The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies

Dahal, Khagendra; Kunwar, Sumit; Rijal, Jharendra; Alqatahni, Fahad; Panta, Raju; Ishak, Noshi; Russell, Roy Patterson

doi:10.1093/ajh/hpv031

Cited by 96 publications

(48 citation statements)

References 26 publications

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“…The use of this drug in RfH observed by Calhoun et al8 was higher (18%), but still lower than expected. A meta‐analysis of studies in which mineralocorticoid receptor antagonists with or without random allocation were used has shown that low‐dose spironolactone is an effective and safe additional drug to achieve BP control in many RH patients, although it is required that renal function is preserved, or only slightly or moderately reduced 18. The results of the PATHWAY‐2 (The Prevention and Treatment of Hypertension With Algorithm based therapy) study,19 the first randomized study evaluating different therapeutic options (spironolactone, doxazosin, bisoprolol, or placebo) as the fourth step in the management of patients with RH, have unequivocally demonstrated that spironolactone is the best option, at least in the short term, to improve BP control in RH subjects.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Clinical Characteristics of Refractory Hypertension

Armario

Calhoun

Oliveras

et al. 2017

JAHA

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BackgroundWe aimed to estimate the prevalence of refractory hypertension (RfH) and to determine the clinical differences between these patients and resistant hypertensives (RH). Secondly, we assessed the prevalence of white‐coat RfH and clinical differences between true‐ and white‐coat RfH patients.Methods and ResultsThe present analysis was conducted on the Spanish Ambulatory Blood Pressure Monitoring Registry database containing 70 997 treated hypertensive patients. RH and RfH were defined by the presence of elevated office blood pressure (≥140 and/or 90 mm Hg) in patients treated with at least 3 (RH) and 5 (RfH) antihypertensive drugs. White‐coat RfH was defined by RfH with normal (<130/80 mm Hg) 24‐hour blood pressure. A total of 11.972 (16.9%) patients fulfilled the standard criteria of RH, and 955 (1.4%) were considered as having RfH. Compared with RH patients, those with RfH were younger, more frequently male, and after adjusting for age and sex, had increased prevalence of target organ damage, and previous cardiovascular disease. The prevalence of white coat RfH was lower than white‐coat RH (26.7% versus 37.1%, P<0.001). White‐coat RfH, in comparison with those with true RfH, showed a lower prevalence of both left ventricular hypertrophy (22% versus 29.7%; P=0.018) and microalbuminuria (28.3% versus 42.9%; P=0.047).ConclusionsThe prevalence of RfH was low and these patients had a greater cardiovascular risk profile compared with RH. One out of 4 patients with RfH have normal 24‐hour blood pressure and less target organ damage, thus indicating the important role of ambulatory blood pressure monitoring in guiding antihypertensive therapy in difficult‐to‐treat patients.

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Section: Discussionmentioning

confidence: 99%

Prevalence and Clinical Characteristics of Refractory Hypertension

Armario

Calhoun

Oliveras

et al. 2017

JAHA

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“…Spironolactone has been shown to reduce blood pressure in the general RHTN population [16,17], and in RHTN patients with heart failure with preserved ejection fraction [30]. It has been found to be a more effective BPlowering agent compared with other medication classes, as demonstrated in PATHWAY-2 [18].…”

Section: Discussionmentioning

confidence: 99%

“…Two meta-analyses of clinical and observational studies conducted from 2002 to 2013 concluded that spironolactone effectively reduces blood pressure in patients with RHTN, although the studies were often nonrandomized, and comparison between other treatment options was limited [16,17]. Subsequent to these meta-analyses, the PATHWAY-2 study, a randomized, double-blind, crossover study, evaluated patients with RHTN rotated through 12 weeks of add-on treatment with spironolactone, bisoprolol, doxazosin, or placebo [18].…”

Section: Background and Study Rationalementioning

confidence: 99%

Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study

et al. 2018

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Background: While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. Methods: Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of 135–160 mm Hg during screening despite taking ≥3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ≤45 mL/min/1.73 m². Screening serum potassium must be 4.3–5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. Results: Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m². Conclusion: AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.

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“…Despite the fact that higher doses of eplerenone are needed, 13 the efficacy of this drug was proved with a lower incidence of side effects. 16,17 Furthermore, according to European Society of Hypertension/European Society of Cardiology guidelines for the management of arterial hypertension, eplerenone might be considered in RH. Unfortunately, the price and prescription limitations in the Czech Republic (eplerenone is indicated only in heart failure according to the summary of product characteristics) 18 do not allow wider implementation of this potent drug in resistant hypertensive patients.…”

Section: Discussionmentioning

confidence: 99%

Role of Adding Spironolactone and Renal Denervation in True Resistant Hypertension

et al. 2016

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C atheter-based renal denervation (RDN) has been considered as a new hope for patients with resistant hypertension (RH). The first studies published by the same pioneering group of experts 1,2 triggered widespread enthusiasm, and the new method was quickly promulgated. However, this was slowed down in 2014 by publication of trials with negative results for RDN. [3][4][5][6] Apart from exceptions, 7 most of these studies failed to prove the satisfactory efficacy of RDN.3-6 Based on these results, the Czech Society for Hypertension does not recommend implementation of RDN in routine practice. 8This study seeks to evaluate the efficacy of RDN in a prospective multicenter randomized trial with the acronym PRAGUE-15 in patients with true RH. Twenty-four-hour ambulatory blood pressure monitoring, exclusion of secondary hypertension, and evaluation of treatment compliance served as confirmation of true resistance. The efficacy of RDN was compared with intensified antihypertensive treatment, including the use of spironolactone. The 6-month results of the PRAGUE-15 study were previously published. 6 To date, only 1 properly designed study has published 12-month results 9 where RDN was compared with a sham procedure. Here we present the 1-year data, including the evaluation of renal artery changes after RDN and hormonal and hemodynamic parameters. See Editorial Commentary, pp 278-280Abstract-This randomized, multicenter study compared the relative efficacy of renal denervation (RDN) versus pharmacotherapy alone in patients with true resistant hypertension and assessed the effect of spironolactone addition. We present here the 12-month data. A total of 106 patients with true resistant hypertension were enrolled in this study: 52 patients were randomized to RDN and 54 patients to the spironolactone addition, with baseline systolic blood pressure of 159±17 and 155±17 mm Hg and average number of drugs 5.1 and 5.4, respectively. Twelve-month results are available in 101 patients. The intention-to-treat analysis found a comparable mean 24-hour systolic blood pressure decline of 6.4 mm Hg, P=0.001 in RDN versus 8.2 mm Hg, P=0.002 in the pharmacotherapy group. Per-protocol analysis revealed a significant difference of 24-hour systolic blood pressure decline between complete RDN (6.3 mm Hg, P=0.004) and the subgroup where spironolactone was added, and this continued within the 12 months (15 mm Hg, P= 0.003). Renal artery computed tomography angiograms before and after 1 year post-RDN did not reveal any relevant changes. This study shows that over a period of 12 months, RDN is safe, with no serious side effects and no major changes in the renal arteries. RDN in the settings of true resistant hypertension with confirmed compliance is not superior to intensified pharmacological treatment. Spironolactone addition (if tolerated) seems to be more effective in blood pressure reduction.

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The Effects of Aldosterone Antagonists in Patients With Resistant Hypertension: A Meta-Analysis of Randomized and Nonrandomized Studies

Abstract: On the basis of the current meta-analysis, we conclude that AA is safe and effective therapy in patients with RH.

Cited by 96 publications

References 26 publications

Prevalence and Clinical Characteristics of Refractory Hypertension

Prevalence and Clinical Characteristics of Refractory Hypertension

Patiromer to Enable Spironolactone Use in the Treatment of Patients with Resistant Hypertension and Chronic Kidney Disease: Rationale and Design of the AMBER Study

Role of Adding Spironolactone and Renal Denervation in True Resistant Hypertension

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