Resistant hypertension (RHTN) is defined as high blood pressure (BP) that requires more than three medicines to treat . The exact prevalence of RHTN is unknown but cross-sectional studies suggest that it affects approximately 10–15% of patients being treated for hypertension by primary care physicians . Patients with RHTN are at increased cardiovascular risk compared with patients with more easily controlled hypertension as suggested by an increased likelihood of comorbidities, such as left ventricular hypertrophy, chronic kidney disease and obstructive sleep apnea, as well as by outcome studies indicating higher rates of cardiovascular complications [3,4].
Treatment of RHTN is predicated upon lifestyle changes and use of effective antihypertensive combinations. We have recently shown that patients with RHTN are exquisitely salt-sensitive such that intensive dietary salt restriction can provide substantial BP reductions . As with hypertension in general, weight loss, regular exercise, and moderation of alcohol will also facilitate BP control.
If tolerated, a regimen consisting of a thiazide diuretic, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), and a long-acting calcium channel blocker is recommended as the initial triple combination for patients needing multiple medications [1,6]. This combination is generally effective and well tolerated and can be prescribed with the use of generic medications or with one or two pills with the use of combination products. Given its superior efficacy, chlorthalidone is recommended for preferential use in patients who remained uncontrolled on less-potent thiazide diuretics [1,7].
The renin–angiotensin–aldosterone system (RAAS) is the main regulator of sodium and fluid balance, and one of the major mechanisms involved in the pathogenesis of hypertension . The development of pharmacologic antagonists to its various components has proved useful in the treatment of hypertension and related target-organ damage. Dual (or even triple) blockade of the RAAS has been used in an attempt to provide greater BP control and/or additional target-organ protection. ACE inhibitors, ARBs, mineralocorticoid receptor blockers and, more recently, renin inhibitors are available to block the RAAS.
Dual blockade of the RAAS with mineralocorticoid receptor antagonists, specifically spironolactone, in combination with an ACE inhibitor or ARB, is now routinely commonly used to treat RHTN. Such use is based on a large number of studies demonstrating specific benefit of aldosterone blockade for treating RHTN [9–13]. The Anglo-Scandinavian Cardiac Outcomes Trial investigators, for example, reported that spironolactone, when added as a fourth antihypertensive drug, reduced BP on average by an additional 20/10 mmHg . Persistence of antihypertensive benefit of spironolactone was observed even at 15-months follow-up.
Although consistent in their findings, the studies reporting substantial benefit of spironolactone for treatment of RHTN have been limited in being open-label assessments and, in general, without the use of an active comparator. It had not been previously addressed whether the observed benefit of spironolactone when used as an add-on therapy for RHTN is unique or the same degree of benefit would occur with the use of other classes of agents. The degree of antihypertensive benefit of adding spironolactone observed in these prior studies seems to be larger than would be anticipated with other classes of agents when used as add-on therapy, but such a presumption had never been rigorously tested. In a retrospective analysis, spironolactone was superior to other classes of drugs as add-on therapy for RHTN , but prospective, randomized assessments of such benefit had been lacking.
In this issue, Alvarez-Alvarez et al.  provide a randomized comparison of spironolactone versus another class of drug for treating RHTN. Forty-two patients with true RHTN, as determined by ambulatory BP monitoring, entered into an open-label, crossover evaluation in which patients received, in addition to their current treatment, an ACE inhibitor if they were already being treated with an ARB, or an ARB if they were being treated with an ACE inhibitor. After withdrawal for 1 month of the added RAAS blocker, patients received spironolactone. Change in BP was compared after 12 weeks of treatment with dual RAAS blockade or spironolactone. The study results are remarkable in that spironolactone reduced office BP by 32.2/10.9 mmHg and 24-h ambulatory BP by 20.8/8.8 mmHg. In contrast, dual RAAS blockade with ACE inhibitor/ARB combinations reduced BP by considerably less, reducing office BP by 12.9/2.2 and 24-h ambulatory BP by 7.1/3.4 mmHg. The degree of BP reduction induced by spironolactone was striking and much larger than has been reported in other studies of patients with RHTN.
The study is strengthened by its randomized design and use of ambulatory BP monitoring to verify antihypertensive efficacy. The study would have been even stronger if done in a blinded fashion and if the study medications had been given in random order. Having all participants received the dual RAAS blockers followed by spironolactone raises concern of a carryover or order effect. Even with these weaknesses, however, the study likely represents the most scientifically rigorous assessment to date of spironolactone as add-on therapy for RHTN.
The current study findings are clinically important in confirming the broad benefit of low-dose spironolactone (generally 25 mg) for treating RHTN. Clearly, use of spironolactone should be considered in all patients whose BP remains uncontrolled after three drugs. The study results are also important in arguing against combining ACE inhibitors and ARBs as a treatment strategy for RHTN. The superiority of add-on spironolactone compared with dual RAAS blockade with ACE inhibitors/ARB combination supports the general therapeutic approach of combining classes of antihypertensive agents with different mechanisms of actions as opposed to using classes of agents with similar or overlapping mechanisms of actions. Additional randomized assessments of spironolactone compared with other classes are needed to further test the validity of preferentially using it compared with other agents for treatment of RHTN. However, it is difficult to imagine a single agent of any class providing the magnitude of antihypertensive benefit observed with spironolactone that has now been reported multiple times by different investigators worldwide.
From a mechanistic standpoint, it remains an intriguing question as to why spironolactone is so effective for treating RHTN compared with other classes of agents. High aldosterone levels are common in patients with RHTN [16,17], and it is not surprising that spironolactone is effective in such patients. It is surprising, however, that spironolactone is equally effective in patients with normal or even low aldosterone levels. Multiple studies [10,12], including now the study of Alvarez-Alvarez et al. , have reported that spironolactone is broadly effective in treating RHTN, with the BP response unrelated to plasma or urinary aldosterone levels, plasma renin activity, or aldosterone/renin ratios. Possible explanations for such a dissociation between BP effect and measured aldosterone levels include that circulating levels of aldosterone do not reflect effective levels within critical organs or tissue beds such as the kidney or vasculature; that important pressure effects of aldosterone occur independent of mineralocorticoid receptor activation, that is, through the so-called nongenomic effects; or that mineralocorticoid receptors are being stimulated by hormones other than aldosterone, such as cortisol. Distinguishing among these possibilities may allow for development of even more effective treatment options for RHTN.
1 Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al
. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51:1403–1419.
2 Egan BM, Zhao Y, Rehman SU, Brzezinski WA, Clyburn B, Basile JN, et al
. Treatment resistant hypertension in a community-based practice network. J Clin Hypertens 2009; OR-12:A6 (abstract).
3 Cuspidi C, Macca G, Sampieri L, Michev I, Salerno M, Fusi V, et al
. High prevalence of cardiac and extracardiac target organ damage in refractory hypertension. J Hypertens 2001; 19:2063–2070.
4 Pierdomenico SD, Lapenna D, Bucci A, Di Tommaso R, Di Mascio R, Manente BM, et al
. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant and true resistant hypertension. Am J Hypertens 2005; 18:1422–1428.
5 Pimenta E, Gaddam KK, Oparil S, Aban I, Husain S, Dell'Italia LJ, et al
. Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 2009; 54:475–481.
6 Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al.
Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens
7 Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, et al
. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006; 47:352–358.
8 Pimenta E, Calhoun DA, Oparil S. Etiology and pathogenesis of systemic hypertension. In: Crawford MH, DiMarco JP, Paulus WJ, editors. Cardiology. Philadelphia: Elsevier; 2009. pp. 511–522.
9 Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H, et al
. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49:839–845.
10 Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003; 16:925–930.
11 Ouzan J, Perault C, Lincoff AM, Carre E, Mertes M. The role of spironolactone in the treatment of patients with refractory hypertension. Am J Hypertens 2002; 15:333–339.
12 de Souza F, Muxfedlt E, Fiszman R, Salles G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension 2009; 55:147–152.
13 Lane DA, Shah S, Beevers DG. Low-dose spironolactone in the management of resistant hypertension: a surveillance study. J Hypertens 2007; 25:891–894.
14 Sharabi Y, Adler E, Shamis A, Nussinovitch N, Markovitz A, Grossman E. Efficacy of add-on aldosterone receptor blocker in uncontrolled hypertension. Am J Hypertens 2006; 19:750–755.
15 Alvarez-Alvarez B, Abad-Cardiel M, Fernandez-Cruz A, Martell-Claros. Management of resistant arterial hypertension: role of spironolactone versus double blockade of the renin–angiotensin–aldosterone system. J Hypertens
16 Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, Calhoun DA. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med 2008; 168:1159–1164.
17 Eide IK, Torjesen PA, Drolsum A, Babovic A, Liledahl NP. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens 2004; 22:2217–2226.