Friday, January 28, 2011

HYDROCHLORTHIAZIDE AS AN ANTI-HYPERTENSIVE. THE CONTROVERSIES.

When I was a medical student, Hydrochlorthiazide ( HCTZ ) was already in use as an anti-hypertensive agent. I remember using alot of it in UHKL, as it was cheap and fairly effective. We were using HCTZ at 50 mg daily. It is true that at that dose, we also saw some patients with hypokalemia, and also impaired glucose tolerance ( those were the days before pre-diabetes ). There were quite a few clinical studies then to support the teaching and use of HCTZ. These were small studies. The larger studies tended to use chlorthalidone and some indapamide.
So it came as somewhat of a surprise to me, when Novartis first came out with an ARB+ diuretic combination, and they chose HCTZ as the diuretic. I remember telling the Novartis rep covering me that your company had made a bad choose. They should have chosen chlorthalidone.
There is a paper now in JACC ( Journal of the American College of Cardiology ), Feb 1st 2011, examining the use of HTCZ as first line in the management of hypertension, as in the current NHLBI guidelines. The paper entitled "Antihypertensive efficacy of HCTZ as evaluated by ABPM. A meta-analysis of randomized trials". J Am Coll Cardiol 2011; 57:590-600. by Dr Frank Messerli et al. is a meta-analysis of 14 large hypertension trials, in the use of HCTZ evaluated by ABPM. The authors concluded that HCTZ at the dose of 12.5-25 mmHg hardly lowers BP. One will need to use 50 mg daily to have any significant effect. And we all know that at HCTZ 50 mg daily, we may run into the side effects of hypokalemia, insulin resistance and also sudden cardiac death.
One wonders why many of the large pharmas, including Novartis, Sanofi Aventis, Boeringher Ingelheim, and Pfizer, had gone on to add HCTZ 12.5-25 mg to their ARB? If what Dr Messerli says is true, then adding the HCTZ would have minimal effect and may in fact be viewed as a marketing strategy, of having you use a diuretic as first-line, and the convincing the practitioner that the logical step next is to have add an ARB i the form of a HCTZ + ARB combo. Knowing full well that HCTZ at 25 mg may do no good. That may not be true if the diuretic used initially was indapamide or chlorthalidone. It would have been better if the large pharmas, hoping to promote combo pills as a firstline, to have an ARB + Chlorthalidone combination, or an ARM + indapamide combination. I suspect that there are such combos on the way. Maybe we have not yet seen it in Malaysia.
I suppose we must keep watching the scene and not take anything for granted. Combination pills are a good concept, but one must also have the right combination. Dr Messerli, seem to suggest that there may be some advantage in a HCTZ + Renin blocker. Early studies seem to suggest that. Of course Novartis have launch their Renin blocker ( aliskerin ). We will need to see more work and results before we are convinced ourselves.
For the moment, it would seem that small dose HCTZ may avoid side effects, but may not be efficacious. So all the Co-ARB drugs may not be as effective as the plain ARB. I think we will be seeing more ARB-chlorthalidone combo pills ans we will certainly watch development in the HCTZ + renin blocker field.

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