Aldosterone antagonist therapy in resistant hypertension

Resistant hypertension is defined as an elevated blood pressure (BP) in spite of treatment with three different antihypertensive agents. It is a common clinical problem reported in as many as 15% of patients treated for hypertension in observational studies as well as in hypertension trials [1–3]. The minimum prevalence of resistant hypertension may be estimated from the ALLHAT trial where at the end of the study, approximately 8% of ALLHAT subjects were prescribed four or more medications [4]. Calhoun [5] calculated that an approximate estimate of 15% of the entire cohort would have been classified as having resistant hypertension. This is likely to be a minimum because all patients receiving three drugs or more did not achieve control of BP. Treatment of resistant hypertension is based upon identification and reversal of secondary causes of hypertension. However, in a number of patients, multidrug regimens are needed. The current guidelines do not provide clinical trial-based advice on the optimal choice of third, fourth and fifth line antihypertensive drugs. To date, this issue has not been addressed in proper randomized trials. As primary hyperaldosteronism may be present in a number of patients with resistant hypertension, the hypothesis that aldosterone antagonists may be effective in this setting is worth investigating. Recent clinical studies indicate that the aldosterone antagonist, spironolactone, provides significant additional BP reduction when added to treatment regimens of patients with resistant hypertension. Based on their personal experience, many hypertension specialists routinely use spironolactone in their patients with resistant hypertension. In this issue of the journal, Lane et al. [6] report their experience in a cohort of patients described as having resistant hypertension. Their findings suggest that spironolactone (at a dose of 25–50 mg daily) was effective in lowering BP further when added to a drug regimen including an angiotensin blocking agent. This is consistent with the findings of four previous reports [7–10]. In one of the earliest reports, Ouzan et al. [7] evaluated the BP response to administering spironolactone (1 mg/kg per day) in 25 subjects with refractory hypertension, defined as clinical BP and mean 24-h ambulatory BP greater than 140/90 mmHg in spite of chronic treatment with at least two antihypertensive medications. In most subjects, this included a diuretic and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Nishizaka et al. [8] prospectively evaluated the BP response to adding spironolactone (12.5–50 mg once daily) to the existing regimen of consecutive subjects referred for resistant hypertension and receiving an average of 4 + 1 antihypertensive medications. Thirty-four subjects were diagnosed with hyperaldosteronism based on a suppressed renin activity and a high urinary aldosterone excretion in the setting of high dietary sodium intake. All patients were receiving a thiazide diuretic and an ACE inhibitor and/or ARB. Saha et al. [9] compared the BP effects of amiloride (10 mg daily), spironolactone (25 mg daily), or a combination of both, when used as add-on therapy in African–American subjects with resistant hypertension. Importantly, the study was prospective, randomized, placebo-controlled and double-blind, using a 2 × 2 factorial design with four treatment groups: amiloride, spironolactone, the combination of both drugs, and placebo. Subjects (n = 98) were diagnosed with resistant hypertension because of an elevated BP despite treatment that included a diuretic and a calcium channel blocker and because of possible hyperaldosteronism (level of plasma renin activity ≤ 0.56 ng/l per second). Most recently, Sharabi et al. [10] retrospectively analysed the effectiveness of spironolactone, compared with a standard add-on treatment, in patients referred to a hypertension clinic with uncontrolled hypertension despite the use of two or more antihypertensive drugs. Unfortunately, in all of these studies, the patient population was poorly characterized. A diagnosis of resistant hypertension differed among the studies with respect to both the number and nature of the baseline therapies. Not all patients in the study by Lane et al. [6] were receiving diuretic therapy, and whether secondary hypertension was properly ruled out is uncertain. Although using different approaches, documentation of hyperaldosteronism was performed in studies by Nishizaka et al. [8] and Saha et al. [9]. Ouzan et al. [7] and Lane et al. [6] opted not to characterize primary hyperaldosteronism. In addition to these striking differences, reports of the BP-lowering effect also varied considerably among the studies. The design of all studies except the one by Saha et al. [9] was open and not controlled, which is far from standard practice in hypertension trials. In the absence of a control group, the cause to effect relationship cannot be established and estimation of the size of BP-lowering effects as well as of safety may be seriously confounded. Therefore, the only study where the magnitude of the BP-lowering effect of adding spironolactone may be properly estimated is the controlled study of Saha et al. [9]. In this study, the respective reductions (mean ± SE) in systolic and diastolic BPs were 9.8 ± 1.6 mmHg and 3.4 ± 1.0 mmHg for amiloride (P < 0.001) and 4.6 ± 1.6 mmHg (P = 0.006) and 1.8 ± 1.0 mmHg for spironolactone (P = 0.07). Thus, the effect of spironolactone was much less impressive than in the other non-controlled studies where BP efficacy has most likely been overestimated. Blood pressure lowering may be influenced by the study population, and background therapy as well as by whether patients indeed had hyperaldosteronism. In the study by Lane et al. [6], the decision to recommend spironolactone was influenced by patient age and gender because of a reluctance to recommend this agent in young men owing to possible adverse effect on sexual function. As a consequence, the age (mean ± SE) of the patients was 62.5 ± 12.1 years and 68% were women. This is an important selection bias, which must have overestimated the benefit of addition of spironolactone because older age and female gender are strong predictors of resistant hypertension. Whether screening patients with resistant hypertension for hyperaldosteronism with assessment of the blood aldosterone/renin ratio is to be recommended is unclear. This assessment may not be reliable or readily available in routine clinical practice conditions. Therefore, after having excluded patients with causes of secondary hypertension other than hyperaldosteronism, selecting patients with characteristics most likely to be associated with hyperaldosteronism and trying them with spironolactone appears to be the most pragmatic approach. Primary hyperaldosteronism may warrant larger doses. Therefore, if small, well-tolerated doses are ineffective and higher doses are needed, investigating the patient for primary hyperaldosteronism, which may be cured by surgical treatment may be recommended. Other characteristics may increase the response rate to spironolactone because of the greater likelihood of hyperaldosteronism. Diabetes and obesity are other factors that may be associated with hyperaldosteronism and may therefore predispose to a greater efficacy of spironolactone. In the study by Lane et al. [6], 38% of patients had concomitant type 2 diabetes mellitus and more than one-half were overweight (mean weight = 86.7 ± 16.3 kg). Grim et al. [11] recently demonstrated, in 397 African–American subjects (46% hypertensive and 50% female), that plasma aldosterone correlated significantly with waist circumference, total cholesterol, triglycerides, insulin and the insulin-resistance index. In 17% of subjects, metabolic syndrome was present and plasma aldosterone levels, but not plasma renin activity (PRA), were elevated. The association of aldosterone with BP, waist circumference and insulin resistance suggests that aldosterone may contribute to obesity-related hypertension in blacks. In addition, the authors speculated that relatively high aldosterone and low PRA levels in these hypertensive individuals may reflect a mild variant of primary aldosteronism [11]. Involvement of renin-independent mechanisms has been suggested in the adrenal stimulation of aldosterone secretion in obese patients. In a group of hypertensive obese women, plasma levels of renin were significantly reduced and the aldosterone: renin ratio was increased compared to obese normotensive women [12]. Treatment of adrenocortical cells with low-density lipoprotein (LDL) led to a sensitization towards stimulation by angiotensin II, dramatically increasing angiotensin II-induced aldosterone production [12]. Thus, the increased aldosterone: renin ratio observed in the hypertensive group may be due to the enhanced LDL levels in these patients and/or other adipocyte-derived mineralocorticoid-stimulating factors [12]. Indeed, it has been suggested that other aldosterone secretagogues originating from adipocytes may be operative in patients with overweight [13]. Recent research suggests that obesity-associated hypertension may be causally related to the accumulation of ‘dysfunctional’ adipose tissue, which may induce activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system and oxidative stress and, hence, promote the development of obesity-associated hypertension and hyperaldosteronism [14]. Whether this mechanism is more operative in resistant hypertension is unknown. Whether aldosterone antagonists may be effective in resistant hypertension in the absence of hyperaldosteronism is an intriguing issue, as raised by the study by Lane et al. [6]. The authors recognize the question of whether the benefits of spironolactone are due specifically to aldosterone blockade on the background of renin–angiotensin system blockade or whether they are simply an effect of an increased dose of diuretic. This issue can be addressed only with a specific trial of spironolactone or eplerenone versus varying doses of a thiazide-type diuretic. Even small doses of spironolactone may have an epithelial diuretic effect. Doses of spironolactone used in all the studies of resistant hypertension were low and lowest in the study by Saha et al. [9] where, indeed, the weak effects on plasma renin activity may suggest that spironolactone may have been underdosed. These low doses are in contrast to the doses used in primary hyperaldosteronism, which may rise up to 400 mg daily. The appropriate dosing range for spironolactone has not been well defined in resistant hypertension, nor in primary hyperaldosteronism. The potential risk/benefit of higher doses in resistant hypertension and lower doses in primary hyperaldosteronism needs to be assessed. Interestingly, even though the higher doses may have been more effective, spironolactone was less effective than amiloride in reducing BP in the study by Saha et al. [9]. Amiloride antagonizes the epithelial sodium channel in the distal collecting duct of the kidney, which is upregulated by aldosterone. In hyperaldosteronism states, amiloride may work as an indirect aldosterone antagonist. Other recent studies suggest that amiloride may be effective as an add-on therapy in patients with resistant hypertension [15]. On the other hand, it has been suggested that aldosterone antagonists may be effective at low doses, in the absence of detectable hyperaldosteronism and with pleiotropic effects likely to be unrelated to a diuretic mechanism [16,17]. Safety In the studies of resistant hypertension reported to date, spironolactone at low doses was well tolerated, with little reported adverse effects. Elevations in serum potassium to more than 5.0 mEq/l as well as acute renal failure (blood urea nitrogen increase of at least 50% and a creatinine increase of more than 25%) are the commonest side-effects. They are usually dose related and may resolve after dose reduction or drug discontinuation. They are most frequent in chronic kidney disease. Aldosterone antagonist therapy is contra-indicated in patients with poor renal function (creatinine clearance < 50 ml/min). As resistant hypertension is defined by resistance to a multi-drug regimen including a diuretic, spironolactone should be given in combination with a diuretic that reduces the risk of hyperkalemia. In addition, potassium supplements are to be discontinued. Based on daily experience as well as on the results of heart failure trials and other published work, in high-risk patients, such as elderly patients, patients with chronic kidney disease and/or diabetes, spironolactone therapy may be initiated at the low dose of 12.5 mg. Potassium is to be monitored 1 week and 4 weeks after drug initiation as well as 1 week and 4 weeks after each dose escalation. Moderate increases of serum potassium below 5.5 mEq/l indicated the need to reduce the dose of spironolactone. The drug is to be discontinued if serum potassium rises above 5.5 mEq/l. Non-steroidal anti-inflammatory drugs are to be discontinued and their use discouraged, in general, in the presence of resistant hypertension. This is even more critical when spironolactone is to be initiated because of the enhanced risk of hyperkalemia and renal insufficiency. Other adverse effects of spironolactone include gynecomastia with breast pain in men and less commonly in women, erectile and libido dysfunction, and menstrual irregularities, all of which are typically dose dependent. The largest available dataset reporting on the efficacy and safety of spironolactone in hypertension, although not specifically in resistant hypertension, is the ARTEMIS databank [18]. In 182 patients (51 men and 131 women) who were treated with spironolactone alone during a mean follow-up period of 23 months, a mean dose of 96.5 mg decreased systolic and diastolic BP by 18 and 10 mmHg, respectively, below pre-therapeutic levels. The BP decrease was greater with doses of 75–100 mg (12.4 and 12.2%) than with doses of 25–50 mg (5.3 and 6.5%; P < 0.001) but no additional decrease was found with doses above 150 mg. Plasma creatinine level increased modestly (8.3 μmol/l), as did the plasma potassium level (0.6 mmol/l) (both P < 0.001); Gynecomastia was reversible and dose-related; at doses of 50 mg or less, the incidence was 6.9%, although the incidence was 52.2% for doses of 150 mg or higher. As eplerenone is a selective aldosterone antagonist, with a low affinity for progesterone and androgen receptors, it does not produce such sexual adverse effects. Therefore, it may be a reasonable alternative to spironolactone. However, its effectiveness, although well established in essential hypertension at doses ranging from 100–400 mg daily, has not been specifically evaluated for treatment of resistant hypertension [19–21]. In the EPHESUS trial, doses as low as 25–50 mg have been shown to be effective in decreasing the incidence of cardiovascular outcomes in heart failure patients after myocardial infarction and might be also effective in resistant hypertension. A combination of spironolactone with ACE inhibitor therapy was proven to be effective and safe in hypertensive patients as early as 1990 [22]. More recently, spironolactone combined with ACE inhibitor therapy was shown to be effective and well tolerated in patients with chronic heart failure [23]. Conclusion Resistant hypertension is common, yet very few well designed trials have investigated the role of add-on therapy. As aldosterone may play a significant role in resistant hypertension, and because aldosterone antagonists may also act through a variety of pleiotropic effects beyond their potassium-sparing diuretic effect, there is a need for the characterization of the dose–response relationship as well as clinical benefit and safety of spironolactone and eplerenone in well defined patients with resistant hypertension.