New Study Finds Hydrochlorothiazide Inferior To All Other BP Drugs

At the doses most often used, hydrochlorothiazide (HCTZ), the most widely used antihypertensive agent in the world, is “consistently inferior” to all other drugs, according to a new meta-analysis published in JACC. Franz Messerli and colleagues performed a systematic review of studies that compared HCTZ to other drugs using 24-hour ambulatory blood pressure monitoring and found that the decrease in blood pressure with HCTZ (6.5 mm Hg systolic and 4.5 mm Hg diastolic) was significantly lower than with ACE inhibitors (12.9/7.7 mm Hg), ARBs (13.3/7.8 mm Hg), beta-blockers (11.2/8.5 mm Hg), and calcium channel blockers (11.0/8.1 mm Hg).

The authors note that HCTZ is as effective as the other antihypertensive agents when blood pressure is measured in the office. They write  that this suggests that HCTZ is likely less effective at night. Although HCTZ is widely perceived to be clinically effective in improving outcomes, Messerli and colleagues write that “all outcome studies were done with higher doses than the currently used 12.5 to 25 mg or with other thiazides such as chlorthalidone or indapamide.”

However, because HCTZ is “suboptimal” as monotherapy “should not prevent it from being useful in combination with” other agents, since many studies have found that HCTZ in combination with other agents yields an incremental reduction in blood pressure.

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Here is a press release issued by the study authors:

Hydrochlorothiazide is inappropriate for first line therapy of Hypertension.

Background: Hydrochlorothiazide (HCTZ) is a diuretic or “waterpill” and has been available for half a century . It remains the most commonly prescribed drug for high blood pressure worldwide. In the U.S. alone, 134.1 million prescriptions of HCTZ were written in the year 2008. For comparison, the second most commonly prescribed drug was atenolol, with 44 million prescriptions. More than a third of the HCTZ prescriptions (47.5 million) were written for HCTZ plain, and the remainder for HCTZ in fixed combination, mostly with blockers of the renin angiotensin system. The dose of HCTZ prescribed was almost exclusively (more than 97%) 12.5 to 25 mg per day, and hypertension remains, by far, the most common indication. Over the past 30 years, this pervasive prescription pattern of HCTZ has been extensively promoted by reports of the Joint National Committee for Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, all 7 of which recommended “thiazides” or “thiazide-like drugs” or “thiazide-type diuretics” as first-line or preferred therapy for hypertension.

Objectives: The purpose of this study was twofold: (1) to evaluate the blood pressure lowering of HCTZ in the most thorough way, i.e. by ambulatory monitoring and (2) to scrutinize the literature for data showing a reduction in heart attacks, strokes or death with HCTZ treatment. A systematic review was made using Medline, Cochrane, and Embase for all the randomized trials that assessed the fall in blood pressure with HCTZ by 24 hour ambulatory monitoring and compared it with other blood pressure drugs.

Results: In fourteen studies with a HCTZ dose of 12.5 to 25 mg in 1,234 patients the decrease in 24 hour ambulatory monitoring blood pressure with HCTZ dose 12.5 to 25 mg was a meager 6.5 / 4.5mm Hg.  In head-to-head comparisons, this fall in blood pressure was significantly inferior to the 24-h BP reduction with all other drug classes such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and calcium antagonists. Of note, HCTZ lowered blood pressure well during daytime when patients are seen in the physician’s office but had less effect during the night and early morning hours. Thus, assessing the blood pressure lowering of HCTZ by office blood pressure measurements only, proved to be deceptive and is prone to lull physicians and patients into a false sense of security. Most importantly, in its commonly used dose of 12.5 to 25 mg once a day, there are no studies or evidence that HCTZ reduces myocardial infarction, stroke, or death.

Take home message: Unfortunately HCTZ still remains by far the most commonly prescribed antihypertensive drug in the U.S. and the National Heart, Lung and Blood Institute continues to advocate the use of “thiazide-type diuretics,” which, for practicing physicians simply means HCTZ in a daily dose of 12.5 to 25 mg. These recommendations notwithstanding, our data clearly show that HCTZ at these doses is an inferior drug in that it lowered blood pressure significantly less well than did all other drug classes as measured most thoroughly in head-to-head studies by ambulatory monitoring. Because of such paltry blood pressure effect and lack of data on reducing heart attack, stroke or death at these doses, physicians should refrain from prescribing HCTZ as first line antihypertensive therapy.



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