Resistant hypertension, defined as a failure of concomitant. Efficacy of Low-Dose Spironolactone in Subjects With Resistant Hypertension

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1 AJH 2003; 16: Efficacy of Low-Dose Spironolactone in Subjects With Resistant Hypertension Mari Konishi Nishizaka, Mohammad Amin Zaman, and David A. Calhoun Background: Previous reports have demonstrated the antihypertensive efficacy of high doses of spironolactone in subjects with primary aldosteronism and, to a lesser degree, subjects with resistant hypertension. Methods: In current analysis, we examined the antihypertensive benefit of adding low-dose spironolactone to multidrug regimens that included a diuretic and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in subjects with resistant hypertension with and without primary aldosteronism. Subjects referred for resistant hypertension were evaluated with an early morning plasma renin activity, 24-h urinary aldosterone and sodium during a high dietary salt ingestion. The diagnosis of primary aldosteronism was confirmed with a renin activity 1.0 ng/ml/h, urinary aldosterone 12 g/24 h and urinary sodium 200 meq/24 h. After biochemical evaluation, spironolactone (12.5 to 25 mg/d) was added to each subject s antihypertensive regimen. If blood pressure (BP) remained uncontrolled, the dose of spironolactone was titrated up to 50 mg/d. Follow-up BP was determined at 6 weeks, 3 months, and 6 months. Results: A total number of 76 subjects were included in the analysis, 34 of whom had biochemical primary aldosteronism. Low-dose spironolactone was associated with an additional mean decrease in BP of 21 21/10 14 mm Hg at 6 weeks and 25 20/12 12 mm Hg at 6-month follow-up. The BP reduction was similar in subjects with and without primary aldosteronism and was additive to the use of ACE inhibitors, ARBs, and diuretics. Conclusions: We conclude that low-dose spironolactone provides significant additive BP reduction in African American and white subjects with resistant hypertension with and without primary aldosteronism. Am J Hypertens 2003;16: American Journal of Hypertension, Ltd. Key Words: Resistant hypertension, spironolactone, aldosterone, renin, ethnicity. Resistant hypertension, defined as a failure of concomitant use of three or more different classes of antihypertensive agents to control blood pressure (BP) to 140/90 mm Hg, remains a common clinical problem. Recent clinical trials suggest that 30% of hypertensive patients may be resistant to triple therapy combinations. 1 In the recently completed Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 34% of subjects did not reach goal BP in spite of use of an intensive multidrug approach. 2 The cause of treatment resistance is in most cases multifactorial, including such factors as poor adherence, obesity, vascular stiffening, or underlying chronic renal disease. Another contributing factor may be failure of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) to suppress circulating aldosterone, 3 6 which may blunt the effect of conventional antihypertensive therapy. Previous reports document the antihypertensive benefit of spironolactone in subjects with primary aldosteronism (PA), 7 14 low or normal renin hypertension, and in a small group of subjects with resistant hypertension. 22 The doses of spironolactone used in these previous studies were usually high (100 to 400 mg/d) and spironolactone was used as monotherapy or in the absence of ACE inhibitors or ARBs. In some of these studies, BP response to spironolactone therapy was correlated with baseline renin activity or aldosterone excretion. The current study was designed to examine in the antihypertensive benefit of low-dose spironolactone (12.5 to 50 mg/d) as an add-on therapy in subjects with resistant hypertension, defined as uncontrolled BP in spite of three or more different antihypertensive agents including both a diuretic and ACE inhibitor or ARB. In all subjects, plasma renin activity (PRA) and 24-h urinary aldosterone excretion had been determined before administration of spironolactone, allowing for correlation of BP response to underlying renin-aldosterone status. Received April 30, First decision June 26, Accepted July 9, From Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, Alabama. This work was supported by American Heart Association Grant-in- Aid N (DAC) and National Heart, Lung, and Blood Institute Grant HL (MAZ). Address correspondence and reprint requests to Dr. Mari K. Nishizaka, 115 CHSB-19th, 933 South 19th Street, Birmingham, AL 35294; marikn@uab.edu 2003 by the American Journal of Hypertension, Ltd. Downloaded from Published by Elsevier Inc /03/$30.00 doi: /s (03)01032-x

2 926 LOW-DOSE SPIRONOLACTONE AND RESISTANT HYPERTENSION AJH November 2003 VOL. 16, NO. 11, PART 1 Methods Subjects This study was approved by the University of Alabama at Birmingham Institutional Review Board and all subjects provided written informed consent before enrollment. All of the subjects had been enrolled into a study determining the prevalence of primary aldosteronism in subjects with resistant hypertension. 23 The current analysis included consecutive subjects enrolled into that protocol over a 24-month period who completed the biochemical evaluation for primary aldosteronism and whose subsequent change in antihypertensive treatment was limited to the addition of spironolactone. Resistant hypertension was defined as uncontrolled hypertension, as determined at two or more clinic visits, in spite of use of three or more antihypertensive medications at pharmacologically effective doses including a diuretic, an ACE inhibitor, and/or an ARB. Subjects were required to have been on the same antihypertensive regimen for at least 4 weeks before biochemical evaluation. Spironolactone, triamterene, or amiloride was discontinued for at least 6 weeks before biochemical evaluation. Serum potassium levels were corrected with oral supplementation to be 3.5 meq/l before evaluation, if necessary. Secondary causes of hypertension other than PA, such as renovascular hypertension, pheochromocytoma, or Cushing s syndrome had been excluded by laboratory analysis or radiological imaging as clinically indicated. Biochemical evaluation was done in all subjects on an outpatient basis. An early morning plasma aldosterone concentration (PAC), PRA, serum potassium, blood urea nitrogen (BUN), and creatinine were determined. A 24-h urinary collection for aldosterone (Ualdo), sodium (UNa), and creatinine was obtained during the subject s ad-lib diet. If the PRA was suppressed ( 1.0 ng/ml/h) and Ualdo was elevated ( 12 g/24 h) with UNa 200 meq/24 h, the urine collection was repeated after 3 days of dietary salt supplementation. Biochemical PA was diagnosed if the PRA was suppressed ( 1.0 ng/ml/h) and the 24-h urinary aldosterone excretion was high ( 12 g/24 h) during high dietary sodium ingestion ( 200 meq/24 h) After biochemical evaluation, all subjects included had been prescribed low-dose spironolactone, 12.5 to 25 mg/d, for continued lack of BP control. Blood pressure assessments were done at 6 weeks, 3 months, and 6 months. Serum potassium, BUN, and creatinine were checked at each follow-up visit and 2 weeks after initiation and uptitration of spironolactone therapy. Blood pressure was measured according to American Heart Association guidelines by trained clinicians. Seated assessments were done at each visit, at least twice (3 min apart) using a conventional mercury sphygmomanometer. If the subject s BP was not controlled, the spironolactone dose was increased up to 50 mg/d. Laboratory Methods The PAC, PRA, Ualdo, and UNa were measured by commercial laboratories using standard techniques. The PAC and PRA levels were measured by radioimmunoassay (Quest Diagnostics, Atlanta, GA). The reference range for PAC is 4.0 to 31.0 ng/dl. The reference range for an upright PRA is 1.31 to 3.95 ng/ml/h. Ualdo was measured by radioimmunoassay (Mayo Clinic Laboratories, Rochester, MN). The reference range for Ualdo is 2 to 16 g/24 h. Statistics Values are expressed as mean SD. Values between groups or between time period were compared by Student t test or by one-way ANOVA. A potential correlation between biochemical values and BP reduction was evaluated by linear regression analysis. A P value.05 was considered significant. Results A total of 76 subjects were included in the analysis, including 41 African American and 35 white subjects (Table 1). Seventy-five percent of the subjects had low renin hypertension defined as a PRA 1.0 ng/ml/h. Thirty-four subjects were diagnosed as having PA. Compared to subjects without PA, subjects with PA were younger (52 11 v years, P.05), had higher diastolic BP levels (95 13 v mm Hg, P.05), and were receiving a greater number of antihypertensive medications ( v , P.05) (Table 1). Subjects with PA were more often hypokalemic or receiving potassium supplements upon presentation compared to subjects excluded from having PA (50% v 12%, P.05). The mean decrease in systolic and diastolic BP was and mm Hg, respectively, after 6 months of spironolactone therapy (Fig. 1). The BP response was similar in subjects receiving an ACE inhibitor or an ARB. The mean number of prescribed antihypertensive medications decreased significantly from baseline compared to 6-month follow-ups ( v , P.05). No significant correlation was found between the degree of BP reduction and baseline biochemical parameters (PAC, PRA, PAC-to-PRA ratio, or Ualdo), body mass index (BMI), or age. This antihypertensive response to spironolactone was similar in subjects with or without PA (Fig. 2). However, PA subjects were more likely to be titrated up to spironolactone 50 mg/d (16 of 34 or 47% v 5of42or12%,P.05). The mean dosage of spironolactone at 6-month follow-up was higher in PA subjects compared to non-pa subjects ( v mg/d, P.05). The number of prescribed antihypertensive medications was similarly reduced in both PA and non-pa subjects at 6-month follow-up ( v ). African American subjects were younger (52 12 v 60

3 AJH November 2003 VOL. 16, NO. 11, PART 1 LOW-DOSE SPIRONOLACTONE AND RESISTANT HYPERTENSION 927 Table 1. Baseline characteristics of evaluated subjects Characteristic Total PA non-pa N Age (y) (30 82) * Male/female 31/45 21/13 10/32* Race: African American/non-African American 45/31 21/13 24/18 BMI (kg/m 2 ) ( ) Systolic BP at baseline (mm Hg) ( ) Diastolic BP at baseline (mm Hg) (62 124) * Number of antihypertensive medications (3 6) * Serum potassium (meq/l) ( ) * Serum sodium (meq/l) ( ) * PAC (ng/dl) ( ) * PRA (ng/ml/h) ( ) * ARR (23 155) * Ualdo ( g/24 h) ( ) * Random UNa (meq/24 h) (58 361) Potassium excretion (meq/24 h) (19 133) * Final dosage of spironolactone (mg/d) ( ) * Values mean SD (range). PA primary aldosteronism; BP blood pressure; PAC plasma aldosterone concentration; PRA plasma renin activity; ARR PAC to PRA ratio; Ualdo urinary aldosterone; UNa urinary sodium. * Different from PA subjects, P years, P.05) and heavier (BMI v kg/m 2, P.05); however, baseline BP and biochemical parameters did not differ significantly (Table 2). Spironolactone-induced reduction in BP was similar in African American and white subjects (Fig. 3). The mean dosage of spironolactone at 6-month follow-up did not differ significantly by ethnicity (African American v white mg/d). During follow-up, 10 subjects experienced adverse effects attributed to spironolactone use. Breast tenderness occurred in 3 of 76 or 4% of the subjects (all three were men). Acute renal insufficiency (BUN 30 mg/dl or 50% increase from baseline or serum creatinine 1.5 mg/dl or 25% increase) occurred in five subjects. In four of these subjects, the acute renal insufficiency occurred in the setting of a large BP reduction and resolved upon discontinuation of the spironolactone. In three of these subjects, spironolactone was resumed at a lower dose with stable renal function. Hyperkalemia (serum potassium 5.5 meq/l) occurred in two subjects. Both of these subjects had chronic kidney disease with a calculated creatinine clearance 60 ml/min. Discussion This is the first report to demonstrate that low doses of spironolactone can induce substantial BP reduction when FIG. 1. Spironolactone-induced reduction in systolic blood pressure (BP) (filled bars) and diastolic BP (open bars) at 6weeks, 3 months, and 6months follow-up in subjects with resistant hypertension (n 76). BP reduction was significant at all time points compared to baseline. FIG. 2. Spironolactone-induced reduction in systolic blood pressure (SBP) and diastolic BP (DBP) at 6weeks, 3 months, and 6 months follow-up in subjects with primary aldosteronism (filled bars, n 34) and without primary aldosteronism (open bars, n 42). BP reduction was not significantly different between primary aldosteronism and non-primary aldosteronism subjects at any time point.

4 928 LOW-DOSE SPIRONOLACTONE AND RESISTANT HYPERTENSION AJH November 2003 VOL. 16, NO. 11, PART 1 Table 2. Baseline characteristics of African American and white subjects Characteristic Black White N Age (y) * Male/female 12/33 19/12* BMI (kg/m 2 ) * Systolic BP at baseline (mm Hg) Diastolic BP at baseline (mm Hg) Number of antihypertensive medications PAC (ng/dl) PRA (ng/ml/h) ARR Ualdo ( g/24 h) Random UNa (meq/24 h) Final dosage of spironolactone (mg/d) Values mean SD (range). Abbreviations as in Table 1. * Different from non-african American subjects, P.05. added to multidrug regimens that include ACE inhibitors and/or ARBs and diuretics. This benefit was true of subjects with and without evidence of primary aldosteronism. Previous reports clearly demonstrate the antihypertensive efficacy of high-dose spironolactone in subjects with PA In an early report, 95 subjects with PA, of whom, 37 had aldosterone-producing adenoma (APA), were treated with spironolactone, 50 to 400 mg/d (average dose, 300 to 400 mg/d) and had a mean BP reduction of 52/27 mm Hg among APA subjects and 45/20 mm Hg among non-apa subjects. 11 In a separate study, Ghose et al 8 reported that APA could be effectively managed medically with 100 to 200 mg/d of spironolactone. In a recent publication, Ouzan et al 22 described the efficacy of spironolactone in 25 subjects with resistant hypertension. Spironolactone therapy was initiated at doses lower than previous reports (1 mg/kg), but presumably 50 mg/d, which is higher than the mean dosage FIG. 3. Spironolactone-induced reduction in systolic blood pressure (SBP) and diastolic BP (DBP) at 6weeks, 3 months, and 6 months follow-up in African American (filled bars, n 45) and white (open bars, n 31) subjects with resistant hypertension. BP reduction was not significantly different between African American and white subjects at any time point. used in the current study. As the investigators did not provide the subjects body weight, the precise dosage was not reported, however, the addition of spironolactone was effective, lowering systolic BP from 152 2to128 2 mm Hg and diastolic from 86 2to76 2 mm Hg, while allowing for the reduction of prescribed antihypertensive medications from to The baseline biochemical parameters (renin or aldosterone) of the study subjects were not reported. The current study is novel in that the antihypertensive benefit as add-on therapy of a low-dose of spironolactone is clearly demonstrated in subjects uncontrolled on multidrug regimens. At these doses, the BP response was not different among subjects with or without PA and was not predicted by the underlying renin activity or aldosterone excretion, in contrast to some previous reports. 10,18,26 This discrepancy may be related to the differences in mean dosages of spironolactone between the current and previous reports. It is also possible that concurrent medication effects may have obscured a possible correlation between BP response and renin-aldosterone status. Although stable use of most antihypertensive agents does not appear to interfere with aldosterone excretion, some agents, specifically -blockers, may alter the relationship between PRA and PAC, and thereby the PAC-to-PRA ratio. 27,28 This or other drug effects may have altered a potential correlation between these parameters and response to aldosterone antagonism. Failure of the response of spironolactone to correlate with baseline renin-aldosterone status in the current study does not preclude a dose-dependent response with higher doses of spironolactone, particularly in subjects with known PA. Although subjects at high doses of spironolactone were not included in the current analysis, we will titrate spironolactone in subjects with known PA as high as 200 mg/d. Anecdotally, it is our experience that, if tolerated, higher doses of spironolactone do provide addi-

5 AJH November 2003 VOL. 16, NO. 11, PART 1 LOW-DOSE SPIRONOLACTONE AND RESISTANT HYPERTENSION 929 tional BP reduction in subjects with confirmed PA. Whether high doses of spironolactone would also provide additional BP benefit in subjects with resistant hypertension in the absence of PA could not be examined in the current study. There is increasing evidence that aldosterone antagonists are beneficial in the treatment of hypertension, even in the absence of PA. Three recent reports demonstrate the antihypertensive efficacy of eplerenone, a selective aldosterone antagonist, in subjects with primary hypertension. In the first report, Weinberger et al 29 demonstrated that, as monotherapy, 100 mg/d of eplerenone provided 75% of the antihypertensive effect compared with 100 mg/d of spironolactone among subjects with mild-to-moderate hypertension. In a second study, Krum et al 30 reported that 50 to 100 mg/d of eplerenone provided additional antihypertensive effect in combination with an ACE inhibitor or ARB, although subjects were not also receiving a diuretic. In the most recent study, Flack et al 31 reported eplerenone to be superior to an ARB as monotherapy, concluding that the antihypertensive efficacy of eplerenone was similar in African American and white subjects with mild-to-moderate hypertension. Our results demonstrate that the antihypertensive effect of aldosterone blockade with spironolactone was additive to use of a diuretic and ACE inhibitor or ARB. This is a clinically relevant observation as recent clinical trials indicate that the large majority of hypertensive patients will require multidrug therapy, which will generally include a diuretic and ACE inhibitor or ARB. Although speculative, the added benefit of spironolactone to treatment with an ACE inhibitor or ARB may reflect failure of such agents to fully suppress aldosterone excretion. 3 6 To our knowledge, there has been no formal comparison of the antihypertensive efficacy of spironolactone in African American and white subjects. In the current study, spironolactone reduced BP similarly in African American and white subjects. As described, similar antihypertensive efficacy was also observed with the selective aldosterone blocker, eplerenone, in African American and white subjects with mild-to-moderate hypertension. 31 In this report, indices of renin-aldosterone status did not correlate with eplerenone-induced BP reductions. This is in agreement with the lack of correlation with spironolactone-induced reductions in BP and renin-aldosterone status in the current analysis. Use of spironolactone is often limited by antiandrogenic and antiprogesteronic effects, including gynecomastia/breast tenderness, erectile dysfunction, and menstrual irregularities. In the current study, spironolactone at a mean dose of approximately 30 mg/d was generally well tolerated, with the most common adverse effect being breast tenderness, occurring in 4% of total subjects or 10% of men. A similar rate of gynecomastia/breast tenderness was observed in men in the Randomized Aldactone Evaluation Study (RALES), 3 in which subjects with severe heart failure were receiving 12.5 or 25 mg/day of spironolactone. Schepkens et al 32 have reported that combined therapy with an ACE inhibitor and spironolactone can cause hyperkalemia, especially among elderly ( 70 years), or subjects with chronic kidney disease. Among our subjects, five developed significant acute renal insufficiency and two developed hyperkalemia. Both of the subjects that developed hyperkalemia were receiving an ACE inhibitor and had chronic kidney disease, supporting the warning of Schepkens et al. The current study is strengthened by analysis of a large number of subjects that was racially inclusive, baseline characterization of renin-aldosterone status of all subjects, and confirmation of resistant hypertension in spite of use of intensive therapy that included an ACE inhibitor/arb and diuretic. The current observations may be relevant to clinicians treating patients with hypertension that remains resistant to multidrug regimens. References 1. Calhoun DA, Zaman MA, Nishizaka MK: Resistant hypertension. 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