Diuretic therapy in hypertension

Arterial hypertension (AH) has long been considered merely as a cardiovascular risk factor, negatively affecting the heart, the kidney, and the arteries through the mechanical effect of elevated blood pressure (BP) levels. Accordingly, BP control has long been considered the sole goal of the antihypertensive treatment. Currently, AH is more realistically considered as a syndrome with multiple causes, characterized by the elevation of arterial BP. Some diseases leading to hypertension are well identified, and in these patients, hypertension is defined as ‘secondary’, in the remaining patients, more than 80%; the cause of hypertension is unknown, and it is defined as ‘essential’. However, even in these cases, it is now clear that high BP values are only one of the pathogenetic determinants of target organ damage. Accordingly, it would seem more useful to establish as the goal of therapy not only BP control but also the prevention or the regression of hypertension induced structural changes affecting the cardiovascular system and the other target organs. The value of antihypertensive treatment in reducing mortality stems from old clinical studies using mainly diuretics and sympatholytic drugs,1–3 which enrolled patients with severe hypertension, in whom the deleterious effect of the high BP dominates the clinical picture, thus masking more or less completely other possible causes of organ damage. This finding accounts for the initial assumption that hypertension is simply a cardiovascular risk factor, a concept very popular in an era in which only patients with significant increase in BP were considered hypertensive, and in whom a decrease in BP values was associated with a clear clinical and prognostic improvement. The BP values differentiating hypertension from normotension has been defined by Sir Stanley Rose as the value for which an antihypertensive treatment is more useful than dangerous. This value depends on a balance between the cardiovascular risk brought by the BP values in each patient and the tolerability of each antihypertensive drug. Improving the quality of antihypertensive drugs has prompted a reduction of the threshold for treatment to a BP level with a pathogenetic potential which may be even smaller than that of other determinants of organ damage, widening the scope of hypertension treatment to the prevention or regression of the ‘not pressure dependent’ organ damage.4 The standard cardiovascular risk factors, such as lipid disorders, diabetes mellitus, and so on, occurring more frequently in hypertensive patients than in normotensive patients, play a major role in the genesis of nonpressure-mediated organ damage. Accordingly, it has been speculated that the observation that antihypertensive treatment failed to induce the expected reduction of ischemic heart disease in hypertensive patients may be accounted for by the fact that the initially available antihypertensive drugs, such as high-dose diuretics, interfere with glucose and lipid homeostasis, thus neutralizing the positive effect of BP reduction. As a consequence, it would seem more reasonable to select, whenever possible, antihypertensive drugs favorably affecting the other cardiovascular risk factors, or at least not worsening their effects.5 Therefore, it has been recommended to avoid the high doses of thiazide diuretics, which do not increase the antihypertensive effect but decrease treatment tolerability, reestablishing these drugs to their evidence-based efficacy. More recent studies have confirmed that reduction of morbidity and mortality derives mainly from the reduction of BP, which could be achieved with a variety of antihypertensive drugs, such as calcium antagonists6,7 and renin angiotensin system modulators,8,9 but also suggested that the goals of antihypertensive treatment should be widened to include control of the patient's global risk. This aspect is clearly emphasized in the current guidelines, recommending that the therapeutic choice should be guided not only by the BP values, but rather by the global cardiovascular risk of the patient. It could be more valuable to treat a slightly hypertensive patient with diabetes and other concomitant conditions, than a severely hypertensive patient without other cardiovascular risk factors, as the probability to develop an adverse cardiovascular event is higher for the first patient for the concurrent presence of metabolic impairment and organ damage. This aspect has received particular attention in the International Guidelines, because the various antihypertensive drugs differ in their capacity to achieve a regression of the organ damage. In this regard, the most influential study has certainly been the Losartan Intervention For Endpoint reduction in hypertension,10 demonstrating that, in two groups of hypertensive patients with left ventricular (LV) hypertrophy diagnosed by electrocardiography, an AT1 receptor blocker (ARB), achieving a similar reduction in BP as beta blockers, was associated with a more significant reduction in the LV hypertrophy (cardiac organ damage). For this reason, when patients present with organ damage, the specific recommendation is to use ARBs, rather than diuretics.4 This recommendation implies Anderson et al.'s11 conclusions, outlining that, in a population of hypertensive patients followed for over 20 years, normalizing BP did not normalize the prognosis of these patients as compared with normotensive patients with similar clinical characteristics. It is then advisable to extend the indication for renin angiotensin system modulators as first choice drugs in hypertensive patients, considering the renin angiotensin system as the mediator of the cardiovascular continuum beginning from the simple presence of risk factors for atherosclerosis to its most serious complications. Albeit definitive evidence for this role of the renin angiotensin system are still lacking, nonetheless, there is the opportunity to affect the possible organ damage mechanism, utilizing the antihypertensive effects of drugs interfering with the renin angiotensin system. Currently, there are two possible strategies to achieve this goal: the inhibition of the angiotensin-converting enzyme, blocking the conversion of angiotensin I into angiotensin II, or the blockade of the effect of angiotensin II at the level of the AT1 receptors that are responsible for the vasoconstrictive and the trophic effect of angiotensin II on cardiac myocytes (organ damage). The choice could stem from clinical pharmacology data suggesting a better tolerability for ARBs than for angiotensin-converting enzyme inhibitors. In addition, ARBs provide a more efficient block of the renin angiotensin system at the tissue level, likely responsible for the initial phase of organ damage in hypertension. Evidence-based medicine supports the choice to interfere with the renin angiotensin system in the treatment of hypertension. In fact, the HOPE (Heart Outcomes Prevention Evaluation) study,12 which compared an inhibitor of the converting enzyme with placebo in high cardiovascular risk patients, suggested that modulating the renin angiotensin system could result in a significant reduction of cardiovascular morbidity and mortality independently from the reduction of the BP. Some methodological aspect of the HOPE study, specifically the accuracy of the BP recordings, raised some doubts on its otherwise momentous conclusions. A possible answer to these uncertainties comes from the ONTARGET and TRANSCEND13,14 studies, investigating Ramipril or Telmisartan, or their combination in almost 30 000 patients with characteristics similar to those of the HOPE study, followed for 5 years. The size of the studies, 150 000 patients/year, and the three arm design confirmed the role of angiotensin II in determining cardiovascular damage, thus making the treatment ethically mandatory not only in hypertensive but also in patients with high cardiovascular risk. Finally, a randomized study brought about by General Practitioners15 has shown that patients starting hypertension therapy with thiazide diuretics required more frequent changes in the therapeutic regimen than patients initially treated with other drugs, so that only 50% of them maintained this treatment (Fig. 1). However, about 30% of patients starting with other drugs require diuretic for the control of BP. These data demonstrate that although diuretics no longer represent the first choice as antihypertensive drugs, more than 40% of the hypertensive population requires these drugs for BP control.Fig. 1: Reasons for changes in the treatment regimen according to family doctors.Acknowledgements Conflicts of interest There are no conflicts of interest.