E-DRUG: Chlorthalidone vs hydrochlorothiazide (2)
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[This long and highly technical debate is probably more suitable for a scientific journal than for E-drug. However as we started this debate, and as the authors clearly spend some energy in answering the issue, I am posting it here. WB]
dear E-druggers,
Leo Offerhaus, debating with Peter Mansfield, claims that the preferred antihypertensive drug should not be chlorthalidone (CHT), but hydrochlorothiaziade (HTZ), because:
1.. CHT is marketed by a limited number of generic drugs producers
2.. 25 mg of CHT cost double 12,5 mg of HTZ (in Netherlands, we suppose)
3.. Its long half-life could be a disadvantage
4.. the higher doses of CHT could be a major problem due to the loss of potassium
5.. in most European Countries CHT is regarded as obsolete.
Our position coincides with that of P.Mansfield. Regarding Offerhaus's arguments (as above numbered), we want to add that:
1-2) in Italy CHT (12.5-25 mg) costs less than the equivalent dose of HTZ (? 12.7-25 for a year of therapy vs ? 16-32), even if its hypotensive efficacy is 1.5-2 times higher. However both of them cost 5 to 15 times less than an equivalent dose of a calcium channel blocker (CCB) or an ACE-inhibitor (ACE-i) and at least 15 to 20 times less than an equivalent dose of an angiotensin II receptor blocker (ARB).
3) We are not certain that the hypotensive effect of thiazides and CHT is due completely to the excretion of water and sodium, also because after some weeks the bothersome enhanced diuresis tends to diminish and then to disappear, while the hypotensive effect stabilizes at a higher level. Independently of its mechanism of action, there is no doubt of its high hypotensive effectiveness even at lower doses, as demonstrated in many trials, ALLHAT among them.
Its effectiveness and long half-life should rise its potential interest for public health, because it could be used as first line in monotherapy (with the ability of controlling 50% of grade 1 hypertensions, as ALLHAT clearly demonstrated, with huge reductions in the cost of treatment) and once daily, increasing the compliance with this chronic treatment.
Paradoxically, however, these extraordinary advantages have contributed to its misfortune, because the choice of antihypertensive treatment (also in guidelines proposed by important public agencies) seems more driven by the interests of the producers than by those of patients' community and of National Health Services. Therefore the market has privileged the proliferation of thiazides of shorter half-life (the hypotensive effects of HTZ dissipates in about 8 hours (1)), that requires 2 administrations a day, being therefore suitable to be associated with the more expensive ACE-is. So the manufacturers have the advantage of starting the treatment with the more profitable drug (ACE-i, presented as the noble component of the association), at the same time maintaining the substantial advantages of the thiazide (but its contribute is presented as ancillary in comparison with the other drug, that the producers want to sell).
[Incidentally, the hypothesis about the mechanism of action of the thiazide-type diuretics - the increase of diuresis - curiously has not led to favour a merely hemodynamic explanation of their so called "diabetogenic effect". Indeed, and simply, the greater percentage of patients crossing the threshold of 125 mg/dl of glycemia with diuretics (compared with other antihypertensive drugs) can mean that the same total amount of circulating glucose is present, but it is slightly more concentrated in a standard quantity of blood drawn from subjects with a circulating volume slightly reduced, because of the diuresis.
This would explain that there is no excess of cardiovascular (CV) and renal events, as seen in ALLHAT in the subjects treated with CHT that developed a glycemia >125 mg/dl, unlike from what happened in the subjects treated with amlodipine or lisinopril who went above that threshold (2-3). Also the analysis of the CV and renal outcomes in all subjects with a 10 mg/dl increase in baseline fasting glucose shows an interesting similar trend: the risk did not rise in the subjects treated with CHT, while it rose as a trend in those treated with amlodipine, and significantly in those treated with lisinopril. The explanation could be simply that a true diabetes does not develop with diuretics more than with other hypertension drugs, and that the apparent excess of diabetes with diuretics. is not diabetes! As a proof of this, such a "diabetogenic effect" clearly tends to diminish in the long run (4), while, on the other side, the "protective" effect of lisinopril and amlodipina tends to diminish. So in new-onset diabetes the scissor between diuretic and other classes tend to close and not to open, like most authors let wrongly believe.
Such an hypotesis could also explain the apparent anti-diabetogenic effect of ACE-i and ARBs (5-6), amply boasted in spite of the lack of proofs of protective effects in the trials specifically designed for documenting them (7), and strangely without logic consequences on CV outcomes of such presumed effect (2-3-8). It could be simply due to a reduction produced by ACE-i and ARBs of the vascular resistance mediated by the angiotensin II (9), with a possible marginal rise of the circulating plasmatic volume, remaining equal the total amount of glucose in circulation].
Again, about CHT and HTZ effectiveness, the main indirect comparison in MRFIT trial (10) clearly shows the superiority of CHT: in fact the coronaric mortality diminished when the patients receiving HTZ were shifted to CHT, until the Stearing Committee decided to use only CHT. Other basic studies supporting the efficacy of thiazide-type diuretics used CHT (ALLHAT, SHEP, Hypertension detection and follow up program study, Treatment of Mild Hypertension Study).
However a specific meta-analysis (11) of 5 trials shows that the difference of efficacy between CHT and other low-dose diuretics (indapamide and HTZ, with or without triamterene and amiloride) probably is not great.
4) The hypopotassiemia feared with CHT was not a major problem in the double blind RCTs in which the drug has been used in low-doses (12.5, at most 25 mg), but it would be still less frequent in a treatment in which doctors and patients were well aware of the prescribed drug. In fact to all hypertensive patients should firstly be prescribed a diet rich in fruit, vegetables and in vegetable food in general (for instance the DASH-sodium diet), that provides by itself the most physiological and effective integration of potassium, of particular value in a thiazide-type monotherapy.
Rather than spreading poorly justified fears for the hypertensive subjects using low-dose CHT and eating what they should, the doctors should be worried to start monotherapies with ACE-i, for the opposite risk of hyperpotassiemia. In effects ACE-is co-prescribed with integration of potassium have been the drugs more associated with jatrogenic hospitalizations in the USA, and it is paradoxical the success of drugs that must put limits to the main proven dietetic measures effective to lower BP!
Notably, even greater worries of hyperpotassiemia should accompany ARBs monotherapies (9).
5) In most European Countries CHT has been presented as obsolete by the media campaigns of the producers of other drugs, to discredit the strongest competitor of their blockbusters! It has even been at risk (in Italy in 2004) of a stop in its production, that compelled the Ministry of Health to an urgent request of explanations to the producer. We must denounce this self-interested marketing game, that is no evidence-based at all, appealing to everybody that care for the interests of citizens and public health.
To conclude, we must point out that in Italy the annual public spending for hypertension drugs is more than 3 billion Euro, for a total of about 150 DDDs/1000 inhabitants. Of these, only 0.2% are made up by CHT in monotherapy (and little more in association with generic ?-blockers), for an insignificant fraction of the total expenditure. Thiazide and thiazide-type diuretics reach just 1% of the DDDs in monotherapy. In comparison, as not associated drugs, ?-blockers, ?-blockers, CCBs, ACE-is and ARBs respectively cover 3%, 12%, 20%, 28% and 13% of DDDs, and associations of ACE-is and ARBs another 10.3% and 10% of the total DDDs. Furthermore, ACE-is and ARBs cause more than 65% of total public spending for antihypertensive drugs, and another 20% is due to CCBs.
But also the rest of the world does not seem to go any better. Besides, the baffling forced interpretation (12) of the NICE Hypertension Guideline (13), that indicates the dihydropyridinic CCBs as the more cost effective class of drugs because of the ASCOT trial, a trial that others - and we too - have rather considered just publicity (14) or commercial speech (15). Between the heavy consequences of the NICE Guideline, there is a change in the composition of the polypill. In this multidrug pill, proposed as an universal low-cost remedy to cut down more than 80% of CV risk in subjects ?55 years (16), "particularly suitable to countries with medium or low income" with scarce resources assigned to health, one of the six components, the thiazide-type diuretic, has been impudently substituted with a CCB (17).
Ergo, dum Romae consulitur.
Alberto Donzelli - Director of Health Education Service of ASL City of Milan
Maria Font - Assitant Editor of Dialogo sui Farmaci. Verona. Italy
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References
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(3) Barzilay JI et al. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment. Arch Intern Med 2006; 166:2191-2201
(4) Barzilay JI et al. Risk and impact of incident glucose disorders. American Society of Hypertension 19th Annual Scientific Meeting, May 2004, New York
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(7) Bangalore S et al. Effect of Ramipril on the Incidence of Diabetes. N Engl J Med 2007; 356:522-524
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(13) NICE/BHS. Clinical Guideline 34: Hypertension: management of hypertension in adults in primary care: partial update: http://nice.org.uk/CG034guidance (accessed June 28, 2006)
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(17) Reddy KS. The preventive polypill - much promise, insufficient evidence. NEJM 2007; 356:212