The 7th report of the Joint National Committee (JNC 7) on the detection, prevention, and treatment of hypertension (HTN) recommends a thiazide diuretic, used singly or in combination with other antihypertensive medications, as initial therapy for patients with HTN.1 Although physicians tend to view the thiazides as a homogenous class of diuretics, significant differences exist among these drugs, especially with respect to their efficacy of blood pressure lowering and, more important, the outcomes data supporting their ability to improve the long-term prognosis for HTN. Although hydrochlorothiazide continues to be US physicians' overwhelmingly favored thiazide for treating HTN, a closer look at the data suggests that its preferred status is not warranted.
A recent meta-analysis adds fuel to the fire of this debate.2 The authors show that hydrochlorothiazide, at doses of 12.5 to 25 mg daily, is inferior to other classes of antihypertensive medications, and they conclude that it should not be the thiazide diuretic of first choice for treatment of HTN. How do these new data fit with what we already know and what inferences can be made from the totality of the available evidence?
Our group has recently published a formal review of published literature evaluating the impact of thiazide diuretics on cardiovascular (CV) prognosis in patients with HTN.3 While studies of head-to-head comparison between thiazide diuretics are lacking, we found that hydrochlorothiazide (25 mg daily) was consistently inferior to other comparators (except atenolol—another antihypertensive agent with poor outcomes data)4 in preventing CV events.5-9 Conversely, data with chlorthalidone (12.5 to 25 mg daily)10-12 and indapamide (0.625 to 2.5 mg daily)13-15 were considerably more robust and showed unequivocal reductions in adverse CV events (Figure). These findings argue against a class effect with thiazide-type diuretics and suggest instead that diuretics with better track records (such as chlorthalidone and indapamide) should be preferentially used when a thiazide is indicated. Put differently, hydrochlorothiazide should not be a first-line thiazide because it has a relatively weak antihypertensive effect and no appreciable evidence supporting its role in improving CV prognosis and outcomes of patients with HTN. Whether or not using hydrochlorothiazide at higher doses (50 mg daily) would be more beneficial is unclear because such high daily doses have been associated with higher risk of hypokalemia and sudden cardiac death.
Data summary from landmark outcomes studies on the impact of thiazide diuretics (hydrochlorothiazide, chlorthalidone and indapamide) on major cardiovascular endpoints: (a) total mortality, (b) CV mortality, (c) CVA.
CV: cardiovascular, CVA: cerebrovascular accidents (INSIGHT: hydrochlorothiazide/amiloride vs. atenolol; MRCT: hydrochlorothiazide vs. atenolol; ANBP2: hydrochlorothiazide vs. enalapril; ACCOMPLISH: hydrochlorothiazide + benazepril vs. amlodipine + benazepril; SHEP: chlorthalidone vs. placebo; ALLHAT: chlorthalidone vs. amlodipine vs. lisinopril; PROGRESS: perindopril ± indapamide vs. placebo; HYVET: indapamide ± perindopril vs. placebo; ADVANCE: indapamide + perindopril vs. placebo).
The reasons for this obvious disconnect between the poor performance of hydrochlorothiazide in improving the long-term outcomes of patients with HTN and its highly favored status among physicians are not entirely clear. Hydrochlorothiazide is mostly used out of habit and/or the ease of its widely recognized abbreviations (HCT or HCTZ).16,17 Moreover, hydrochlorothiazide is available in a host of fixed-dose combinations with a variety of other blood-pressure lowering medications, likely another key reason for its widespread use. Using indapamide or chlorthalidone combined with other antihypertensive agents with more compelling outcomes data (such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) will not only improve blood pressure (BP) control, but is also likely to impact CV prognosis favorably. Moreover, this combination is likely to mitigate the risk of hypokalemia, a potential complication typically seen at higher doses of more potent thiazides. The use of antihypertensive combinations becomes particularly important when we realize that two-thirds of patients with HTN require at least 2 medications to achieve BP targets.18
As a final practical matter, all of these thiazide diuretics are available for $4 per month; therefore, cost should not be a significant barrier to using either chlorthalidone or indapamide instead of hydrochlorothiazide, even for those without insurance coverage for prescription medications.
With scientific evidence consistently indicating that hydrochlorothiazide is suboptimal for reducing the risk of adverse CV events and optimizing BP control, its use as the thiazide of choice for patients with HTN becomes exceedingly hard to justify. On the other hand, the available evidence strongly supports the use of chlorthalidone19 or indapamide when a thiazide diuretic is indicated for HTN.
- Academic Division of Ochsner Clinic Foundation
