone in the same dose, because chlorthalidone at a dose of 12.5 to 25 mg was compared with 25 to 50 mg of HCTZ combined with a potassium-sparing diuretic.

Of note, results of the HCTZ-based Second Australian National Blood Pressure study¹¹ showed that angiotensin-converting enzyme inhibitors were superior to thiazides in reducing composite cardiovascular events. This result contrasted with the results of the chlorthalidone-based ALLHAT study. Could this difference in outcome be because of a different diuretic choice at a less effective dose?

There is no other direct comparative study of HCTZ and chlorthalidone forthcoming, and it is unlikely that anyone will be willing to undertake such an enormous task. However, the study with findings of better nighttime blood pressure lowering with chlorthalidone⁸ may be used as a reasonable surrogate outcome study if confirmed by larger studies. A large cohort study using ambulatory blood pressure monitoring found that, for a similar level of daytime systolic blood pressure, persons with larger nighttime dipping had a significantly lower risk of cardiovascular morbidity.¹²

For the past several years, our clinics and several others have adopted the practice of using chlorthalidone preferentially, and of changing HCTZ to chlorthalidone in many patients who were referred for uncontrolled hypertension. In these anecdotal experiences and in at least one published account,¹³ the improvement in the overall blood pressure control with this change was obvious. These types of experiences from many hypertension specialists, and their preference for the use of chlorthalidone (especially in patients with blood pressure that is difficult to control), were discussed in a special session during the 2007 annual meeting of the American Society of Hypertension.¹⁴

Although chlorthalidone was a favorite thiazide in clinical trials for two decades, HCTZ somehow became the favorite thiazide for practicing physicians. Very few physicians know about this difference between chlorthalidone and HCTZ, and most of them limit their use of HCTZ to 12.5 to 25 mg per day, despite the recommended dose of chlorthalidone being 12.5 to 25 mg per day and HCTZ being 12.5 to 50 mg per day (recommended by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure).¹⁵ It does not make sense to continue to use HCTZ at a dose that is only one half of the effective dose used in clinical trials. Some physicians still have concerns that chlorthalidone may be more likely than HCTZ to cause hypokalemia. However, two recent studies did not show any significant difference in serum potassium levels when comparing the use of HCTZ with chlorthalidone. Also, incidences of hypokalemia were not unusually high in the two large studies (i.e., ALLHAT [n = 42,000] and SHEP [n = 4,700]) that used chlorthalidone.^1,3 Although 12.5 to 25 mg daily is the dose used most often clinically and in other studies, even 6.25 mg daily had been used in the SHEP trial and in clinical practices in patients older than 70 years, and women with a low body weight (i.e., less than 100 lb [45 kg]), especially at the beginning. Hypokalemia remains a concern for HCTZ, chlorthalidone, and other thiazides, but potassium-sparing diuretics (e.g., spironolactone [Aldactone]) can correct hypokalemia and give additional help in blood pressure control and cardiovascular protection.¹⁶

These clinical differences between chlorthalidone and HCTZ merit our considering chlorthalidone in preference to HCTZ. This simple change in our treatment habits may help our patients achieve better blood pressure control and prevent additional cardiovascular events.