Thiazide-Like: What Are We Really Talking About?

Henry R. Black, MD; Robert W. Morrow, MD


April 06, 2012

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Henry Black, MD: Hi, I'm Dr. Henry Black. I'm a Clinical Professor of Internal Medicine; Director, Hypertension Research, Center for the Prevention of Cardiovascular Disease, at New York University School of Medicine. I'm Immediate Past President of the American Society of Hypertension and a member of the Center for the Prevention of Cardiovascular Disease at New York University. I'm here with my colleague, Bob Morrow. Bob?

Robert Morrow, MD: Hi. I'm an Associate Professor in the Department of Family and Social Medicine, Albert Einstein College of Medicine, and I'm a family practitioner, in practice since 1980. I have my own practice, and I'm also the Associate Director of Interventional Continuing Medical Education at the Center for Continuing Medical Education at Einstein. I think right now we're going to try to address one of the issues that have been bugging me almost all of that time: What's the right thiazide? Some of the studies were done with chlorthalidone. Many were done with other thiazides, particularly hydrochlorothiazide, which is the inexpensive, easily accessible drug nowadays, whereas chlorthalidone is not. When I had substantially more hair, the saying was that if you use chlorthalidone then you deplete potassium stores, and then people have arrhythmias and drop dead. This is not even evidence-based medicine. This is old doctor's tales, but it seemed to engender a shift, and I'm just curious about what we should be doing now. You can't really buy a generic combination of chlorthalidone. Is it better? Is it the same?

Dr. Black: I'm glad you asked this question because this is one of my favorite subjects. When I was starting to practice about a decade before, we had hydrochlorothiazide. Other thiazides, such as trichlormethiazide (Naqua) -- if you remember that one -- were also competing in some ways with chlorthalidone (Regroton, Hygroton). Chlorthalidone was made by USV, a small company, and hydrochlorothiazide (Diuril, Hydrodiuril) was made by Merck, whose marketing power was much more than that of USV. So a thiazide diuretic, most often hydrochlorothiazide, became the drug used, also in combination with other agents. There were 9 of us who worked on JNC 7 and 4 had been ALLHAT principles.[1]

So why was chlorthalidone the drug in ALLHAT? This goes back to the MRFIT study.[2] MRFIT was started in the 1970s and finished at the end of the 1970s. One interesting thing about that trial was that 22 sites could pick either chlorthalidone or hydrochlorothiazide as the diuretic they preferred. Six took chlorthalidone, 9 took hydrochlorothiazide, and the others mixed it. About 2 years into the study, the Data and Safety Monitoring Board noted that the people who were in the treatment group getting hydrochlorothiazide were doing worse than those taking placebo, so they mandated that everybody switch to chlorthalidone, and things evened out. In fact, by the end of the study there was no particular benefit either way. The National Heart, Lung, and Blood Institute made chlorthalidone its diuretic of choice. I was a SHEP investigator, which began in 1984, and we used chlorthalidone.[3] As you know, we had very good results with this diuretic.

I was an ALLHAT principle and we also used chlorthalidone. When that trial was over I think we showed that chlorthalidone was as good as everything else, although one of the confusions was that it didn't show that chlorthalidone was better. Our purpose, however, was to show that newer drugs were better, and we clearly showed that they weren't, regardless of subgroup -- even for heart failure.

When ALLHAT was published, the question I always got from people was, "Why did you morons use chlorthalidone? Nobody uses that." The question I'm getting now from the same people is, "Why don't you use chlorthalidone more?" So that message has gotten there, and, finally, we have fixed combinations that include chlorthalidone. Unfortunately, we don't have a low dose of chlorthalidone.

Dr. Morrow: And it's very expensive.

Dr. Black: It doesn't have to be. It's a generic product. There's a 25-mg dose so that patients I know who [have started using] chlorthalidone since [the] SHEP [results were reported] now cut it in half. You can't get the 6.25-mg dose because you can't cut it in half again. There's a 15-mg dose as well. For a while I couldn't get chlorthalidone, but I kept insisting and now I can. I think it's only a matter of time before people realize that.

Dr. Morrow: So, the general sense of JNC 8, whenever it comes out, would be to stick with chlorthalidone and try to move away from the --

Dr. Black: When we wrote JNC 7, with 4 of us being ALLHAT principles, we said "thiazide-like" diuretic. If we'd said "chlorthalidone" then that guideline would have been dead on arrival because doctors simply didn't use it. I think by now it's a possibility. [Hydrochlorothiazide and chlorthalidone] work in the same place in the nephron in the distal tubule. They have similar metabolic effects. I think Barry Carter and Michael Ernst at Iowa[4] have shown that there is about a 2-in-1 difference,[4]but when we did JNC 7 we couldn't find a single comparison between the 2 drugs that was done after 1979. Now this has been done, and clearly chlorthalidone has longer action so it works better at night, and it also has some interesting properties on carbonic anhydrase inhibition, which may have changes in platelet aggregability and may in fact then show why chlorthalidone does better in the trials. If we're an evidence-based society, as maybe we are, chlorthalidone ought to be what we use. Thanks very much.


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