A large number of studies have demonstrated the seemingly preferential benefit of spironolactone to reduce blood pressure (BP) when used as a fourth or fifth medication in patients with uncontrolled resistant hypertension. In one of the earliest studies to have specifically evaluated spironolactone for treatment of resistant hypertension, Ouzan et al. reported in 2002 that a spironolactone dose of 1 mg/kg of body weight per day reduced 24-h ambulatory SBP and DBP by 24 and 10 mmHg, respectively, in 25 patients with uncontrolled BP on an average of three medications. In 2003, Nishizaka et al. extended these findings in reporting that low doses of spironolactone (25–50 mg) provided substantial additional antihypertensive action in both African-American and white patients when added to existing multidrug regimens, including, in all cases, an angiotensin-converting enzyme inhibitor (ACEi) or an AT1 blocker (ARB), amlodipine, and hydrochlorothiazide . This study was also informative in reporting that the antihypertensive benefit of spironolactone was not limited to patients with apparent hyperaldosteronism in that the degree of BP reduction was similar regardless of serum or 24-h urinary aldosterone levels.
The recently published findings of the PATHWAY-2 study firmly establish spironolactone as the most effective fourth drug in patients with uncontrolled resistant hypertension . This study is, by far, the most scientifically rigorous evaluation of spironolactone as add-on therapy having been performed as a double-blind, randomized, crossover evaluation of spironolactone 25–50 mg, bisoprolol 5–10 mg, doxazosin 4–8 mg, and placebo in patients uncontrolled on a standardized three-drug regimen of an ACEi or ARB, calcium channel blocker, and a diuretic. Spironolactone was clearly superior to the other interventions in reducing home SBP by −8.70 mmHg compared with placebo, −4.40 mmHg compared with bisoprolol, and −4.03 mmHg compared with doxazosin. Interestingly, there was a strong inverse relation between BP lowering and the plasma renin concentration, such that the BP reduction induced by spironolactone approached on average 20 mmHg in patients with the lowest renin levels. In contrast, no significant relation was observed between the degree of BP lowering and renin levels with use of bisoprolol or doxazosin. Combined, the findings of the above studies, as well as many others, clearly establish spironolactone as the best fourth antihypertensive agent for treatment of resistant hypertension. Benefit occurs with relatively low doses (25–50 mg), is similar in black and white patients, and although benefit occurs even in patients with high renin levels (or plasma renin activity), it is clearly the most pronounced in patients with suppressed renin, no doubt reflecting some degree of aldosterone excess.
Coinciding temporally with the more recent studies evaluating benefit of spironolactone for treatment of resistant hypertension have been studies evaluating the benefit of renal nerve denervation (RND) also for the treatment of uncontrolled resistant hypertension. As is no doubt well known to the readers of this Journal, early, unblinded assessments of RND reported large reductions in office SBP of more than 25–30 mmHg compared with continued pharmacologic therapy . Recent studies, however, have not always confirmed such large reductions in BP, whereas a limited number of studies have not observed a significance difference between RND and sham procedure [5–7]. Ongoing studies of RND are rigorously testing the benefit of RND both in resistant hypertension and in patients with uncontrolled hypertension while taking no medications.
With studies of spironolactone and RND to treat resistant hypertension seemingly being done in parallel, no studies had directly compared the antihypertensive benefit of spironolactone versus RND in patients with resistant hypertension. With spironolactone having been established as being very effective for treating resistant hypertension and if RND is also confirmed to provide meaningful BP reduction in patients with resistant hypertension, establishing the relative benefit of the two interventions is of considerable interest in at least two regards. First, from a mechanistic standpoint, superiority of spironolactone compared with RND might suggest a more volume-dependent versus neurogenic cause of resistant hypertension (although recognizing that the mechanisms of action of mineralocorticoid receptor blockade and RND are not likely to be mutually exclusive). Second, a comparison of efficacy will begin to address the clinical question of in what order should we use the two approaches if patients remain uncontrolled on a standard three-drug regimen.
In this edition of the Journal of Hypertension, Oliveras et al. provide insight into these considerations in having directly compared the antihypertensive effects of spironolactone versus RND in patients with resistant hypertension . The study was done as an open-label, randomized comparison of adding spironolactone 25–50 mg daily versus RND with use of a single electrode, radiofrequency catheter in patients with uncontrolled BP on three or more antihypertensive medications, one of which was a diuretic. The primary endpoint was a change in 24-h ambulatory SBP at 6-month follow-up. Thirteen patients in the spironolactone arm and eleven patients in the RND arm completed the protocol. Patients randomized to RND received a median of 10 renal artery ablations done by the same trained and experienced interventionalist.
After 6 months of follow-up, the mean reduction in 24-h SBP was significantly superior with spironolactone compared with RND. After adjusting for age, sex, and baseline 24-h SBP, the mean difference between the two treatment groups was −17.9 mmHg. There was also a significant reduction in 24-h ambulatory DBP, also in favor of spironolactone, with a mean difference between the two groups of −6.6 mmHg. Daytime SBP and DBP reflected the superiority of spironolactone, whereas, interestingly, there was no significant difference in night-time BP levels between the two groups. The SBP control rate was also in favor of spironolactone, with 54% of spironolactone-treated patients having a mean 24-h SBP less than 130 mmHg, compared with none who had undergone RND. Overall, there was no significant difference in the change of number or dose of medications between the two groups at the 6-month time point.
If confirmed in larger cohorts, these results, combined with other recent assessments of spironolactone, provide important clinical guidance in suggesting that intensification of diuretic therapy, with a combination of a thiazide diuretic and spironolactone, is superior to RND for treatment of resistant hypertension. The recently published PATHWAY-2 results clearly demonstrate the superiority of spironolactone compared with other classes of antihypertensive agents as the fourth-line antihypertensive agent . The study of Oliveras et al. extends those findings in suggesting that spironolactone is also superior to RND in terms of antihypertensive efficacy as a fourth-line intervention. So, simply in terms of better BP reduction, these current findings suggest that spironolactone would be the appropriate treatment after the initial three medications. However, treating hypertension is not simply about lowering BP, but also about quality of life, long-term persistence of benefit, and affordability. In this regard, additional studies are needed to test the earlier use of both spironolactone and/or RND, perhaps as second-line or third-line treatments, or even as the initial intervention for treating hypertension, either generally or in special subgroups of hypertensive patients that, as of yet, lack identification.
A large body of literature implicates persistent fluid retention as an important cause of antihypertensive treatment resistance [9,10]. Accordingly, recommendations for treating uncontrolled resistant hypertension have been largely predicated on overcoming that fluid retention by intensification of diuretic therapy. Toward that end, use of spironolactone has come to the forefront of treatment options based on increasingly rigorous demonstrations of its preferential benefit as add-on therapy [2,3]. The findings of Oliveras et al. are in line with those recommendations in reporting that spironolactone is likewise superior to RND for treating resistant hypertension. Such superiority is consistent with the conjecture that resistant hypertension is broadly an issue of excess volume as opposed to excess sympathetic output. No doubt, the two mechanisms are not mutually exclusive in that aldosterone excess may stimulate sympathetic output and sympathetic hyperactivity likely promotes sodium and fluid retention. However, assuming the predominant effects of spironolactone and RND are related to their primary mechanisms of action, that is, natriuretic and diuretic effects versus inhibiting sympathetic output, the current study findings suggest that intensification of diuretic treatment, including specifically with preferential use of aldosterone antagonists, may still be the most effective way to treat uncontrolled resistant hypertension. However, it may be that failure to control BP with thiazide/spironolactone combinations identifies patients whose treatment resistance is less volume dependent and is perhaps more likely neurogenic in cause. If so, failure to control BP with spironolactone may predict increased likelihood of a favorable BP response to sympatholytic therapies, such as RND.
Conflicts of interest
Consulting: Valcencia Technologies. Grant Support: Medtronic, ReCor.
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