Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study P. O. Lim, R. T. Jung & T. M. MacDonald Hypertension Research Centre, Department of Clinical Pharmacology and Therapeutics, and Department of Endocrinology and Diabetes, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK Aims Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio. Methods We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed-up for a period of up to 3 years. Results We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmhg, 39% with systolic BP >160 mmhg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BP 90 mmhg and 78% achieved a systolic BP 160 mmhg. In total 48% had BP 140/90 mmhg and 13/27 (48%) were treated with spironolactone monotherapy. Assessing only patients on drug treatment at baseline (n=24), spironolactone significantly reduced the need for antihypertensive drugs by 0.5 (CI 0.1 1.0), P=0.02, as well as reducing blood pressure [systolic BP 15 mmhg (CI 5 25), P=0.007 and diastolic BP (mmhg) by 8 mmhg (CI 4 13), P=0.001]. Conclusions Spironolactone was a highly effective antihypertensive agent in hypertensive patients who had a raised aldosterone/renin ratio. As a raised ratio was highly predictive of nonsuppression of plasma aldosterone suggesting primary aldosteronism, it might be worthwhile using spironolactone in this subgroup of hypertensive patients with raised aldosterone/renin ratios, provided that adrenal adenomas are excluded with imaging techniques. Keywords: aldosterone/renin ratio, hypertension, primary aldosteronism, spironolactone Introduction The prevalence rate of primary aldosteronism is controversial but it may be more common than previously thought, accounting for up to 15% of clinic hypertensives Correspondence: Dr P. O. Lim, Hypertension Research Centre, Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Tel: +44(01382)632180, Fax: +44(01382)644972, E-mail: pitt@clinpharm.dundee.ac.uk Received 16 April 1999, accepted 27 July 1999. [1 3]. We have recently reported that in a single GP practice, the prevalence of primary aldosteronism may be equally prevalent [4]. These studies utilized the aldosterone to plasma renin activity ratio (ARR) as a screening test. We believe that a raised ARR indicates inappropriate aldosterone activity, and we found that 94% of subjects with an ARR 750 failed to suppress plasma aldosterone with salt loading [3]. We have treated a cohort of these patients with oral spironolactone, and we report the response to this intervention. 756
Short report Methods Subjects Plasma renin activity (PRA) was measured using Biodata Renin MAIA assay (Serono Diagnostics Ltd, Woking, Surrey) with an intra-assay coefficient of variation of <10% between 0.3 and 18 ng ml 1 h 1, and a least detectable concentration of 0.3 mg ml 1 h 1. The interassay batch variation over a year was 11% (QC mean values 2.3 and 6.1 ng ml 1 h 1 ). Plasma aldosterone was measured using a solid-phase (coated tube) radioimmunoassay technique, DPC Coat- a-count assay (DPC, Llanberis, Caernarfon, Gwynedd) with an intra-assay coefficient of variation of <10% between 200 and 3300 pmol l 1, and a least detectable concentration of 70 pmol l 1 ). The interassay variation as calculated from QC pools run in each assay over a year was 10% (QC mean values 400 and 1050 pmol l 1 ). We screened for primary aldosteronism in all hypertensive patients referred for assessment in our Hypertension Research Centre in Tayside, using the ambulant plasma aldosterone (pmol ml 1 ) to plasma renin activity (ng ml 1 h 1 ) ratio of greater than or equal to 750 [3, 5] as our selection criteria (see below). Those subjects with a raised aldosterone to renin ratio were admitted for a standard salt loading and fludrocortisone suppression test (see below). Patients with a positive test (nonsuppress- ible serum aldosterone 140 pmol l 1 ) had adrenal CT scanning to screen for an adenoma. We also screened for glucocorticoid suppressible hyperaldosteronism (GSH) using genetic testing in patients who exhibited a drop in plasma aldosterone at 12.00 h midday following salt loading. Patients without an adrenal adenoma on CT scanning and GSH on genetic testing were included in this follow-up cohort. Blood pressure measurements Seated blood pressure measurements were carried out using standard mercury sphygmomanometer in accordance to the British Hypertension Society guidelines. Salt loading and fludrocortisone suppression test Laboratory testing Intervention Subjects with raised ARR and a positive salt loading and fludrocortisone suppression test had oral spironolactone 50 mg once daily added to their usual antihypertensive regime. The first clinic visit was at 1 month, and subsequent duration between clinic visits varied between 4 weeks to 12 weeks at the discretion of the clinicians based on blood pressure responses and possible adverse effects. The usual antihypertensive drug treatment was withdrawn if blood pressure was 150/90 mmhg after the addition of spironolactone. The dose of spironolactone was reduced to 25 mg if adverse effects occurred or blood pressure normalized on a 50 mg monotherapy. The usual antihypertensive medications were withdrawn for between 7 and 10 days. None of these patients was on oral spironolactone which would require a more prolonged drug withdrawal period. Where necessary, an a-adrenoceptor blocker, doxasozin, was prescribed to Statistics control the blood pressure if the diastolic blood pressure was greater than or equal to 110 mmhg. All patients were routinely given two tablets of Slow-K (600 mg potassium chloride each) daily to avoid hypokalaemia. On day 1, each patient was given five Slow-Sodium (600 mg sodium chloride each) tablets at 18.00 h and was defined at a P value of 0.05. 22.00 h following baseline supine 08.00 h and ambulant 12.00 h blood samplings for electrolytes, plasma cortisol Data are presented as mean (s.d.). Paired Student s t-test was used to assess the effect of spironolactone on the number of drugs used as well as its blood pressure lowering efficacy during follow-up. Statistical significance and aldosterone. On day 2, each patient was given four Results Slow-Sodium tablets with fludrocortisone 0.5 mg at We prospectively studied a cohort of 28 subjects (12 08.00 h, and further Slow-Sodium tablets, five at 12.00 h, males, mean age 55 years, s.d. 10) These patients were four at 18.00 h and four at 22.00 h. The day 2 regime followed up for a mean of 12.9 months (range was repeated on day 3. On day 4, the 08.00 h treatment 3 35 months). Prior to spironolactone, the mean number regime was given following supine blood sampling, and of drugs the patients were taking was 2.1 (s.d. 1.2), the midday bloods were sampled following 4 h of despite which 16/28 (57%) had diastolic BP >90 mmhg ambulation at 12.00 h. In total, 48 Slow-Sodium tablets (11/28) 39% with systolic BP >160 mmhg. One patient or 28 800 mg of sodium chloride with 1.5 mg of could not tolerate spironolactone and had to stop fludrocortisone were given over a 4 day period. Patients the drug after 4 months of treatment (nonspecifically had their blood pressures carefully monitored throughout unwell). Of the remaining 27 patients, the mean the study period to identify possible complications. number of antihypertensive drugs required dropped to 757
P. O. Lim et al. spironolactone plus 0.7 (s.d. 0.9). All but one patient carcinoma in women [19], this link being tenuous bearing (96%) achieved a diastolic BP 90 mmhg and 78% in mind the high prevalence of this form of malignancy achieved a systolic BP 160 mmhg. In total 48% had a in the female population. In contrast to those studies BP 140/90 mmhg and 13/27 (48%) needed only performed in the late sixties and early seventies, we have spironolactone therapy (Table 1). used lower doses of spironolactone. This may explain the Table 2 shows that treatment with spironolactone relatively low incidence of adverse effects and the small significantly reduced antihypertensive drug treatment as dropout rate from our cohort. well as improving blood pressure control in patients who Based on our results, we believe that ARR may be an were on drug treatment at baseline. effective way of identifying hypertensive subjects who would respond to spironolactone who represent a Discussion significant proportion of the hypertensive population. We believe that there is now good evidence to mount a The favourable blood pressure lowering response to randomised trial of spironolactone vs other therapy in this spironolactone in this cohort of patients suggested that a group of patients. If our results are generalizable, and raised ARR was an effective index in identifying patients confirmed by further studies, our management strategy who would benefit from this drug treatment. About 60% has the potential to make a major impact on the of these patients were treated with nonspironolactone management of hypertension especially as about 1 in diuretics at baseline, and most of the remaining patients 10 hypertensives may fall into this subcategory. had had diuretics tried at some stage. Blood pressure control remained suboptimal however, suggesting that the favourable blood pressure response with spironolactone Limitations in our study was not related to its diuretic We do not think that regression to the mean explains effect alone. our results. Our patients had their blood pressures Our study has parallels with previous studies indicating measured for 3 6 months by their general practitioners a favourable response to spironolactone in subjects with before being labelled hypertensive, and were then referred low stimulated renin hypertension [6 8]. Further small to our hypertension clinic for assessment. Furthermore, scale studies however, revealed that other hypotensive the response to spironolactone was remarkable, in that agents (methydopa [9] and thiazide diuretics [10, 11]) nearly half the patients needed only spironolactone to were equally effective in low renin hypertensives, and control their hypertension. Previously, many of these this blood pressure lowering effects were not dependant patients needed three or more drugs to achieve blood on the renin status [12] (thiazide diuretics [11, 13], pressure control. However, we note that in six of the 27 nifedipine [14], and methydopa [9]). We believe that the patients who continued on spironolactone either systolic use of ARR is more specific than stimulated renin in or diastolic blood pressures or both were higher at the identifying primary aldosteronism, which forms the bulk follow-up, so this treatment is not uniformly effective in of mineralocorticoid related hypertension. We have all subjects. reported that the frusemide stimulation test, a commonly Our study is not free from the inherent biases of an used test to assess renin responsiveness had poor negative uncontrolled nonrandomized design, and the blood predictive value in screening for subjects with possible pressure measurements were carried out by at least three primary aldosteronism [15]. In other words, many subjects different individuals. However, the strength of our study with primary aldosteronism retain their renin responsive- is that it was carried out as part of routine clinical practice ness. In contrast, a raised ARR in our centre predicted and therefore relevant to day-to-day medical care of primary aldosteronism in 94% of subjects [3]. The finding hypertensive patients. We believe that our results point of hypertensive subjects with low renin and nonsuppressible to the need for a randomised controlled study to assess serum aldosterone is not new, and was described the response to spironolactone in this subgroup of about 20 years ago [16]. In our hands this test appears hypertensives. reasonably specific for primary aldosteronism if a ratio 750 is used. The use of spironolactone for treating essential Conclusions hypertension was curtailed in Britain following the Low dose spironolactone was highly effective in reducing Committee on Safety of Medicines (CSM) report in blood pressure in hypertensive patients with nonaden- 1988 that it was associated with monomyelocytic leu- omatous primary aldosteronism identified with a raised kaemia in rats [17]. However, spironolactone has been aldosterone to renin ratio. Treatment with spironolactone used in humans for more than 30 years [18], with no significantly reduced the need for antihypertensive drug reported risk of malignancy apart from five cases of breast therapy. 758
759 Table 1 Anti-hypertensive treatment and blood pressure readings at baseline and during follow-up. Age Baseline Follow-up Last recorded clinic entry Patient (years) Sex Treatment SBP DBP (months) Treatment SBP DBP Comments 1 56 F Tenoretic 172 92 15 Amlodipine 5, spiro 50 160 90 2 55 F Atenolol 50 160 100 17 Spiro 25 118 82 3 55 M Amlodipine 5, bendrofluazide 2.5, atenolol 50 180 90 12 Spiro 50, doxazosin 2 twice daily 170 80 4 41 F Nil 154 100 3 Spiro 50 150 74 5 62 M Tenoretic 1, doxazosin 4 162 84 11 Atenolol 50, spiro 25 176 90 Breast tenderness 6 63 F Atenolol 50, dyazide 1, amlodipine 10 158 76 13 Spiro 75 170 78 7 52 M Sotalol 80 twice daily, bendrofluazide 2.5, 154 100 26 Spiro 25, sotalol 40 twice daily, 120 84 amlodipine 5 felodipine 5 8 71 F Losartan 50, amlodipine 5, atenolol 50 224 94 13 Atenolol 50, valsartan 80, 240 90 Intolerant of spiro, last amlodipine 5 BP on spiro 180/90 9 41 M Tenoretic 1, amlodipine 5 156 84 11 Amlodipine 5, spiro 25 140 78 Breast tenderness 10 49 F Atenolol 100 150 80 12 Spiro 25 160 90 11 64 M Lisinopril 10, atenolol 100 156 88 10 Lisinopril 10, amlodipine 5, 140 80 spiro 50 12 55 M Amlodipine 10 182 102 7 Spiro 50, amlodipine 5 162 90 13 43 F Lisinopril 40, amlodipine 10 190 108 6 Spiro 50 114 80 14 44 F Nil 156 100 11 Spiro 50, atenolol 100 134 90 15 55 F Atenolol 50, bendrofluazide 2.5 180 110 35 Spiro 50 140 82 16 62 M Atenolol 50, enalapril 10, amlodipine 5 144 86 10 Spiro 50, atenolol 25 132 88 17 46 M Bendrofluazide 156 96 25 Spiro 50 170 86 18 38 F Nil 154 96 7 Spiro 25 150 90 19 70 F Atenolol 50, amlodipine 10, 180 82 8 Spiro 50 160 82 lisinopril 20 twice daily, bendrofluazide 2.5 20 53 M Bendrofluazide 2.5 154 94 7 Spiro 50 134 82 21 77 F Atenolol 50, amlodipine 10 150 80 5 Spiro 50, amlodipine 5 160 84 22 54 M Lisinopril 5, tenoretic 1 146 88 19 Spiro 50, atenolol 50 146 88 23 59 F Lisinopril 20, frusemide 40, 160 94 10 Lisinopril 40, frusemide 40, 188 100 bisoprolol 10, doxazosin 4 bisoprolol 10, doxazosin 4, spiro 50 24 48 F Tenoretic 1 170 100 12 Spiro 50 150 82 25 65 M Atenolol 100, lisinopril 20, 140 74 24 Spiro 50 140 68 Breast tenderness frusemide 40, amlodipine 5 26 45 F Nifedipine 10 SR 124 88 15 Spiro 25 112 78 27 45 F Atenolol 50, bendrofluazide 2.5 174 94 10 Spiro 50, atenolol 50 130 68 28 59 M Tenoretic 1 168 94 6 Atenolol 50, spiro 50 120 80 Short report
P. O. Lim et al. Table 2 Blood pressure lowering efficacy of spironolactone during follow-up. n=24* Baseline Follow-up** Outcome P value Number of antihypertensive agents used 2.3 (1.0) 1.8 (0.9) 0.5 (CI 0.1 1.0) 0.02 Systolic blood pressure (mmhg) 161 (15) 146 (21) 15 (CI 5 25) 0.007 Diastolic blood pressure (mmhg) 91 (9) 83 (7) 8 (CI 4 13) 0.001 *Excluding cases 4, 14, and 18 who were untreated at baseline, and case 8 who could not tolerate spironolactone. **Including spironolactone. We thank Margaret Coull for her secretarial assistance. All authors normal renin hypertension. Act Med Scand 1975; 197: were jointly involved in the design and implementation of the 451 456. study. All authors contributed to writing the paper. 10 Adlin EV, Marks AD, Channick BJ. Spironolactone and hydrochlorothiazide in essential hypertension. Blood pressure response and plasma renin activity. Arch Intern Med 1972; References 130: 855 858. 1 Gordon RD. Mineralocorticoid hypertension. Lancet 1994; 11 Ferguson RK, Turek DM, Rovner DR. Spironolactone and 344: 240 243. hydrochlorothiazide in normal-renin and low-renin essential 2 Anis Anwar Y, White WB, Mansoor GA, et al. hypertension. Clin Pharmacol Ther 1977; 21: 62 69. Hyperaldosteronism is a common cause of secondary 12 Sundsf jord JA, Odegaard AE. Renin levels and hypertension missed by primary care physicians and spironolactone treatment in general practice: similar blood associated with normokalaemia. Am J Hypertens 1998; 11 pressure lowering effect of spironolactone in low and normal (4 part; 2): 199A (M001). renin patients. Eur J Clin Invest 1977; 7: 389 392. 3 Lim PO, Brennan G, Shiels P, et al. Unexpectedly high 13 Drayer JI, Kloppenborg PW, Festen J, et al. Intrapatient prevalence of primary aldosteronism in a hypertensive comparison of treatment with chlorthalidone, spironolactone population in Dundee. J Endocrinol 1998; 156(Suppl): P22. and propranolol in normoreninemic essential hypertension. 4 Lim PO, Rodgers P, Cardale K, et al. Potentially high Am J Cardiol 1975; 36: 716 721. prevalence of primary aldosteronism in a primary-care 14 Henry M, Wehrlen M, Pelletier B, et al. Spironolactone population. Lancet 1999; 353: 40. versus nifedipine in essential hypertension. Am J Cardiol 5 Gordon RD, Stowasser M, Klemm SA, et al. Primary 1990; 65: 36K 38K. aldosteronism and other forms of mineralocorticoid 15 Lim PO, Brennan GM, Jung RT, et al. Diagnosing primary hypertension. In Textbook of Hypertension, ed. Swales J. aldosteronism with frusemide stimulation test in hypertensive Oxford: Blackwell Scientific, 1994: 865 892. patients with raised aldosterone to renin ratio. Med Biochem 6 Carey RM, Douglas JG, Schweikert JR, et al. The syndrome 1999 in press. of essential hypertension and suppressed plasma renin 16 Helber A, Wambach G, Hummerich W, et al. Evidence for activity. Normalization of blood pressure with a subgroup of essential hypertensives with non-suppressible spironolactone. Arch Intern Med 1972; 130: 849 854. excretion of aldosterone during sodium loading. Klin 7 Spark RF, Melby JC. Hypertension and low plasma renin Wochenschr 1980; 58: 439 447. activity: presumptive evidence for mineralocorticoid excess. 17 Anonymous. Spironolactone: no longer for hypertension. Ann Intern Med 1971; 75: 831 836. Drug Ther Bull 1988; 26: 88. 8 Karlberg BE, Kagedal B, Tegler L, et al. Renin 18 Takeda R, Yamazaki T, Ito Y, et al. Twenty-four year concentrations and effects of propranolol and spironolactone spironolactone therapy in an aged patient with aldosterone- in patients with hypertension. Br Med J 1976; 1: 251 254. producing adenoma. Acta Endocrinol 1992; 126: 186 190. 9 Solheim SB, Sundsf jord JA, Giezendanner L. The effect of 19 McInnes GT. Diuretics. In Meyler s Side Effects of Drugs 13, spironolactone (Aldactone) and methyldopa in low and ed. Dukes MNG. Amsterdam: Elsevier, 1996: 558 582. 760