June 15, 2009 Lisa NainggolanHydrochlorothiazide (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 [1]. These are the controversial 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 here at the European Meeting on Hypertension 2009 this weekend.
"In a nutshell, HCTZ has lousy antihypertensive efficacy, there are no outcomes data for it, and it should not be used as initial therapy," Messerli told heartwire. 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."
HCTZ weak as monotherapy, but what about in combination?
Most doctors polled by heartwire 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 (Hôpital Europeén Georges Pompidou, 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." Chalmers told heartwire: "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."
Most doctors polled by heartwire 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 (Hôpital Europeén Georges Pompidou, 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." Chalmers told heartwire: "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."
And Dr Gordon McInnes (Western Infirmary, Glasgow, Scotland) said: "I agree with Messerli—and it's not very often I agree with him. We tend to forget that the evidence base for thiazide diuretics is based on trials done in the 1980s and 1990s, when the dose of diuretics that we used was about four times greater than the dose we use nowadays. It's our feeling in the British Hypertension Society that we may have trimmed the dose of diuretics too much, and that that's why they are not so effective. It has worried me for some time that a lot of the comparative studies have used HCTZ as the standard. If your standard is not very effective, your comparisons are therefore a little bit uncertain."
But 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
Messerli explained to heartwire that he had been using HCTZ for 30 years: "I prescribed it to many, many of my patients, and I thought it was a fairly efficacious antihypertensive, and I thought that it reduced heart attack and stroke. But then I came across this paper recently [by Lacourciere et al [2]] and I was rather struck by how little HCTZ actually lowered BP when measured by 24-hour ambulatory means, which is the most accurate, the most thorough way of measuring BP, and that irked me."
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).
Messerli explained to heartwire that he had been using HCTZ for 30 years: "I prescribed it to many, many of my patients, and I thought it was a fairly efficacious antihypertensive, and I thought that it reduced heart attack and stroke. But then I came across this paper recently [by Lacourciere et al [2]] and I was rather struck by how little HCTZ actually lowered BP when measured by 24-hour ambulatory means, which is the most accurate, the most thorough way of measuring BP, and that irked me."
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).
No evidence HCTZ reduces morbidity or mortality
Messerli continued: "And then we were curious: what are the data showing HCTZ reduces heart attack and stroke? There are none. 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."JNC recommendations "deceptive"; JNC 8 eagerly awaited
Messerli says the recommendations of the JNC reports from 1977 to 2003 have thus been "deceptive." The most recent (JNC 7) guidelines state that "in trials comparing diuretics with other classes of antihypertensive agents, diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension," Messerli told the conference. And the JNC 7 recommendations say that, for uncomplicated hypertension, a thiazide diuretic should be used in drug treatment "for most [people], either alone or combined with drugs from other classes," he noted. Due to this dictum, and because HCTZ is cheap, the latter is embraced by regulatory bodies, he says.
Laurent agrees. He told heartwire: "We [Europeans] were disappointed because the JNC 7 put too much emphasis on diuretics, mainly for cost reasons. But the problem is the cost of the drug treatment is small compared with the cost of a stroke or an MI."
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."
Messerli continued: "And then we were curious: what are the data showing HCTZ reduces heart attack and stroke? There are none. 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."JNC recommendations "deceptive"; JNC 8 eagerly awaited
Messerli says the recommendations of the JNC reports from 1977 to 2003 have thus been "deceptive." The most recent (JNC 7) guidelines state that "in trials comparing diuretics with other classes of antihypertensive agents, diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension," Messerli told the conference. And the JNC 7 recommendations say that, for uncomplicated hypertension, a thiazide diuretic should be used in drug treatment "for most [people], either alone or combined with drugs from other classes," he noted. Due to this dictum, and because HCTZ is cheap, the latter is embraced by regulatory bodies, he says.
Laurent agrees. He told heartwire: "We [Europeans] were disappointed because the JNC 7 put too much emphasis on diuretics, mainly for cost reasons. But the problem is the cost of the drug treatment is small compared with the cost of a stroke or an MI."
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."
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