Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2007;116:268-275
Published online before print July 2, 2007, doi: 10.1161/CIRCULATIONAHA.107.690396
CLINICAL PERSPECTIVE
Free Article
This Article
Free upon publication Free Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
116/3/268    most recent
CIRCULATIONAHA.107.690396v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hood, S. J.
Right arrow Articles by Brown, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hood, S. J.
Right arrow Articles by Brown, M. J.
Related Collections
Right arrow Clinical Studies

(Circulation. 2007;116:268-275.)
© 2007 American Heart Association, Inc.

Hypertension

The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) Double-Blind Crossover Trial in Patients With Low-Renin Hypertension and Elevated Aldosterone-Renin Ratio

Susan J. Hood, RGN; Kevin P. Taylor, MSc; Michael J. Ashby, BSc; Morris J. Brown, FMedSci

From the Clinical Pharmacology Unit, Department of Medicine, University of Cambridge (S.J.H., M.J.A., M.J.B.), and Clinical Biochemistry, Addenbrookes Hospital (K.P.T.), Cambridge, UK.

Correspondence to Professor Morris Brown, Clinical Pharmacology Unit, Box 110, Addenbrookes Hospital, Cambridge CB2 2QQ, UK. E-mail m.j.brown{at}cai.cam.ac.uk

Received December 10, 2006; accepted May 11, 2007.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background— There is continuing variation in diagnosis and estimated prevalence of primary hyperaldosteronism. The higher estimates encourage search for adrenal adenomas in patients with elevated ratios of plasma aldosterone to renin. However, it is more likely that patients with normal plasma K+ and aldosterone belong to the polygenic spectrum of low-renin hypertension rather than have the same monogenic syndrome as classic Conn’s. Our primary hypothesis was that in low-renin patients with normal plasma K+ and aldosterone, a thiazide diuretic, bendroflumethiazide, would be as effective as spironolactone in overcoming the Na+ retention and lowering blood pressure. Secondary objectives were to compare the dose response for each diuretic and to evaluate amiloride as an alternative to spironolactone.

Methods and Results— Fifty-seven patients entered and 51 patients completed a placebo-controlled, double-blind, randomized crossover trial. Entry criteria included low plasma renin, normal K+, elevated aldosterone-renin ratio, and a previous systolic blood pressure response to spironolactone of ≥20 mm Hg. Two doses each of spironolactone and bendroflumethiazide were compared. The crossover also included amiloride and losartan. Outcome measures were blood pressure, plasma renin, and other biochemical markers of diuretic action. Spironolactone 100 mg and bendroflumethiazide 5 mg caused similar falls in systolic blood pressure, whereas bendroflumethiazide 2.5 mg was 5/2 mm Hg less effective in reducing blood pressure than either bendroflumethiazide 5 mg or spironolactone 50 mg (P<0.005). Amiloride 40 mg was as effective as the other diuretics. Biochemical indices of natriuresis showed bendroflumethiazide to be less effective than either spironolactone or amiloride; plasma renin rose 4-fold on spironolactone but only 2-fold on bendroflumethiazide (P=0.003).

Conclusions— In hypertensive patients with a low plasma renin but normal K+, bendroflumethiazide 5 mg was as effective as spironolactone 100 mg in lowering blood pressure, despite patients being selected for a previous large fall in blood pressure on spironolactone. Because this result differs from that expected in primary hyperaldosteronism, our finding argues against low-renin hypertension including a large, undiagnosed pool of primary hyperaldosteronism. However, spironolactone was the more effective natriuretic agent, suggesting that inappropriate aldosterone release or response may still contribute to the Na+ retention of low-renin hypertension.


Key Words: aldosterone • atrial natriuretic factor • diuretics • pharmacology • renin


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
In recent years, several studies have suggested that primary hyperaldosteronism (PHA) is much more common than previously thought, occurring in at least 10% of all patients with hypertension.1,2 The proportion in whom hypertension is cured by removal of a unilateral adrenal adenoma remains much smaller, at 1% to 2% of hypertension; instead, the major practical outcome of diagnosing PHA has been greater use of spironolactone for patients who have appeared resistant to more conventional drugs.3,4 The test that led to increased diagnosis of PHA has been the aldosterone-renin ratio, which seemed to permit detection of PHA in patients with an apparently normal plasma aldosterone level.5,6

Clinical Perspective p 275

However, the estimated prevalence of PHA remains quite variable and controversial.7–10 Opinion on validity and value of the aldosterone-renin ratio covers a spectrum between the opposing views either that some patients with PHA would not be diagnosed without its measurement11,12 or that the ratio confers little independent added value to measurement of renin and aldosterone themselves.8,13,14 Unlike patients with classic PHA (or Conn’s syndrome), most patients diagnosed through an increased aldosterone-renin ratio are normokalemic.11 In an open-label study, we found a low plasma renin to be at least as useful as increased aldosterone-renin ratio in predicting response to spironolactone and noted that the logarithmic distribution of plasma renin explains the previously noted dominance of a low plasma renin in determining the ratio.13,15 The question therefore is whether there is truly a common condition of normokalemic PHA, which requires investigation for adrenal adenoma and treatment with spironolactone, or whether most cases represent a rediscovery of low-renin hypertension by another name, in which case thiazides at sufficient doses should be equally effective.8

There have been few formal comparisons of diuretics in the patients in whom a suppressed plasma renin indicates Na+ retention to be the principal cause of hypertension. Anecdotal observations in the rare monogenic syndromes suggest that such patients can differ markedly in their response to differing diuretics, depending on the site within the nephron where elevated Na+ reabsorption occurs.16 Thiazide responsiveness has been the clinical hallmark of low-renin hypertension,17 whereas "true PHA" is classically resistant to thiazides but responsive to spironolactone.18 If, therefore, there is a common subgroup of patients with low-renin hypertension in whom further investigations for PHA should be performed, we hypothesized that hypertension in such patients would respond well to spironolactone and that a comparison of the 2 types of diuretic would show spironolactone to be superior. If, on the other hand, a higher than usual dose of thiazide is as effective as spironolactone, even when patients have been selected for elevated aldosterone-renin ratio and a previous good response to spironolactone, we may be able to conclude that it is dose rather than type of diuretic that is critical in reducing the Na+ load responsible for most low-renin hypertension.19

The practical problem with higher doses of thiazides is the metabolic side effects. Spironolactone is also problematic, partly because of the cumulative burden of gynecomastia at modest long-term doses. A possible alternative is amiloride. This has been compared previously with thiazides but generally at the small doses present in current diuretic formulations rather than the higher doses used in patients with genetic causes of low-renin hypertension or as an alternative to spironolactone in PHA.20–25

The primary objective of the present study, therefore, was to establish whether there is a common group of patients in whom spironolactone is superior to bendroflumethiazide in overcoming renin suppression and reducing blood pressure. The secondary objectives were to determine whether low-dose thiazide is submaximal in low-renin hypertension and whether we could establish noninferiority for amiloride against either of the other diuretics.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) study compared responses to 3 diuretics in patients with low-renin hypertension and elevated aldosterone-renin ratio, who had responded well to previous treatment with spironolactone. The design was a double-blind, placebo-controlled, randomized crossover with 5-week cycles of treatment. In addition to the placebo, we included an active, nondiuretic control.

Patients
The inclusion criteria were as follows: (1) clinic seated blood pressure of 140/90 to 170/110 mm Hg while either untreated for at least 1 month or receiving a calcium channel blocker, if untreated blood pressure was expected to exceed the inclusion limits; (2) plasma renin of ≤12 mU/L measured off ß-blockade; this is equivalent to the limit of 0.65 ng/mL per hour commonly used as a cutoff for low-renin hypertension26,27; (3) plasma aldosterone-renin ratio >750, when renin activity is measured or calculated from renin mass27; (4) previous fall in systolic blood pressure (SBP) of at least 20 mm Hg after 1 month of open-label treatment with spironolactone 50 mg daily.

Patients with known secondary causes of hypertension, contraindications to trial drugs, or history of hypokalemia were excluded. All patients gave informed written consent to participate in the study, which was approved by the Cambridge Research Ethics Committee.

Drugs and Randomization
Patients began the study with a single-blind placebo run-in phase lasting 1 month (see schema in Figure 1). The dose of any open-label background treatment (amlodipine 5 to 10 mg or lercanidipine 10 to 20 mg) was titrated before this phase and continued unchanged for the rest of the study. Patients then received 10 cycles of double-blind treatment comprising spironolactone 50 to 100 mg, amiloride 20 to 40 mg, bendroflumethiazide 2.5 to 5 mg at the 2 doses shown, losartan 100 mg, and placebo. Order of drugs and doses were randomized, except that the higher doses of diuretic and the placebo were administered in alternate cycles, and the 2 doses of each diuretic were separated by at least 3 intervening cycles. Each cycle of treatment lasted 5 weeks. There were no washout periods, and the entire study lasted 44 weeks for each patient.


Figure 1184778
View larger version (16K):
[in this window]
[in a new window]

  		Figure 1. Study schema. Each visit was the last day of treatment shown in the previous column. Thus, measurements listed in the bottom row relate to treatment in the top row of the previous column. Higher doses of each diuretic and placebo were randomly assigned to 1 of the cycles ending on an even-numbered visit. Lower doses of each diuretic and losartan were randomly assigned to 1 of the cycles ending on an odd-numbered visit. At least 3 cycles separated the 2 doses of each diuretic. The drugs are listed by their initial in the row of doses. BP indicates blood pressure; CCB, calcium channel blocker; Amlo, amlodipine; Lerc, lercanidipine; Elecs, electrolytes; Bendro, bendroflumethiazide; and ABPM, ambulatory blood pressure monitor.

Randomization was performed by an in-house program that randomly ordered the 48 possible permutations of the even-numbered phases (high-dose diuretics and placebo), with the use of blocks of 12 in which all permutations of the first 2 of these phases were covered. A similar block was generated for the final 12 patients. The program then randomly assigned the odd-numbered phases, rejecting any assignment of the same diuretic to sequential phases. Over the 8 phases, each patient had a unique sequence of drugs.

Measurements
Seated blood pressure was measured in triplicate with the use of the A&D 767 at the same time of day at the end of run-in and each subsequent cycle. At the even-numbered visits (end of high-dose and placebo treatment), blood samples were taken after completion of blood pressure measurement for analysis of plasma electrolytes, renin, aldosterone, and atrial natriuretic peptide (ANP). After sampling, patients were fitted with an A&D 24-hour ambulatory blood pressure monitor. Blood samples were separated for immediate assay of electrolytes and batched assay of hormone immunoassay. Renin was measured as renin mass by the Nichols Advantage assay and log-normalized for statistical analyses.27

Analyses
The primary outcomes were the difference in SBP and plasma renin between the end of high-dose spironolactone and high-dose bendroflumethiazide. Secondary blood pressure outcomes were the differences in SBP between amiloride and the other diuretics and between lower and higher doses of each diuretic; secondary biochemical outcomes were indices, additional to plasma renin, of Na+ loss during diuretic treatment. The study was powered for the primary clinical outcome, namely, blood pressure, for which previous data enabled a precise prediction of plausible difference and SD if the primary hypothesis was correct. Given the variety of available tests and definitions for normokalemic PHA, our cohort is intended to satisfy some but not all suggested criteria for this diagnosis.28–31 Thus, we considered that, if PHA was a common component of low-renin hypertension, at least half of the patients selected for a previous ≥20 mm Hg fall in SBP on spironolactone should show a ≥10 mm Hg greater fall on spironolactone than on bendroflumethiazide. We therefore wished to detect a mean (for all patients in the study) of ≥5 mm Hg greater fall on spironolactone than bendroflumethiazide. Because patients were selected 1-sidedly, ie, for a previous large fall in SBP on only 1 of the trial drugs, we considered that large falls on spironolactone in half of the patients were unlikely to be cancelled by similarly larger falls on bendroflumethiazide in the other half of the patients. We used the sample size module of WSTATA to calculate that in a 1-sample (crossover) test, assuming SD for blood pressure of 10 mm Hg, 60 patients would give us the necessary power ({alpha}=0.01, ß=0.9). Because, however, full analysis of a crossover trial is limited to those completing all randomized treatment, we calculated that 43 completed patients were adequate for {alpha}=0.05, ß=0.9. The primary analysis was undertaken by paired t test, followed by repeated-measures ANOVA incorporating age, gender, background treatment, and drug order as factors. For noninferiority to be established of 1 diuretic against another, we required that the upper 95% CI of the difference in SBP should be no more than 2.5 mm Hg, this being half the expected difference for superiority and equating to a difference in 5-year stroke risk of <10%.32

The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
Fifty-seven patients were recruited, of whom 51 completed all cycles of the study. Their demographics are shown in Table 1. In 30 patients, the month’s trial of open-label spironolactone was part of our previous study investigating prevalence of PHA15; in the remainder, spironolactone had been tried as an option for treating patients referred to our clinics with difficult hypertension.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Patient Demographics and Entry Criteria

Blood Pressure
In brief, all diuretics achieved substantial reduction in placebo-corrected SBP. On this outcome, the superiority hypothesis for spironolactone over higher-dose bendroflumethiazide was not supported, whereas the secondary hypothesis of a dose response for bendroflumethiazide was confirmed. Amiloride had efficacy similar to that of the other diuretics, meeting the preset noninferiority hypothesis against bendroflumethiazide.

In more detail, the placebo-corrected falls for each drug are shown in Table 2, and absolute values are shown in Figure 2. Spironolactone 50 mg reduced SBP more than bendroflumethiazide 2.5 mg (t=2.95, P=0.005), but at their higher doses there was no significant difference between the mean placebo-corrected falls in clinic SBP of 10.5 mm Hg on bendroflumethiazide 5 mg and 11.6 mm Hg on spironolactone 100 mg (t=0.77, P=0.44). This was because bendroflumethiazide 2.5 mg was submaximal, with a 5.5/2.6 mm Hg greater fall in blood pressure on 5 mg (t=3.7, P=0.0005). The repeated-measures ANOVA on SBPs and diastolic blood pressures at both doses excluded order effect and showed no overall difference between spironolactone and bendroflumethiazide (F=2.00, P=0.16).


View this table:
[in this window]
[in a new window]

  		TABLE 2. Blood Pressure Responses


Figure 2184778
View larger version (22K):
[in this window]
[in a new window]

  		Figure 2. Blood pressure of subjects on the 3 diuretics compared with placebo and nondiuretic controls. Mean values for higher (green bars) and lower (red bars) doses of each diuretic, for placebo in black on the left, and for losartan in blue on the right are shown. The error bars are 95% CIs. All drug effects differed from placebo. There were also highly significant differences, as stated in the text, between low-dose bendroflumethiazide (Bendro) and each of high-dose bendroflumethiazide (P=0.0005) and low-dose spironolactone (Spiro) (P=0.005).

Amiloride 20 to 40 mg was similar in efficacy to both bendroflumethiazide and spironolactone, with a dose response midway between that of the other diuretics for steepness. The noninferiority analyses, shown for the higher dose of each diuretic in Table 3, permit a claim of noninferiority for amiloride 40 mg compared with bendroflumethiazide 5 mg.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Noninferiority Comparisons Between Diuretics

We found that the 24-hour ambulatory blood pressure monitor performed on placebo and the higher doses of diuretic showed no significant differences between the latter. However, satisfactory tracings were obtained for all time points in only 26 of 51 patients completed.

Biochemistry
In brief, spironolactone was substantially more effective than bendroflumethiazide in reversing the suppression of plasma renin. Of the secondary indices of natriuresis, spironolactone caused greater increase in plasma urea and greater falls in plasma Na+ and ANP. The effects of amiloride were similar to those of spironolactone, except for a rise in plasma ANP (Table 4, Figures 3 to 5DownDown). More detail is given below for each measurement.


View this table:
[in this window]
[in a new window]

  		TABLE 4. Biochemical Data


Figure 3184778
View larger version (7K):
[in this window]
[in a new window]

  		Figure 3. Effects of bendroflumethiazide (Bendro) and spironolactone (Spiro) on plasma renin. Renin was log-normalized and plotted as log-renin. Error bars are 95% CIs. The probability value refers to repeated-measures ANOVA across the 3 values.


Figure 4184778
View larger version (9K):
[in this window]
[in a new window]

  		Figure 4. Effects of bendroflumethiazide (Bendro) and spironolactone (Spiro) on plasma sodium and urea. Error bars are 95% CIs. The probability value refers to repeated-measures ANOVA across the 3 values.


Figure 5184778
View larger version (8K):
[in this window]
[in a new window]

  		Figure 5. Effects of bendroflumethiazide (Bendro) and spironolactone (Spiro) on plasma ANP and on weight. Error bars are 95% CIs. The probability value refers to repeated-measures ANOVA across the 3 values.

Renin
Renin was log-normalized for analysis. Levels increased 2-fold on bendroflumethiazide but 4-fold on spironolactone (t=3.1 for the comparison, P=0.003) (Figure 3). Amiloride increased renin in a manner similar to that of spironolactone.

Other Indices of Natriuresis
Plasma urea rose by almost 1 mmol/L on spironolactone, twice as much as on bendroflumethiazide (t=3.1, P=0.003), and the pattern for plasma Na+ was similar, falling by >2 mmol/L on spironolactone compared with <1 mmol/L on bendroflumethiazide (t=2.35, P=0.02) (Figure 4). Plasma ANP also fell more on spironolactone than on bendroflumethiazide (t=2.35, P=0.02). Small falls in weight mirrored the other differences in natriuretic indices (Figure 5). Amiloride had effects similar to those of spironolactone except that it caused a significant increase in plasma ANP (t=2.6, P=0.01).

K+ and Aldosterone
There were the expected differences in plasma K+, which fell by 0.4 mmol/L on bendroflumethiazide but rose by 0.5 mmol/L on spironolactone and even more on amiloride. Plasma aldosterone rose 3-fold on the K+-sparing diuretics but was unchanged on bendroflumethiazide.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The primary hypothesis was that if PHA was a common cause of low-renin hypertension in our cohort of previous spironolactone responders, we would find spironolactone superior to bendroflumethiazide in reducing Na+ retention and blood pressure. Although we did indeed find a greater effect of spironolactone on all indices of Na+ retention, there was no significant difference in blood pressure reduction. The secondary hypotheses were that, in low-renin patients, an increase from the usual dose of bendroflumethiazide would cause a further reduction in blood pressure and that amiloride would be noninferior to bendroflumethiazide and spironolactone. The dose response for bendroflumethiazide was confirmed, and amiloride met the preset noninferiority hypothesis against bendroflumethiazide.

What conclusions and caveats should be applied to these findings? Having selected a group of low-renin patients who would include many of the candidates for the putative diagnosis of normokalemic PHA, we did not find the hypothesized superiority of spironolactone over bendroflumethiazide. Although our higher doses of both primary diuretics were higher than current usage in hypertension,33,34 even higher doses of both have been used in the past. We cannot therefore completely exclude the possibility of a common group of patients in whom a maximal dose of spironolactone would be superior to maximal-dose thiazide. However, doses of spironolactone >100 mg seem most likely, in theory, to be required when aldosterone secretion is elevated,35 and our blood pressure dose response (Figure 2) suggests that, if anything, a higher dose of diuretics would have favored bendroflumethiazide. Moreover, it is the apparent efficacy of spironolactone 25 to 50 mg in patients with resistant hypertension, and the consequent suspicion of underlying PHA, that stimulated the present study.3,33,36

Although there has not been a similar study of different diuretics in patients with proven Conn’s adenomas, such patients have the reputation of being resistant to thiazides, best documented in a review from the Mayo Clinic conducted at a time when thiazides were commonly used in higher doses than is now usual.18,37 Our patients were selected for having a high aldosterone-renin ratio and minimum fall in SBP of 20 mm Hg on previous open-label exposure to spironolactone 50 mg. We considered that if these were also selection criteria for PHA, at least half of our cohort would have a <10 mm Hg fall on bendroflumethiazide. As expected, placebo correction and regression on the mean led to generally <20 mm Hg falls on double-blind rechallenge with spironolactone. Because currently patients with true PHA are unlikely to have received bendroflumethiazide 5 mg (or an equivalent dose of hydrochlorothiazide) before diagnosis and prospective testing is unlikely to receive ethical approval, we will probably have to rely on likelihood rather than proof that the similar blood pressure response of our patients to spironolactone 50 mg and bendroflumethiazide 5 mg is different from that of true PHA.

Although we had only 1 primary and 2 secondary hypotheses, the number of comparisons (and therefore the potential for spurious results) was increased by the number of drugs and doses and by the inclusion of both blood pressure and biochemical end points. The purpose of the latter was to permit any superiority of spironolactone in blood pressure reduction to be ascribed to a difference in natriuretic efficacy rather than postulated extrarenal effects of aldosterone blockade.35,38,39 In the present study, we found a difference in the biochemical but not blood pressure response to spironolactone, and the interpretation will be discussed below. The main secondary finding was the substantial dose response for the blood pressure fall on bendroflumethiazide. At 5 mm Hg for SBP, this was the same as we had hypothesized might exist between bendroflumethiazide and spironolactone. It is therefore tempting to conclude that the clinical efficacy of spironolactone in patients apparently resistant to thiazides, for instance, to atenolol 100 mg and bendroflumethiazide 2.5 mg in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),33 could be achieved alternatively by increasing the dose of thiazide.

In recent years, there has been a view that low-dose thiazides achieve maximal blood pressure reduction.40–42 However, the studies that led to this conclusion, mainly in younger patients with mild hypertension, are likely to have included only small numbers of low-renin patients in whom hypertension is due in part to inappropriate renal Na+ retention. In older or low-renin patients, studies using hydrochlorothiazide have suggested that 25 or even 50 mg is not maximal.19,43 In the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study, for instance, in which the average patient’s age was 65 years, the increase in dose from hydrochlorothiazide 25 to 50 mg was associated with a larger fall in blood pressure than from nifedipine 30 to 60 mg.43 The present study, in which dose and duration of treatment were separated as factors, appears to confirm that in low-renin patients, bendroflumethiazide 2.5 mg is submaximal. There are few head-to-head comparisons of bendroflumethiazide with hydrochlorothiazide (which is not available in the United Kingdom except in fixed-dose combinations), but the 2.5-mg dose is probably equivalent to between 12.5 and 25 mg hydrochlorothiazide. This statement is based on common usage and meta-analysis of their dose response in different trials.34 A Cochrane Review is in progress. If correct, and if treatment with a renin-angiotensin system blocker effectively converts a patient’s hypertension to a functionally low-renin type, it is notable that none of the angiotensin-converting enzyme inhibitor plus thiazide fixed-dose combinations includes a maximal dose of thiazide. This impression is supported by data for recently introduced angiotensin receptor blocker combinations with hydrochlorothiazide 25 mg, showing greater blood pressure reduction than the same angiotensin receptor blocker with hydrochlorothiazide 12.5 mg.44

We included a renin-angiotensin system blocker, losartan, as a negative control. This was because we expected a number of patients to require background treatment with a calcium channel blocker. We therefore wished to confirm that patients with a low plasma renin measured while on a calcium channel blocker still behaved like low-renin patients, responding better to a diuretic than to a renin-angiotensin system blocker.45,46 As seen in Figure 2, this was indeed the case. The study was not powered or intended to compare losartan with the individual diuretics or doses.

One of the stimuli to rediscover or reinvestigate diuretics and doses has been the advent of high-throughput immunochemiluminometric assays for plasma renin mass.27 Thus, recognition of low-renin status in resistant hypertension is not just a research activity but is potentially cost-effective in the routine clinic. The "reinvention" of low-renin hypertension as normokalemic PHA could have discouraged renin measurement because the simultaneous assay for aldosterone remains a slower, more expensive radioimmunoassay. The reporting of elevated aldosterone-renin ratios in older low-renin patients also leads to an unnecessary burden of diagnostic tests—fludrocortisone suppression, computed tomographic/magnetic resonance imaging scan, adrenal vein sampling—in the search for curable adrenal adenomas, with the need for even further investigations in the 4% (at least) of patients with adrenal incidentalomas.47 Our previous study, in which screening of 846 community-based patients identified 119 with an elevated aldosterone-renin ratio and led to adrenal computed tomographic/magnetic resonance imaging in 78 of these, discovered only 2 adenomas.15 Some investigators have reported adrenal lesions that are detected only by adrenal vein sampling, but removal of such adrenals from normokalemic patients does not usually cure the hypertension.48 Others have therefore favored long-term medical treatment of normokalemic PHA with spironolactone. However, SALT suggests that the excellent blood pressure response to spironolactone predicted by a high aldosterone-renin ratio is no better than can be achieved by a diuretic acting upstream of the aldosterone receptor in the nephron. The ratio is driven by log-normally distributed renin rather than aldosterone, and SALT would seem to demote value of the ratio. A normal value may have use in excluding the diagnosis of PHA in low-renin, hypokalemic patients. A high ratio in the absence of hypokalemia is probably an expensive and misleading way of describing low-renin hypertension. Because it was impracticable in such a number, we did not confirm nonsuppression by fludrocortisone in our patients. Because, however, the ratio has previously been shown to predict nonsuppression, and our patients came from the top decile of aldosterone-renin ratio in an unselected primary care population, they can be assumed to include virtually all patients who might have been diagnosed with normokalemic PHA in that population.3,15

Crossover studies offer the opportunity of comparing drugs in small numbers of selected subjects. Had we found, as hypothesized, that half of the patients responded better to spironolactone than bendroflumethiazide, we could have discovered who these patients were. However, although crossovers can lead to changes in treatment, as we saw in the United Kingdom after the Angiotensin-converting enzyme inhibitor, ß-adrenergic blocker, Calcium channel blocker, Diuretic (ABCD) studies, there is usually a lag and a need for them to predict similar findings in larger, parallel group studies of less selected patients before their conclusions are adopted by guidelines.45,46,49,50 Clearly, neither spironolactone nor amiloride has the outcome data of thiazides in hypertension, even if most of the latter is for doses of thiazide closer to bendroflumethiazide 5 mg or hydrochlorothiazide 50 mg than for the lower doses used currently.32 Confirmation of our findings may lead to an expanded choice of diuretics and a possible return to using higher doses of thiazides as one of the choices. Key questions for further study will be whether K+-sparing diuretics avoid the glucose intolerance associated with thiazides and, if so, whether this translates into improved cardiovascular outcome.38,51

Finally, what if anything should be read into the apparently greater natriuretic responses to spironolactone than bendroflumethiazide? Because of the concordance both among all our indices of natriuresis and between the 2 K+-sparing diuretics, we think that the multiple results support the validity of the observation rather than its being a spurious product of the multiple testing. It has long been thought that thiazides work in part as vasodilators, although the mechanism remains uncertain.52 Our head-to-head comparison of a thiazide with other diuretics now seems to confirm this supposition, with possible further evidence being an apparently greater fall in diastolic blood pressure on bendroflumethiazide. If the diuretics acting downstream of thiazides in the nephron are indeed more effective at eliminating Na+ in low-renin patients, this finding suggests a role for aldosterone in causing the Na+ retention. The lack of hypokalemia, compared with true PHA, is to be expected because low-renin hypertension is almost certainly polygenic and aldosterone is but 1 of many players. Rather than diagnostic tests aimed at finding an unlikely cure for individual patients, systematic research can be encouraged that is directed at the many pathways controlling either aldosterone secretion or response.


*    Acknowledgments
 
Amlodipine, lercanidipine, and losartan were gifts of Pfizer, Napp, and MSD, respectively.

Source of Funding

The present study was funded by a British Heart Foundation program grant.

Disclosures

Dr Brown has received honoraria from and has served as a consultant for or on the advisory board of MSD. The other authors report no conflicts.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol. 1994; 21: 315–318.[Medline] [Order article via Infotrieve]
  2. Lim PO, Jung RT, MacDonald TM. Screening for primary hyperaldosteronism in a hospital hypertensive population: is it the commonest form of secondary hypertension? J Hypertens. 1997; 15: 1531–1532.
  3. Lim PO, Jung RT, MacDonald TM. Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study. Br J Clin Pharmacol. 1999; 48: 756–760.[CrossRef][Medline] [Order article via Infotrieve]
  4. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002; 40: 892–896.[Abstract/Free Full Text]
  5. Hiramatsu K, Yamada T, Yukimura Y, Komiya I, Ichikawa K, Ishihara M, Nagata H, Izumiyama T. A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity: results in hypertensive patients. Arch Intern Med. 1981; 141: 1589–1593.[Abstract]
  6. Gordon RD, Ziesak MD, Tunny TJ, Stowasser M, Klemm SA. Evidence that primary aldosteronism may not be uncommon: 12% incidence among antihypertensive drug trial volunteers. Clin Exp Pharmacol Physiol. 1993; 20: 296–298.[Medline] [Order article via Infotrieve]
  7. Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens. 2004; 22: 863–869.[CrossRef][Medline] [Order article via Infotrieve]
  8. Padfield PL. Primary aldosteronism, a common entity? The myth persists. J Hum Hypertens. 2002; 16: 159–162.[CrossRef][Medline] [Order article via Infotrieve]
  9. Nishizaka MK, Pratt-Ubunama M, Zaman MA, Cofield S, Calhoun DA. Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension. Am J Hypertens. 2005; 18: 805–812.[CrossRef][Medline] [Order article via Infotrieve]
  10. Mulatero P, Milan A, Fallo F, Regolisti G, Pizzolo F, Fardella C, Mosso L, Marafetti L, Veglio F, Maccario M. Comparison of confirmatory tests for the diagnosis of primary aldosteronism. J Clin Endocrinol Metab. 2006; 91: 2618–2623.[Abstract/Free Full Text]
  11. Stowasser M, Gordon RD, Gunasekera TG, Cowley DC, Ward G, Archibald C, Smithers BM. High rate of detection of primary aldosteronism, including surgically treatable forms, after ‘non-selective’ screening of hypertensive patients. J Hypertens. 2003; 21: 2149–2157.[CrossRef][Medline] [Order article via Infotrieve]
  12. Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM, Kong AP. The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab. 2005; 90: 72–78.[Abstract/Free Full Text]
  13. Montori VM, Schwartz GL, Chapman AB, Boerwinkle E, Turner ST. Validity of the aldosterone-renin ratio used to screen for primary aldosteronism. Mayo Clin Proc. 2001; 76: 877–882.[Medline] [Order article via Infotrieve]
  14. Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism: a systematic review of the literature. Endocrinol Metab Clin North Am. 2002; 31: 619–632, xi.
  15. Hood S, Cannon J, Foo R, Brown M. Prevalence of primary hyperaldosteronism assessed by aldosterone/renin ratio and spironolactone testing. Clin Med. 2005; 5: 55–60.[CrossRef][Medline] [Order article via Infotrieve]
  16. Garovic VD, Hilliard AA, Turner ST. Monogenic forms of low-renin hypertension. Nat Clin Pract Nephrol. 2006; 2: 624–630.[CrossRef][Medline] [Order article via Infotrieve]
  17. Laragh JH. Modern system for treating high blood pressure based on renin profiling and vasoconstriction-volume analysis: a primary role for beta blocking drugs such as propranolol. Am J Med. 1976; 61: 797–810.[CrossRef][Medline] [Order article via Infotrieve]
  18. Bravo EL, Fouad-Tarazi FM, Tarazi RC, Pohl M, Gifford RW, Vidt DG. Clinical implications of primary aldosteronism with resistant hypertension. Hypertension. 1988; 11: I207–I211.[Medline] [Order article via Infotrieve]
  19. Hollifield JW. Thiazide treatment of hypertension: effects of thiazide diuretics on serum potassium, magnesium, and ventricular ectopy. Am J Med. 1986; 80: 8–12.[Medline] [Order article via Infotrieve]
  20. Frohlich ED. Multiclinic comparison of amiloride, hydrochlorothiazide, and hydrochlorothiazide plus amiloride in essential-hypertension. Arch Intern Med. 1981; 141: 482–486.[Abstract]
  21. Pratt JH, Eckert GJ, Newman S, Ambrosius WT. Blood pressure responses to small doses of amiloride and spironolactone in normotensive subjects. Hypertension. 2001; 38: 1124–1129.[Abstract/Free Full Text]
  22. Thomas JP, Thomson WH. Comparison of thiazides and amiloride in treatment of moderate hypertension. BMJ (Clin Res Ed). 1983; 286: 2015–2018.[Medline] [Order article via Infotrieve]
  23. Janmohamed S, Bouloux P-MG. The pharmacological treatment of primary aldosteronism. Exp Opin Pharmacother. 2006; 7: 563–573.[CrossRef][Medline] [Order article via Infotrieve]
  24. Baker EH, Duggal A, Dong YB, Ireson NJ, Wood M, Markandu ND, MacGregor GA. Amiloride, a specific drug for hypertension in black people with T594M variant? Hypertension. 2002; 40: 13–17.[Abstract/Free Full Text]
  25. Jeunemaitre X, Bassilana F, Persu A, Dumont C, Champigny G, Lazdunski M, Corvol P, Barbry P. Genotype-phenotype analysis of a newly discovered family with Liddle’s syndrome. J Hypertens. 1997; 15: 1091–1100.[CrossRef][Medline] [Order article via Infotrieve]
  26. Alderman MH, Cohen HW, Sealey JE, Laragh JH. Plasma renin activity levels in hypertensive persons: their wide range and lack of suppression in diabetic and in most elderly patients. Am J Hypertens. 2004; 17: 1–7.[CrossRef][Medline] [Order article via Infotrieve]
  27. Hartman D, Sagnella GA, Chesters CA, MacGregor GA. Direct renin assay and plasma renin activity assay compared. Clin Chem. 2004; 50: 2159–2161.[Free Full Text]
  28. Quinkler M, Lepenies J, Diederich S. Primary hyperaldosteronism. Exp Clin Endocrinol Diabetes. 2002; 263–271.
  29. Perschel FH, Schemer R, Seiler L, Reincke M, Deinum J, Maser-Gluth C, Mechelhoff D, Tauber R, Diederich S. Rapid screening test for primary hyperaldosteronism: ratio of plasma aldosterone to renin concentration determined by fully automated chemiluminescence immunoassays. Clin Chem. 2004; 50: 1650–1655.[Abstract/Free Full Text]
  30. Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto J, Gomez L, Pinto M, Huete A, Oestreicher E, Foradori A, Montero J. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab. 2000; 85: 1863–1867.[Abstract/Free Full Text]
  31. Stowasser M, Gordon RD. Primary aldosteronism: careful investigation is essential and rewarding. Mol Cell Endocrinol. 2004; 217: 33–39.[CrossRef][Medline] [Order article via Infotrieve]
  32. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362: 1527–1535.[CrossRef][Medline] [Order article via Infotrieve]
  33. Chapman N, Dobson J, Wilson S, Dahlof B, Sever PS, Wedel H, Poulter NR, on behalf of the Anglo-Scandinavian Cardiac Outcomes Trial I. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension. 2007; 49: 839–845.[Abstract/Free Full Text]
  34. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003; 326: 1427.[Abstract/Free Full Text]
  35. Goodfriend TL. Treating resistant hypertension with a neglected old drug. Hypertension. 2007; 49: 763–764.[Free Full Text]
  36. Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003; 16: 925–930.[CrossRef][Medline] [Order article via Infotrieve]
  37. Kaplan NM. Resistant hypertension. J Hypertens. 2005; 23: 1441–1444.[Medline] [Order article via Infotrieve]
  38. Nishizaka MK, Zaman MA, Green SA, Renfroe KY, Calhoun DA. Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation. 2004; 109: 2857–2861.[Abstract/Free Full Text]
  39. Farquharson CA, Struthers AD. Aldosterone induces acute endothelial dysfunction in vivo in humans: evidence for an aldosterone-induced vasculopathy. Clin Sci (Lond). 2002; 103: 425–431.[Medline] [Order article via Infotrieve]
  40. Carlsen JE, Kober L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990; 300: 975–978.[Medline] [Order article via Infotrieve]
  41. Girvin B, Johnston GD. A randomized comparison of a conventional dose, a low dose and alternate-day dosing of bendrofluazide in hypertensive patients. J Hypertens. 1998; 16: 1049–1054.[CrossRef][Medline] [Order article via Infotrieve]
  42. MacGregor GA, Banks RA, Markandu ND, Bayliss J, Roulston J. Lack of effect of beta-blocker on flat dose response to thiazide in hypertension: efficacy of low dose thiazide combined with beta-blocker. BMJ (Clin Res Ed). 1983; 286: 1535–1538.[Medline] [Order article via Infotrieve]
  43. Brown MJ, Palmer CR, Castaigne A, De Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with once-daily calcium channel blockade or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000; 356: 366–342.[CrossRef][Medline] [Order article via Infotrieve]
  44. Pool JL, Glazer R, Weinberger M, Alvarado R, Huang J, Graff A. Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults. Clin Ther. 2007; 29: 61–73.[CrossRef][Medline] [Order article via Infotrieve]
  45. Dickerson JEC, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of anti-hypertensive treatment by crossover rotation of four major classes. Lancet. 1999; 353: 2008–2013.[CrossRef][Medline] [Order article via Infotrieve]
  46. NICE/BHS. CG34 Hypertension: NICE guideline (all the recommendations). Available at: http://www.nice.org.uk/guidance/CG34/niceguidance/pdf/English 2006. Accessed June 11, 2007.
  47. Young WF Jr. The incidentally discovered adrenal mass. N Engl J Med. 2007; 356: 601–610.[Free Full Text]
  48. Stowasser M, Klemm SA, Tunny TJ, Storie WJ, Rutherford JC, Gordon RD. Response to unilateral adrenalectomy for aldosterone-producing adenoma: effect of potassium levels and angiotensin responsiveness. Clin Exp Pharmacol Physiol. 1994; 21: 319–322.[CrossRef][Medline] [Order article via Infotrieve]
  49. Deary A, Schumann A, Murfet H, Haydock S, Foo R, Brown M. Double-blind, placebo-controlled crossover comparison of five classes of antihypertensive drugs. J Hypertens. 2002; 20: 771–777.[CrossRef][Medline] [Order article via Infotrieve]
  50. Williams B, Poulter NR, Brown MJ, Davies M, McInnes G, Potter J, Sever PS, Thom S. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004: BHS IV. J Hum Hypertens. 2004; 18: 139–185.[CrossRef][Medline] [Order article via Infotrieve]
  51. Ramsay LE, Yeo WW, Jackson PR. Diabetes, impaired glucose tolerance and insulin resistance with diuretics. Eur Heart J. 1992; 13 (suppl G): 68–71.[Medline] [Order article via Infotrieve]
  52. Hughes AD. How do thiazide and thiazide-like diuretics lower blood pressure? J Renin Angiotensin Aldosterone Syst. 2004; 5: 155–160.[Abstract/Free Full Text]
 

CLINICAL PERSPECTIVE

The present study addressed 2 related questions. The first was whether low-dose thiazides are really adequate to achieve maximal blood pressure reduction. We considered this unlikely in patients with low-renin (salt-dependent) hypertension and hypothesized that underdosage contributes to apparent treatment resistance. The second question was whether primary hyperaldosteronism is frequently the cause of low-renin hypertension; in this case, treatment with an aldosterone antagonist should be more effective than a thiazide and prompt investigations for a possible adrenal adenoma. We designed a head-to-head comparison of diuretics in a group in which suspicion of primary hyperaldosteronism often arises: those with suppressed plasma renin but normal plasma K+ and aldosterone. In a 40-week double-blind, crossover rotation, bendroflumethiazide 2.5 mg ({cong}hydrochlorothiazide 25 mg) was 5/2 mm Hg less effective in reducing blood pressure than either bendroflumethiazide 5 mg, spironolactone 50 mg, or amiloride 40 mg (P<0.005). These results show that doubling the thiazide dose is as effective as switching to spironolactone; the choice among effective diuretics in individual patients can be influenced by their tolerability. Because spironolactone was not superior in our patients despite their having an elevated aldosterone-renin ratio, the study supports abandonment of the ratio as a useful predictor of primary hyperaldosteronism in patients with normal K+ and aldosterone. It is likely that, even without renin measurement, our conclusions apply broadly to the 3 (overlapping) groups whose hypertension is often salt dependent: older patients, blacks, and patients receiving renin-system blockers. Clearly, further study is required, which can provide important information on the influence of diuretics on glucose tolerance.


*    Footnotes
 
Clinical trial registration information—URL: http://www.controlled-trials.com. Unique identifier: ISRCTN85520592.




This article has been cited by other articles:


Home page
 CirculationHome page
M. J. Brown
Aliskiren
Circulation, August 12, 2008; 118(7): 773 - 784.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
B Rayner
Primary aldosteronism and aldosterone-associated hypertension
J. Clin. Pathol., July 1, 2008; 61(7): 825 - 831.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. M. C. Connell, S. M. MacKenzie, E. M. Freel, R. Fraser, and E. Davies
A Lifetime of Aldosterone Excess: Long-Term Consequences of Altered Regulation of Aldosterone Production for Cardiovascular Function
Endocr. Rev., April 1, 2008; 29(2): 133 - 154.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
P. Mulatero, A. Milan, and F. Veglio
Letter Regarding Article by Hood et al, "The Spironolactone, Amiloride, Losartan, and Thiazide (SALT) Double-Blind Crossover Trial in Patients With Low-Renin Hypertension and Elevated Aldosterone-Renin Ratio"
Circulation, February 5, 2008; 117(5): e151 - e151.
[Full Text] [PDF]

Home page
 HeartHome page
M. J Brown
Renin: friend or foe?
Heart, September 1, 2007; 93(9): 1026 - 1033.
[Abstract] [Full Text] [PDF]

This Article
Free upon publication Free Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
116/3/268    most recent
CIRCULATIONAHA.107.690396v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar