E-drug: Re: Hypertension: the ALLHAT study
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Thanks to Kirsten Myhr for summarizing the recently published findings of
ALLHAT. The findings with the diuretic, chlorthalidone, are remarkable.
But ...
It is a mistake to equate the results found in the chlorthalidone arm of
ALLHAT with what would be found with other drugs in the thiazide class. The
reason is that chlorthalidone has a uniquely long duration of action
compared to other drugs in the class.
To illustrate, following are figures give in Table 1.1 on p. 68 of the
latest edition of the Melmon-Morelli textbook, Clinical Pharmacology, 4th
ed.. (New York: McGraw Hill, 2000).
Drug Duration of effect (hrs)
Chlorthalidone 48-72
Hydrochlorothiazide 6-12
Chlorothiazide 6-12
Cyclothiazide 18-24
Bendroflumethazide 6-12
Polythiazide 24-48
Others are listed but none approach the uniquely long duration of effect of
chlorthalidone.
Basically, the long duration of chlorthalidone's action means that it can
'forgive' dosing lapses of 1-2 days' duration, which can be expected to
reduce or even nullify the impact of the most frequently occurring dosing
lapses. From electronic compilation of the dosing histories of ambulatory
patients being treated for hypertension and other chronic diseases, it is
now well established that the most common errors in dosing are, in order of
incidence: (a) a delay of the next-scheduled dose, (b) omission of the
next-scheduled dose, and (c) omission of two sequential doses. Beyond
those, the next most common error is omission of three sequential doses,
then four, and so forth. These errors usually occur episodically. Against
that background of quantitative information, consider the various durations
of diuretic action of the thiazides listed in the table. Clearly,
chlorthalidone will be able to maintain action in the face of 1-2 doses
being occasionaly missed. Polythiazide is, all other things being equal,
the runner-up.
The foregoing perspective indicates the need to recognize a therapeutic
property of prescription drugs, which is called 'forgiveness'. It is
defined as the drug's duration of action after a last-taken dose minus the
recommended interval between doses. Forgiveness denotes the limits of
variation in the timing of successive doses, consistent with full
therapeutic action. From the table, one would estimate that the forgiveness
of chlorthalidone is (48-72) minus 24 = 24-48 hrs. In contrast, the
estimated forgiveness of hydrochlorothiazide is (6-12) minus 24 = minus
12-18 hrs, i.e., incomplete action during part of the interval between
once-daily doses.
Unfortunately, the thinking in the field of hypertension has yet to advance
past the slogan: "once a day is best". It is certainly clear that
prescribing once-daily products does not result in uniformly punctual dosing
by all patients. Abundant data show that the usual errors of delayed dosing
and omitted doses occur in about half of treated patients prescribed
once-daily medicines for hypertension or other chronic diseases. The notion
of forgiveness distinguishes between once-daily products that allow only a
few hours of variation of the interval between doses, and other once-daily
products that allow occasional lapses in dosing of a day or two or even
three without loss of therapeutic action. (The all-time champion for
forgiveness was
reserpine, which has a once-daily dosing regimen and an approximately 2-week
duration of pressure-lowering action. It was one of the two agents used in
the VA Cooperative Trials back in 1970 that first showed the benefits of
treating hypertension, and thus launched the whole field of antihypertensive
pharmacotherapy. The exceptionally clear-cut results of those trials
perhaps arose in part from the exceptional forgiveness of reserpine.) In
contrast, consider atenolol, which is a widely-used, once-daily beta
blocker. It has a mean duration of antihypertensive action of about 30 hrs,
based on careful studies by Johnson & Whelton, in which a controlled
substitution of placebo for active drug was done coincident with continuous
ambulatory blood pressure monitoring. In contrast, another beta blocker,
betaxolol, which has the longest plasma half-life of the commercialized beta
blockers, can maintain blood pressure control out to at least 48 hrs after
the last-taken dose -- clearly a more forgiving agent than atenolol. It is
important to note that these durations of action are not satisfactorily
predicted by plasma half-lives of the drugs, because the antihypertensive
actions of both drugs persist considerably longer than one might expect from
their respective plasma half-life data. The fact is that 'duration of
action' is a pharmacodynamic parameter which has to be measured
experimentally using a protocol similar to that of Johnson & Whelton. That
protocol came originally from the contraceptive field where
placebo-substitution studies were run during the 1980's to define the limits
of dose-timing with low-dose combined estrogen-progestin oral
contraceptives -- another group of once-daily products in which erratic
dosing undermines effectiveness, and patients need reliable data on the
limits on dose-timing consistent with full action.
Given the prevailing mind-set in the hypertension field, it is hardly
possible to introduce an antihypertensive drug that does not have a
once-daily dosing regimen, but some of the resulting products are extremely
unforgiving, e.g., atenolol. What's missing is information on other
antihypertensive drugs, such as Johnson & Whelton provided for atenolol and
betaxolol, on how much forgiveness each product affords, which in turn
informs both prescribers and patients how much latitude they have in
dose-timing to insure full benefits and no interruptions in antihypertensive
drug action.
In contrast to chlorthalidone, a drug like hydrochlorothiazide, which is the
most commonly used of the thiazide diuretics, and often combined with
non-diuretic antihypertensive agents in single dosage forms indicated for
once-daily use, will be correspondingly more impacted by the omission of a
single dose, or two or three doses omitted sequentially.
If we are going to be true to the spirit of 'evidence-based medicine', we
should insist on experimental data on how well the various thiazide products
perform in the face of common errors in dosing by ambulatory patients. The
editorialist for JAMA, commenting on the results of ALLHAT, gives us
pontifical assurance that all thiazides are the same, and that only
"purists" would quibble that there are substantive differences among them.
On the basis of the above considerations, plus simple arithmetic, that view
does not hold water. An intermediate step towards an evidence-based view
would be to model the actions of the various thiazides, based on
experimental data already in hand on their pharmacokinetic/pharmacodynamic
properties, and then simulate how they can be expected to act in the face of
the common errors in dose-timing made by half or more of ambulatory
patients. The final and definitive step, however, is experimental
verification. That is evidence-based medicine. In the interim, the best
advice is to use chlorthalidone in the regimen employed in ALLHAT.
Reference:
Johnson BF, Whelton A. A study design for comparing the effects of missing
daily doses of antihypertensive drugs. Am J
Therapeutics 1: 260-7, 1994.
John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology, Maastricht University,
Maastricht, NL
Chief Scientist, AARDEX Ltd, Zug CH, Maastricht
Vise' BE, Union City, CA USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
home office: 975 Hamilton Ave, Palo Alto, CA 94301 USA
email: urquhart@ix.netcom.com
[if one agrees compliance/concordance in the case of uncomplicated
hypertension is important, then of course this would be a point to consider.
But may be, if the patient is compliant, the long halflife could be
disadvantageous? I have not checked the history of chlorthalidone, but
somebody said chlorthalidone some years ago was discredited and withdrawn in
some countries because of side effects due to high doses being used.
If/when I have checked and found additional useful information, I will post
it on E-drug. The situation now is that some countries hardly have any
thiazides at all as monotherapy. KM]
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