Pathophysiological mechanisms should be taken into account and guide the treatment of essential arterial hypertension.

In the review on diuretics use in primary hypertension published in the Indian Heart Journal, Professor Mishra, concluded that low-dose thiazide diuretics are safe but lack of the mortality benefit data shown by high-dose, while indapamide (INDAP) and low-dose chlorthalidone (CTDN) have fewer side-effects but continue to provide mortality benefit.

The anti-hypertensive effect of diuretics is mainly based on blood volume reduction determined by enhanced renal sodium and water excretion. However, as a consequence of these effects, diuretics cause a reactive increase in sympathetic and RAAS activity, resulting in opposed vasoconstriction and reduced sodium loss and enhancing metabolic side effects.

Thiazide diuretics have been the mainstay of antihypertensive treatment for almost 40 years and have also been confirmed as a first line choice in the last European Society of Cardiology (ESC) hypertension guidelines and JNC 8. However, even if the evidence about clinical outcomes benefits seems stronger for thiazide-like diuretics, the latest ESC guidelines underline that a real recommendation cannot be given in favor of a specific drug from the available data, especially when considering the lack of randomized head-to-head comparisons.

In the present review it is underlined how CTDN was found superior in preventing cardiovascular complications in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The real value of the ALLHAT study has been widely debated, receiving several criticisms. Among the others, it should be noted that diuretic therapy was withdrawn in several patients at the time of enrollment and many of them had a history of previous myocardial infarction or hypertensive cardiomyopathy: withdrawal of diuretics in such patients could have increased the risk of developing heart failure.

Moreover, hydrochlorothiazide (HCTZ) has often been compared with CTDN, but relatively little is known about HCTZ versus INDAP. It must be underlined that there are only a few trials directly comparing HCTZ with INDAP and all the available trials lack of cardiovascular events as outcomes. However, a systematic analysis of the recent literature did not show a superiority of INDAP over HCTZ in terms of metabolic and/or electrolytes adverse effects.

All in all, when feasible and economically affordable, we believe that treating hypertension by directly counterbalancing its main pathogenetic mechanisms, rather than just reducing blood volume, still remains the most intelligent therapeutic approach. In case the “deflating balloon” approach is sought, repeated phlebotomies, a low-cost and minimally invasive technique, can effectively reduce blood pressure with a mechanism that is independent of insulin resistance. Routine phlebotomies in these patients may reduce health care costs related to the epidemic metabolic syndrome and, eventually, also contribute to increase the rate of blood donations.