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HCTZ Not a Drug of Choice for Treating Hypertension

Hydrochlorothiazide (HCTZ), the most commonly employed blood-pressure-lowering drug in the US, used at the usual doses prescribed—12.5 mg to 25 mg/per day—is a “paltry” antihypertensive, inferior to all other drug classes, and there is no published evidence that it reduces heart attack or stroke.
These are the conclusions of a new pooled analysis of trials reported by Dr. Franz Messerli (St Luke’s-Roosevelt Hospital, New York, NY) during a late-breaking clinical-trial session at the European Meeting on Hypertension 2009.
Messerli stressed that his conclusions relate to 24-hour ambulatory BP monitoring and that, “When it comes to office BP, HCTZ isn’t that bad. In the clinic, BP [with HCTZ] looks fairly decent, it’s almost as good as other antihypertensive drugs, which means very simply that HCTZ lowers the BP fairly well during the day, when the patient sees the doctor in the office, but at night and early-morning hours, it loses its antihypertensive efficacy, so it creates a false sense of security for the patient and the doctor alike.” 
Messerli in an interview stated that, “In a nutshell, HCTZ has lousy antihypertensive efficacy, there are no outcomes data for it, and it should not be used as initial therapy.” He added that since conducting this analysis, he has pretty much ceased to use HCTZ. “I used it extensively before this analysis, absolutely. I personally use much more chlorthalidone now, for which we have good, solid outcomes data. But unfortunately there are numerous fixed-dose combinations with HCTZ available at the current time, so you cannot escape the use of it completely.” And Messerli says he fears the new US Joint National Committee (JNC) guidelines on hypertension, due to be updated later this year (JNC 8), will continue to recommend use of thiazide diuretics as first-line therapy, “and they are fully aware that thiazides translate—at least to the American physicians—as HCTZ and nothing else.”
Many of the doctors that were asked the same question, said that Messerli had a point, particularly with regard to the lack of antihypertensive strength of HCTZ at doses of 12.5 mg to 25 mg. 
Dr. Stephane Laurent (Paris, France) said, “I think it is important to have this message, but it is for monotherapy only—I am convinced that there is no strong evidence for using HCTZ as first-line monotherapy, but he answered only part of the question.” The broader issue, says Laurent, is whether this is sufficient to consider that HCTZ should not be used in combination. “Most combinations contain a diuretic, and many times there is a volume overload and we need a diuretic,” says Laurent. 
Chair of the late-breaking clinical-trials session, Dr. John Chalmers (George Institute for International Health, Sydney, Australia), commented that Messerli’s data were “provocative, as ever…. The results with diuretics are very dose-dependent: the BP lowering is more effective [with higher doses], so you get more bang for your buck, but you also tend to get more bad bang, side effects are much higher with higher doses. I guess he’s saying that it’s important to differentiate between diuretics because he acknowledged benefits with indapamide and chlorthalidone, so we have to differentiate the specific drug from the class. Duration of action is important: chlorthalidone and indapamide go around the clock. I prefer those because of their longer duration of action.” 
Dr. Michael Alderman (Albert Einstein College of Medicine, Bronx, NY) maintains, “HCTZ is a great antihypertensive. It saves lives.” However he acknowledged, “Chlorthalidone is a more powerful antihypertensive than HCTZ.” 
All other antihypertensives reduce ambulatory BP to a greater extent than HCTZ, as mentioned by Messerli.
So Messerli and his colleagues decided to pull together all the studies in which HCTZ was compared, by 24-hour ambulatory BP monitoring, head-to-head with other antihypertensive drug classes. There were a total of 18 studies. 
“To our big surprise, HCTZ turned out, in its usual dose, 12.5 to 25 mg, to be a rather inferior antihypertensive drug. This is the most commonly prescribed drug in the US and in the world. In the US alone, 135 million prescriptions were written for this drug in 2008, and over 96% of these were for 12.5 mg to 25 mg. Nobody uses 50 mg [because of side effects],” he says.
In their combined analysis, the researchers found that HCTZ alone, at doses of 12.5 to 25 mg per day, reduced ambulatory blood pressure by an average of 7.5 mm Hg systolic and 4.6 mm Hg diastolic. 
The decrease in BP with HCTZ as measured by ambulatory BP monitoring was significantly inferior to that of angiotensin receptor blockers (ARBs) (n=398), beta blockers (n=236), calcium-channel blockers (n=270) and ACE inhibitors (n=209).
Reductions in mean ambulatory BP with HCTZ and other drug classes 

Drug class

Reduction in 24-h ABPM (mm Hg)—systolic

Reduction in 24-h ABPM (mmHg)—diastolic




ACE inhibitors






Beta blockers



Calcium antagonists



Messerli also stated that, “there is no evidence HCTZ reduces morbidity or mortality.  No study showing that 12.5 mg to 25 mg of HCTZ reduces morbidity and mortality.” Messerli said they found one VA study, from 1970, in which a fixed-dose combination of HCTZ and reserpine improved outcomes, but this employed a 50-mg dose of HCTZ, given twice a day, which meant a total HCTZ dose of 100 mg a day. “When you go to 50 mg, HCTZ becomes a pretty decent drug, but at that dose the side effects really prohibit its use,” he explained. 
All other trials that have shown improvements in outcomes with diuretics have employed drugs other than HCTZ, he said, “In SHEP and ALLHAT, chlorthalidone was used, and in PROGRESS it was indapamide.” 
“HCTZ is a lousy antihypertensive drug, inferior to every other single drug class in head-to-head comparisons,” Messerli concluded. “There is no evidence that the most commonly prescribed antihypertensive drug, in its usual dose, reduces heart attack, stroke, or death.”
The JNC guidelines are due to be updated later this year. While eagerly awaiting the new JNC 8 recommendations, many experts are unsure of what to expect in the upcoming publication. 
But Messerli says he isn’t holding his breath, “I have a crystal-ball view. I’m sure the thiazide diuretics again will be unsurpassed and preferred in the new JNC report as first-line therapy.” 

1. Messerli FH, Makani H, Bangalore S, et al. Hydrochlorothiazide is inappropriate for first-line antihypertensive therapy. European Meeting on Hypertension; June 12-16, 2009; Milan, Italy. Abstract LB1.3.

2. Lacourcière Y and Poirier L. Antihypertensive effects of two fixed-dose combinations of losartan and hydrochlorothiazide versus hydrochlorothiazide monotherapy in subjects with ambulatory systolic hypertension. Am J Hypertens 2003; 16:1036-1042.