Abstract
The purpose of this study was to evaluate the effects of spironolactone on dialysis patients with refractory hypertension and possible adverse effects. This was a 12‐week prospective, randomized, double‐blind trial of 82 patients randomly assigned to 12‐week treatment with 25 mg/d spironolactone or placebo as add‐on therapy. Visits were scheduled at the start of treatment and after 12 weeks. Measurements of 24‐hour ambulatory blood pressure (BP) monitoring and morning BP were performed. After 12 weeks, spironolactone significantly improved refractory hypertension. Average placebo‐corrected morning BP was reduced by 16.7/7.6 mm Hg. Mean 24‐hour ambulatory BP was reduced by 10.9/5.8 mm Hg. In contrast, serum aldosterone levels in the spironolactone group slightly increased and serum potassium levels insignificantly increased. This study has demonstrated that spironolactone (50 mg) safely and effectively reduces BP in patients with refractory hypertension undergoing dialysis.
Nearly 40% of Chinese people aged 45 years or older have a hypertension disorder.1 Its control is poor in low‐ and middle‐income countries.2 The achievement rates in hypertension control are similarly low worldwide.3, 4, 5 Hypertension is more common among patients with end‐stage renal disease (ESRD). In general, hypertension in patients with ESRD, especially dialysis, is therapy‐resistant and often refractory against common medical interventions. Accordingly, effective blood pressure (BP) reductions for such patients necessitate multiple antihypertensive medications. Refractory hypertension is an increasingly common clinical problem especially among dialysis patients. It is defined as uncontrolled BP on optimal doses of ≥3 antihypertensive agents.6 Secondary causes of hypertension, including obstructive sleep apnea, primary aldosteronism, and renovascular disease are common in patients with refractory hypertension and often coexist in the same patient.
Management of hypertension is of particular importance in such patients because of its substantial effects on prognosis. According to a meta‐analysis of prospective studies,7 control of morning BP can significantly reduce the risk of cardiovascular events. Thus, reduction of morning BP can be a new therapeutic target for preventing target organ damage and subsequent cardiovascular events in hypertension patients.7 Spironolactone is a potassium‐sparing diuretic that prevents the body from absorbing too much salt and keeps the potassium levels from getting too low. Spironolactone is used to diagnose or treat a condition in which the body contains too much aldosterone. Spironolactone also treats fluid retention in people with congestive heart failure, liver cirrhosis, and nephrotic syndrome. It can also be used in many dermatologic conditions because of its antiandrogenic effect. Recently, spironolactone was satisfactorily used in patients with refractory hypertension.8, 9
However, spironolactone is not widely studied in dialysis patients because of potential side effects. To address this clinical concern, we conducted a prospective, randomized trial to evaluate its effects on antihypertensive potency and various clinical parameters in dialysis patients with refractory hypertension.
Methods
Study Design
This 12‐week prospective, randomized, double‐blind study was conducted in two dialysis centers. The study was approved by local ethics committees. All patients gave informed consent before taking part in the study. The primary end point of the study was to compare the effects of spironolactone on BP in dialysis patients. Advice on lifestyle modification such as a daily salt intake <3 g10 was followed throughout the study. A daily potassium intake <1.5 g was also advised.
Patients and Methods
Participants were adults 16 years or older undergoing stable dialysis for at least 3 months. All patients had refractory hypertension, which was defined as predialysis BP >160/90 mm Hg or postdialysis BP >140/80 mm Hg in hemodialysis patients and mean clinical systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg in peritoneal patients in spite of treatment with ≥3 antihypertensive drugs according to previous studies.11, 12 To evaluate the effect of spironolactone independent of its diuretic action, we included only oliguric and anuric patients. Since most of the long‐term dialysis patients presented with anuria or oliguria, diuretics were not used except for spironolactone in our study. We also diagnosed refractory hypertension by ruling out the use of diuretics. The dialysis adequacy was also evaluated to distinguish the reasons for hyperkalemia and hypertension. Patients were randomly assigned to receive 12 weeks of 25 mg/d spironolactone (n=40) or placebo (n=36). Medication was administered orally following hemodialysis or in the morning for spironolactone and placebo.
Inclusion and Exclusion Criteria
Inclusion criteria were as follows: diagnosis of ESRD, receiving current conventional hemodialysis (3 times per week) or maintenance peritoneal dialysis (PD), older than 16 years, voluntary participation, and signing consent form. All patients had hypertension for 6 months without any apparent cause in spite of treatment with 3 antihypertensive drugs given at the optimal dosage except for diuretics. Patients with prior use of spironolactone or potassium level >5 mmol/L were excluded.
BP Monitoring and Spironolactone Therapy
Ambulatory BP monitoring and morning BP measurements were performed before (baseline) and 12 weeks after introduction of spironolactone therapy. All morning BP levels were measured by the same cardiologist using a mercury sphygmomanometer with the cuff size adjusted appropriately for the arm and placed at the level of the heart. Patients were required to undergo morning BP measurement in a sitting position within 30 minutes after awakening before taking medications in a fasting state. Ambulatory BP levels were monitored for 24 hours using an ABMP6100 SpaceLabs ambulatory BP monitor (Welch Allyn, Skaneateles Falls, NY). The pressure was measured every 15 minutes between 6 am and 10 pm and every 30 minutes from 10 pm to 6 am.
A dose of 25 mg/d was prescribed for patients in the spironolactone group. Dose titration of spironolactone to 2 tablets of 25 mg/d or 2 tablets of placebo was implemented after 4 weeks if clinical BP was above 135/85 mm Hg. Initial dose of study drug was maintained if clinical BP was below 135/85 mm Hg and above 115/75 mm Hg. The dose was halved if clinical BP was below 115/75 mm Hg after 4 weeks. The dose was reduced to half the initial dose if plasma potassium increased to more than 5.0 mmol/L, and was withdrawn if exceeded 5.5 mmol/L. Patients were instructed not to change the dose or number of concomitant medications during the trial.
Demographic and Laboratory Measurements
We measured basic laboratory parameters such as hemoglobin, serum potassium, serum sodium, serum intact parathyroid hormone, and high‐sensitivity C‐reactive protein (hs‐CRP) at baseline. Blood samples were collected before dialysis from hemodialysis patients and on the morning of the day from PD patients. Measurements were performed employing standard methods. Age, sex, primary kidney disease for renal failure, weight, smoke status, and number of hypertensive medications taken were obtained from medical records or by asking the patients. Comorbidity was scored on the number of comorbid conditions using a comorbidity index.13 Serum potassium levels, hs‐CRP, and aldosterone levels were also evaluated after 12 weeks. In addition, we measured serum potassium level any time a cardiac discomfort occurred.
Statistical Analysis
The results are expressed as mean±standard deviation and P<.05 was considered significant (α=0.05 2‐tailed). Differences in means were assessed using independent t test or Mann‐Whitney test. Quartiles were compared with one‐way analysis of variance, Kruskal‐Wallis test, or χ2 test, as appropriate. Nonparametric tests were used for non‐normally distributed data. All statistical analyses were evaluated on SPSS 17.00 (IBM Corporation, Armonk, NY).
Results
Characteristics Study Patients
Finally, 76 of the 82 screened dialysis patients were evaluated in terms of eligibility. Six patients were excluded after randomization but included in the intention‐to‐treat analysis: 4 in the spironolactone group (2 due to hyperkalemia, 1 due to gynecomastia, and 1 due to nausea) and 2 in the placebo group (due to recurrent chest discomfort). Basic laboratory data and sociodemographic characteristics of the entire study population are depicted in Table 1. There was no difference in systolic or diastolic BP, as well as other parameters between the spironolactone group and the placebo group at baseline.
Table 1.
Sociodemographic and Clinical Data of Study Groups
| Characteristics | Spironolactone (n=40) | Placebo (n=36) |
|---|---|---|
| Age, y | 55.7±12.3 | 54.9±14.2 |
| Male sex, % | 60.0 | 58.3 |
| Primary kidney disease, % | ||
| Nephritis | 60 | 61.1 |
| Hypertensive nephropathy | 5 | 5.5 |
| Diabetic nephrology | 15a | 19.4 |
| Polycystic kidney disease | 5a | 8.3 |
| Other | 15 | 5.7 |
| Hypertension medications, No. | 5.1±1.7 | 4.8±0.9 |
| Type of antihypertensive medications, No. (%) | ||
| Calcium channel blockers | 40 (100) | 36 (100) |
| β‐Blockers | 26 (65) | 24 (66.7) |
| α‐Blockers | 12 (30) | 10 (27.8) |
| Vasodilators | 30 (75) | 28 (77.8) |
| ACE inhibitors/ARBs | 22 (55) | 19 (52.8) |
| Central‐acting agents | 36 (90) | 33 (91.7) |
| Modality of dialysis, HD, % | 65.0 | 61.1 |
| Smoking, % | 12.5 | 11.1 |
| Smoker | 30 | 30.6 |
| Mean body weight, kg | 67.5±10.8 | 66.8±12.2 |
| Mean urine volume, % | ||
| <100 mL/24 h | 77.5 | 80.6 |
| >100 mL/24 h | 22.5 | 29.4 |
| Mean morning BP, mm Hg | ||
| Systolic BP | 153.5±12.5 | 151.5±16.5 |
| Diastolic BP | 92.5±14.5 | 89.5±12.0 |
| Mean 24‐h ambulatory BP, mm Hg | ||
| Systolic BP | 147.0±12.5 | 145.5±9.5 |
| Diastolic BP | 90.5±11.5 | 90.0±13.5 |
| Mean hemoglobin, g/L | 12.3±5.7 | 12.2±4.9 |
| Mean serum potassium, mmol/L | 4.1±1.5 | 3.9±0.9 |
| Mean serum sodium, mmol/L | 137.3±1.7 | 139.2±2.5 |
| Mean serum intact parathyroidhormone, pg/mL | 215.6±89.4 | 217.0±97.6 |
| High‐sensitivity C‐reactive protein, mg/L | 7.8±2.6 | 8.3±0.9 |
| Mean time on dialysis, mo | 56.5±10.2 | 54.9±14.7 |
| Comorbidity index | 5.7±0.6 | 5.3±1.9 |
| KT/V | 1.55±0.37 | 1.49±0.16 |
Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; HD, hemodialysis. The differences in proportions were tested using Pearson chi‐square test and differences in means were tested using Independent t or Mann‐Whitney test. Each group was compared separately with the placebo group. Values are expressed as mean±standard deviation. a P<.05.
Efficacy and Safety Assessments
Change in primary and secondary variables in dialysis patients with refractory hypertension is shown in Table 2. After 12 weeks of treatment, the mean morning BP significantly decreased (P<.001) in the spironolactone group in both systolic BP (153.5±12.5–133.5±10.5 mm Hg) and diastolic BP (92.5±14.5–83.5±9.0 mm Hg). The average morning BP was reduced by 17.0 (16–18)/8 (6.1–10) mm Hg, and the average 24‐hour ambulatory BP was reduced by 12.5 (11.2–13.8)/7.0 (5.4–8.6) mm Hg after placebo correction at 12 weeks of follow‐up.
Table 2.
Change in Primary and Secondary Variables After Intervention According to Study Group
| Spironolactone (n=40) | Placebo (n=36) | |
|---|---|---|
| Primary variables | ||
| Mean morning SBP, mm Hg | ||
| Baseline | 153.5±12.5 | 151.5±16.5 |
| 12 weeks | 133.5±10.5 | 148.5±14.0 |
| Mean change from baseline vs placebo (95% CI) | −17.0 (−18 to −16) | – |
| P value | <.05 | – |
| Mean morning DBP, mm Hg | ||
| Baseline | 92.5±14.5 | 89.5±12.0 |
| 12 weeks | 83.5±9.0 | 88.5±14.5 |
| Mean change from baseline vs placebo (95% CI) | −8 (−10 to −6.1) | – |
| P value | <.05 | – |
| Mean 24‐h ambulatory SBP, mm Hg | ||
| Baseline | 147.0±12.5 | 145.5±9.5 |
| 12 weeks | 135.5±9.0 | 146.0±11.5 |
| Mean change from baseline vs placebo (95% CI) | −12.5 (−13.8 to −11.2) | – |
| P value | <.05 | – |
| Mean 24‐h ambulatory DBP, mm Hg | ||
| Baseline | 90.5±11.5 | 90.0±13.5 |
| 12 weeks | 83.0±7.5 | 88.5±10.5 |
| Mean change from baseline vs placebo (95% CI) | −7.0 (−8.6 to −5.4) | – |
| P value | <.05 | – |
| Secondary variables | ||
| Mean body weight, kg | ||
| Baseline | 67.5±10.8 | 66.8±12.2 |
| 12 weeks | 67.8±14.2 | 66.9±9.8 |
| Mean change from baseline vs placebo (95% CI) | 0.2 (−1.1 to 1.5) | – |
| P value | >.05 | – |
| Urine volume, mL/24 h | ||
| Baseline | 336.8±209.4 | 344.5±178.5 |
| 12 weeks | 321.5±197.3 | 353.9±183.2 |
| Mean change from baseline vs placebo (95% CI) | −24.7 (−28.9 to 20.5) | |
| P value | >.05 | |
| Mean serum potassium, mmol/L | ||
| Baseline | 4.1±1.5 | 3.9±0.9 |
| 12 weeks | 4.4±0.7 | 4.1±1.4 |
| Mean change from baseline vs placebo (95% CI) | 0.1 (−0.2 to 0.4) | – |
| P value | >.05 | – |
| Mean plasma aldosterone, pg/mL | ||
| Baseline | 23.8±10.9 | 23.4±10.2 |
| 12 weeks | 24.5±11.0 | 23.5±9.8 |
| Mean change from baseline vs placebo (95% CI) | 0.6 (0.5–0.7) | – |
| P value | >.05 | – |
| Mean high‐sensitivity C‐reactive protein, mg/L | ||
| Baseline | 7.8±2.6 | 8.3±0.9 |
| 12 weeks | 8.1±3.6 | 8.5±1.7 |
| Mean change from baseline vs placebo (95% CI) | 0.1 (−0.3 to 0.5) | – |
| P value | >.05 | – |
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. The change in blood pressure during intervention within the groups is expressed as the mean difference and 95% confidence interval (CI).
In the spironolactone group, 34 of the 40 patients had a clinical BP <140/90 mm Hg, and 23 (57.5%) reached the target morning BP <135/85 mm Hg as opposed to 3 of 36 (8.3%) in the placebo group at 12 weeks of follow‐up (P<.05). Target mean ambulatory BP <130/80 mm Hg was achieved by 26 of 40 patients (65%) in the spironolactone group and by 2 of 36 patients (5.6%) in the placebo group (P<.05). At the end of follow‐up, the mean dose of spironolactone was 42.5 mg/d. None received 12.5 mg of spironolactone, 30% (12 of 40) received 25 mg/d, and 70% (28 of 40) received 50 mg/d. At 12 weeks after introduction of spironolactone, 4 patients required discontinuation because of adverse effects, such as gynecomastia, nausea, and hyperkalemia as opposed to 2 in the placebo group.
The potassium level rose in the spironolactone group, but not significantly different from the placebo group during the 12 weeks (P>.05). Serum potassium levels increased to >5 mmol/L in 3 patients. Adverse events including mastauxy and nausea were observed with the use of spironolactone. Adverse events led to discontinuation of medication in patients receiving spironolactone (2 due to hyperkalemia [5.66 vs 5.92 mmol/L], 1 due to gynecomastia, and 1 due to nausea).
There was no difference in hs‐CRP or brain natriuretic peptide before and after dialysis or between the spironolactone and placebo groups. The aldosterone level slightly increased in response to treatment with spironolactone (23.8±10.9–24.5±11.0 pg/mL), but not significantly (P>.05).
Discussion
Refractory hypertension is a common clinical problem with an increasing prevalence rate that, if not sufficiently treated, causes a high risk for cardiovascular morbidity and mortality. The prevalence of refractory hypertension is estimated to be up to 5% to 10%.14 Refractory hypertension is more common in ESRD patients. The probability of ESRD in patients with refractory hypertension in China is as high as 50%.
The precise pathogenesis of refractory hypertension is not well known, but the probable important factors include aldosterone and increased mineralocorticoid receptor activity.15, 16 The pathogenesis of ESRD in patients with hypertension is more complex, and the main connection between hypertension and ESRD is the renin‐angiotensin‐aldosterone system (RAS). Clinical studies show that high BP in patients is often accompanied by RAS activation and secondary high aldosterone hematic disease, which is often associated with refractory hypertension.17 The current study focuses on the efficacy of spironolactone among patients referred with high BP refractory to treatment with ≥3 antihypertensive agents.
We demonstrated that mean morning BP and mean ambulatory BP were significantly reduced and the hypertension in most patients within 3 months of initiation of spironolactone was adequately controlled. To date, only a few studies on dialysis patients demonstrate that spironolactone can effectively reduce BP, especially morning BP. The present study confirms such an effect. Morning BP measurement instead of clinical BP measurement was used in our study since the efficacy of BP control can be evaluated by reduction of morning BP. Ambulatory BP monitoring is necessary to assess the diagnosis of refractory hypertension by eliminating the white coat syndrome.
Several studies confirm that low‐dose spironolactone is clinically effective for refractory hypertension.18, 19 After 12 weeks of treatment, the mean placebo‐corrected morning BP/24‐hour ambulatory BP significantly decreased in patients taking spironolactone in both systolic and diastolic BPs. The reduction extent was in accordance with a previous trial, but was obtained at higher doses (50 mg/d vs 12.5 mg/d or 25 mg/d) and other studies were only short trials. The reason is that refractory hypertension among dialysis patients was multifactor and more uncontrollable. About 23 of 40 patients in the spironolactone group reached the goal of lowering morning BP <135/85 mm Hg recommended by most guidelines, and thus reduced general cardiovascular risk by such intensive BP lowering in clinical intervention studies.20, 21, 22 Moreover, mean 24‐hour ambulatory BP was reduced significantly in our trial, as ambulatory BP was particularly associated with cardiovascular morbidity and mortality.23, 24, 25
Spironolactone is more than a diuretic in the sense that it has specific vascular effects that are independent of any modification of electrolyte or water balance. Body weight before or after 12 weeks of treatment with spironolactone did not change, suggesting that volume status was unchanged. Volume overload was excluded as a contributor to hypertension. Spironolactone decreased BP by a mechanism that is independent of the drug's diuretic properties as shown by the constant urine volume during the study. At the same time, we did not observe a change in plasma aldosterone concentration before and after treatment, in accordance with previous studies. There were some reasons for antihypertensive effect of spironolactone.26 First, spironolactone decreased BP in oliguric and anuric dialysis patients through epithelial target. Second, spironolactone decreased BP in oliguric or anuric dialysis patients through nonepithelial target, such as modulating vascular reactivity to vasoconstrictors by acting on mineralocorticoid receptors and a protective enzyme, 11β‐hydroxysteroid, in the vasculature.
Hyperkalemia is a well‐recognized complication of treatment with spironolactone. Concern for hyperkalemia, a fatal complication of dialysis patients, might cause a physician to avoid spironolactone. The present study demonstrates that spironolactone did not increase serum potassium level, confirming the previous observations. Two patients dropped out from the study because of hyperkalemia in hemodialysis patients other than PD patients. Spironolactone was safer among dialysis patients than nondialysis patients,27 since the kidneys account for only a small part of potassium metabolism, and most of the potassium is excreted by dialysis. This may be a great advantage when selecting it for PD patients who are constantly prone to hypokalemia.28
Study Limitation
A limitation in the present randomized controlled study is that the sample size is relatively small. There is no evidence proving the effect of spironolactone on clinical outcomes in hypertensive patients. The optimal range of systolic BP for predialysis patients may be 130 mm Hg to 159 mm Hg.29 Further studies with more patients studying the long‐term effects of aldosterone and clinical outcomes evaluation will help to improve the findings of this study.
Conclusions
This study has demonstrated that spironolactone (50 mg) safely and effectively reduces BP in refractory hypertension patients undergoing dialysis.
Disclosure
There are no competing financial interests in relation to the current work.
J Clin Hypertens (Greenwich). 2014;16:658–663 © 2014 Wiley Periodicals, Inc.
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