Additional drug treatment in resistant hypertension

Interest in resistant hypertension, customarily defined as failure to control blood pressure (BP) by a treatment based on adequate doses of a diuretic and two additional drugs, has grown enormously in the last few years. This has occurred because previously unknown or abandoned interventional procedures such as renal denervation and carotid receptor stimulation have been found to have promising BP-lowering effects in this clinical condition [1,2]. It has also occurred, however, because of the increased awareness that, depending on the population examined and the level of medical screening, the prevalence of resistant hypertension may range between 5 and 30% of the overall hypertensive population, which means that in Europe many millions of individuals may be affected. Given its high cardiovascular risk [3], this translates into a large number of morbid and fatal events with a high economic burden for public health. The first therapeutic approach to be adopted in resistant hypertension is to add antihypertensive drugs of different classes to the existing treatment in order to oppose the multifactorial origin of a persistently marked BP elevation by as many BP-lowering mechanisms as possible. This can be successful in a number of patients, and respectable BP-lowering effects have indeed been reported with the addition as a fourth treatment step of anti-aldosterone agents, α-blockers and diuretics such as amiloride [4–8]. With few exceptions [9], however, evidence has been obtained by a nonrandomized treatment approach, which means that limited information is available on which drug can be more useful in which type of patients with no or only an unsatisfactorily response to three previous drugs. The article by Bobrie et al.[10] published in this issue of the Journal of Hypertension scores in this direction by comparing, via a randomized trial design, how resistant hypertensive patients respond to two different treatment strategies, one based on the sequential use of different diuretics, each given at low to moderate dose, and the other on the sequential use of different blockers of the renin–angiotensin system. The results showed not only that the former strategy lowered BP more than the latter but also that with the multiple diuretic treatment strategy, the magnitude of the BP reduction was so marked as to bring on-treatment average ambulatory BP values close or within their normal range [7], which was achieved in almost 60% of the previously uncontrolled patients. Although in some patients this was accompanied by some increase in plasma creatinine (possibly due to the BP reduction ‘per se’) and uricemia, the overall inconveniences were limited and treatment discontinuation for adverse events rare. This establishes low-dose multiple diuretic treatment as a feasible therapeutic approach in resistant hypertension. The article by Bobrie et al.[10] has two further merits but also some limitations that are noteworthy. An additional merit is that the therapeutic strategies were selected not empirically but according to pathophysiological and pharmacodynamic considerations. For the strategy based on progressive blockade of the renin–angiotensin system they were, that the renin–angiotensin system may be markedly activated in severe and resistant hypertension [11] and second, that even at high doses, a single angiotensin receptor blocker may not provide full 24-h opposition to the harmful effects of angiotensin II [12] and prevent aldosterone secretion from escaping the initial blockade [13]. For the strategy based on different diuretics they were, that resistant hypertension may be associated with hypervolemia [14] and that the combined administration of different diuretics acting at different renal sites may neutralize the intrarenal counter regulatory mechanisms triggered by an action of a single site only. As to the latter merit, it is commendable that the BP-lowering effect was assessed not just by office but also by ambulatory and home BP measurements. This makes the results extremely solid and offers an example to be followed more frequently by future studies, given that the lowering effect of treatment on the three BPs show quantitative and even qualitative discrepancies [15,16] that do no guarantee that what is seen with one type of measurement is fully reflected by the others. The study of Bobrie et al.[10] also has limitations that warn against concluding that sequential use of a variety of diuretics should be the preferred strategy in all resistant hypertensive individuals. This is because the study recruited patients with a relatively low dose (12.5 mg daily) of hydrochlorothiazide, which left a reserve for the effects of a dose increase and, thus, somehow favored the diuretic-based strategy. Furthermore, resistant hypertensive patients may also have, as a major pathophysiological marker, activation of the sympathetic [17] and renin–angiotensin systems [11], which are linked by an interrelationship of a positive feedback type [18]. These patients might respond more to central agents and α-blockers. They may also benefit from a particularly effective renin–angiotensin system blockade, although the results of its achievement by double or triple drug administration has so far been disappointing not only in hypertension but also in other conditions such as diabetes and heart failure [19–21]. This makes further studies with a controlled design, such as that of Bobrie et al.[10], desirable to expand our knowledge on which treatment should be adopted in which resistant hypertensive patients, based on their different pathophysiological characteristics. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.