[e-drug] Chlorthalidone vs Hydrochlorothiazide

[e-drug@healthnet.org]

E-DRUG: Chlorthalidone vs Hydrochlorothiazide
---------------------------------------------

[dear E-druggers, your moderator has been copied in an offline discussion
between Leo Offerhaus and Peter Mansfield. As the debate might be useful for
professionals selecting essential drugs for hypertension, I asked both
authors whether they agreed to their discussion being public. Here is the
moderator's edited choice. More debate is welcome in E-drug. Wilbert
Bannenberg]

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This debate was preceded by: E-DRUG messages: Abandoned essential medicines
(3) and (7)

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Joel is obviously right that the 2 drugs are different. What the moderator
tried to suggest is that not chlorthalidone but hydrochlorothiazide might be
the preferred drug.

The discussion, which drug is best is then done by exchange of offline
emails:

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From: Leo Offerhaus [mailto:offerhausl@euronet.nl] 
Sent: Saturday, 13 January 2007 11:58 PM
To: Peter Mansfield
Subject: Chlorthalidone

Dear Peter,

I am writing as a former clinician/clinical pharmacologist with some solid
experience in diuretics and their antihypertensive effect. 

Most textbooks, including the BNF, mention chlorthalidone as equivalent to
thiazides. It is definitely not. Chlorthalidone used to be heavily marketed
by Geigy (now part of Novartis) because they did not produce a thiazide. It
is now off patent since many years, and only sold by a limited number of
generics manufacturers. As 25 mg chlorthalidone costs about double 12.5 mg
hydrochlorthiazide or the equivalent dose of bendrofluazide (which for
obscure historic reasons replaced HCT in the UK) there is no clear reason to
use it. On the other hand, its long half-life is a disadvantage rather than
an advantage, because thiazides cannot influence water and sodium diuresis
unless they are excreted in the lumen of the proximal tubule, they don't act
via the blood stream. 

There is a certain threshold value in the urine below which they are
ineffective. The same holds true for loop diuretics (at a lower target), and
that is the main reason why slow-release furosemide is an ineffective
diuretic; the few clinical studies done with that product (marketed because
Hoechst (Aventis) did not have a thiazide available) were not controlled,
and the normal nycthemeral rhythm of diuresis was mistaken for an effect of
the drug.

So seen from the point of view of the mechanism of action chlorthalidone is
inferior to the more rapid acting thiazides unless higher doses are used,
and then potassium excretion becomes a problem because the potassium ion is
transported by a different pump mechanism. The few lethal cases of
hypopotassaemia reported in the literature and to WHO - I have seen such
cases myself many years ago - were almost all caused by the use of
chlorthalidone, and at the height of the popularity of chlorthalidone
combinations with potassium chloride, amiloride or triamterene were often
used. The long duration of action of chlorthalidone (48-72 h) is an
additional hazard, and the difference in handling the potassium ion also has
some connection to its high degree of binding to carbonic anhydrase in the
blood stream. We now know that the lowest dose of HCT, 12,5 mg., is just as
effective in hypertension as the doses originally advocated, and
hypopotassaemia has not been a real problem.

It is interesting that we had the same discussion in Geneva at a meeting of
the Essential Drugs Committee of WHO some years ago with the same
conclusions.

I don't know why the ALLHAT study used chlorthalidone instead of HCT.

Best wishes,

Leo Offerhaus, Bussum, The Netherlands

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[by Peter Mansfield]

Leo,

Thank you but you comments are all about mechanisms. Mechanisms are
important for developing hypotheses but are unreliable for predicting
clinical effects because there may be other mechanisms we don't know about
or our understandings of the mechanisms may be wrong. 

I am aware that chlorthalidone is not a member of the thiazide class.

As a clinician I need to know which antihypertensive drug is most effective
for delaying morbidity and mortality and best gives the best improvement in
QALY/$ regardless of current knowledge of mechanisms.  The ALLHAT trial
found that chlorthalidone 12.5-25mg is slightly better on the key clinically
significant endpoints than the more expensive alternatives. 

I am not aware of any such good evidence to support any of the thiazides.
The Australian ANBP2 trial of "diuretics" (mostly HCT) found them slightly
worse than ACE Inhibitors. (Wing LM, et al. A comparison of outcomes with
angiotensin-converting--enzyme inhibitors and diuretics for hypertension in
the elderly. N Engl J Med. 2003 Feb 13;348(7):583-92.)

Consequently my first choice for hypertension is chlorthalidone. I don't
want it to be effective as a diuretic. I want it to be effective for
delaying morbidity and mortality. 

regards,

Peter

Dr Peter Mansfield
GP
Director, Healthy Skepticism Inc
Countering misleading drug promotion.
www.healthyskepticism.org
Receive free Healthy Skepticism Updates about once a month:
www.healthyskepticism.org/lists/?p=subscribe
Research Fellow, Discipline of General Practice, University of Adelaide
peter.mansfield@adelaide.edu.au See publication list at:
www.adelaide.edu.au/directory/peter.mansfield

----

Dear Peter,

An important issue is price as long as the effect is approximately the same.
If you are happy with chlorthalidone, then use it. In most European
countries it is regarded as obsolete. 

I don't know about any randomized trials comparing chlorthalidone with HCT
in low doses; perhaps Lindon Wing knows or can retrieve them. Such studies
are uninteresting and not required by registration authorities, and might
therefore be absent from the literature. I only tried to explain my
preference for thiazides on the basis of their comparative pharmacological
and pharmacokinetic properties.  

There is now little doubt that the antihypertensive effect of thiazides and
related drugs is only the result of the diuretic and natriuretic effect and
not by - unproven - vasodilator effects. Pickering and Borst already told us
50 years ago.

Best wishes,

Leo Offerhaus
---
Leo,

We have different beliefs about what questions are important and how they
should be answered. 

You may not be interested to know which drug is best for delaying heart
attacks and stokes for people with high blood pressure but that question is
interesting for them and the clinicians (like me) who care for them.
Currently we don't know which is best: chlorthalidone 12.5mg or
hydrochlorothiazide 12.5mg. 

Decisions about drugs should not be based on conforming with peer pressure
such as the European belief that chlorthalidone is obsolete that you
mentioned. (see: http://en.wikipedia.org/wiki/Argumentum_ad_populum).  It is
in the interests of drug companies to mislead people to think that all off
patent drugs are obsolete except for drugs that are being sold in
combination with more expensive drugs (as is happening with
hydrochlorothiazide).

Decisions about drugs should be based on evidence re clinically important
endpoints (eg heart attacks and strokes) rather than on mechanisms. You
could prove that low dose chlorthalidone has no known mechanism but if it is
better than other drugs and placebo for delaying heart attacks and stokes
then it is the drug we should use. If a drug is effective clinically despite
basic science evidence ruling out all known mechanisms then either the basic
science is wrong or it works via an unknown mechanism.

Decisions about use of drugs in low doses should not be based entirely on
adverse reaction reports for those drugs at higher doses.

There is no good evidence re which drug is best for delaying heart attacks
and stokes for people with high blood pressure out of chlorthalidone 12.5mg
and hydrochlorothiazide 12.5mg.

All we have that I am aware of is:

Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB,
Bergus GR. Comparative antihypertensive effects of hydrochlorothiazide and
chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006
Mar;47(3):352-8.

This small study found that chlorthalidone was more effective for reducing
24 hour BP. The study was too small and short to measure clinically
important endpoints. Also, whilst subjects started on 12.5mg doses they were
titrated up to higher doses. 

The other evidence that we have is the high quality ALLHAT study which found
chlorthalidone 12.5 - 25mg was slightly superior to more expensive drugs.
There is no study of similar quality that included hydrochlorothiazide. 

I conclude that we don't know which is best out of chlorthalidone and
hydrochlorothiazide but there is better evidence supporting chlorthalidone
so until we have better evidence we should use chlorthalidone as the first
line drug. 

The lack of good quality evidence re which drug should be first line for
high blood pressure is another example of market failure. 


regards,

Peter

Dr Peter Mansfield
GP
Director, Healthy Skepticism Inc
Countering misleading drug promotion.
www.healthyskepticism.org
Receive free Healthy Skepticism Updates about once a month:
www.healthyskepticism.org/lists/?p=subscribe

Research Fellow, Discipline of General Practice, University of Adelaide
peter.mansfield@adelaide.edu.au See publication list at:
www.adelaide.edu.au/directory/peter.mansfield