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Authors: Stormi Gale, PharmD, Jeannie L. Poon, PharmD, and Kristin Watson, PharmD, BCPS-AQ Cardiology
The efficacy of mineralocorticoid receptor antagonists (MRAs) in resistant hypertension is not surprising given that hyperaldosteronism is the most common underlying etiology for this condition. Resistant hypertension is defined as blood pressure (BP) above goal despite 3 antihypertensives at optimal doses, including a diuretic, or BP that is controlled on 4 or more agents.1 The 2014 Eighth Joint National Committee Hypertension Guidelines recommend MRAs as 4th line therapy in patients not controlled on a maximally tolerated angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), calcium channel blocker (CCB), and thiazide-type diuretic.2 Multiple trials evaluating the safety and efficacy of spironolactone in this population have been published over the last several years.
In 2003, Nishizaka et al. described the use of spironolactone 25-50 mg as add-on therapy in resistant hypertension, demonstrating a mean BP lowering of 21/10 mmHg after 6 weeks. Patients enrolled in this study were uncontrolled on 3 antihypertensives, including an ACEi/ARB and a diuretic (not specified)3 The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) later evaluated the effects of various antihypertensives on cardiovascular (CV) events in patients aged 40-79 with at least 3 other CV risk factors.4 Although the major arms of this trial compared amlodipine (with the addition of an ACEi, as needed) to atenolol (with the addition of bendroflumethiazide, as needed), a post-hoc analysis demonstrated similar BP reductions in patients who received spironolactone, as a fourth-line agent, to those previously published in the Nishizaka et al. trial.5 The Addition of Spironolactone in Patients With Resistant Arterial Hypertension (ASPIRANT) trial included patients with treatment resistant hypertension who were receiving an ACEi/ARB, CCB, and a diuretic (mostly thiazide-like). Despite being a treatment-resistant patient population, a statistically significant decrease in mean 24-hour systolic BP (SBP) of -6.6 mmHg (p=0.004) was observed with the addition of spironolactone compared to placebo.6 This finding was supported by the most recent Prevention and Treatment of Hypertension with Algorithm based therapY trial (PATHWAY-2), a randomised, double-blind, crossover trial, in which a similar patient population rotated through 12 weeks of spironolactone, bisoprolol, dozazosin, and placebo plus baseline anti-hypertensive medications. Spironolactone was found to be superior to all other agents with an average decrease in SBP of approximately 4 mmHg (p<0.001 for all comparisons). There was no difference in BP lowering between the other agents and placebo.7
Hyperkalemia is a major limiting adverse effect (AE) that prevents the use of MRAs in many patients. In the Randomized Aldactone Evaluation Study (RALES) and Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) trials, potassium increased by an average of 0.3 mEq/L after one year of treatment. Both RALES and EPHESUS defined serious hyperkalemia as > 6 mEq/L. In RALES, there was no difference in the incidence of serious hyperkalemia in the spironolactone group compared to placebo (2% vs. 1%, p=0.42)8 whereas in EPHESUS, eplerenone increased the risk of serious hyperkalemia (5.5% vs. 3.9%, p=0.002)9. Impaired renal function was found to be a predictor of this effect, with increased incidence seen in the strata of patients with creatinine clearance (CrCl) < 50 mL/min.9 A population-based time-series of 1.3 million patients in Canada evaluated the incidence of hyperkalemia with spironolactone in a real-world setting. A statistically significant increase in the spironolactone prescription rate, hospitalizations for hyperkalemia (2.4 per 1000 patients to 11.0 per 1000 patients, p<0.001), and hyperkalemia-associated mortality (0.3 per 1000 patients to 2.0 per 1000 patients, p<0.001) were seen after the publication of RALES. This was in addition to no significant decreases in the rates of heart failure (HF) readmissions or all-cause mortality, suggesting that the risks and benefits of this class may differ in a real-world setting.10
Patients in clinical trials are rigorously followed according to strict protocols for AEs, whereas in clinical practice patients are more loosely monitored. The results of this publication strengthen the idea that combination drug therapy may simultaneously improve clinical outcomes and enhance the risk of potassium-related AEs; therefore, an appropriate balance of benefit and risk depends heavily on careful patient selection and adequate surveillance of serum potassium and renal function. he American College of Cardiology Foundation/American Heart Association guideline for the management of patients with HF recommend that serum potassium and creatinine should be measured 2 to 3 days after initiation, again in 1 week, then monthly for 3 months after starting an MRA, as well as with any dose increases.11 For patients without HF, it is recommended to monitor potassium and creatinine one week after MRA initiation or with any dose increase, monthly for the first 3 months, then quarterly for a year, followed by every 6 months.12 Furthermore, it is recommended that MRAs be discontinued or held in patients with potassium > 5 mEq/L or a creatinine of > 4 mg/dL.
Additionally, conditions that may develop during therapy that predispose patients to hyperkalemia (e.g., renal dysfunction) and concomitant medications (e.g., ACEi/ARBs) should be taken into consideration. It is imperative that other sources of potassium are identified and eliminated to reduce this risk in patients on MRAs. Patients should be counseled regarding avoidance of potassium-containing salt substitutes and potassium supplements should typically be removed from patient’s medication lists.
Exclusion criteria in various trials evaluating MRAs often limit its use in patients with renal dysfunction. However, it is widely accepted that CV events are the leading cause of death in patients with end-stage renal disease (ESRD).13 In fact, ESRD is itself a condition associated with hyperaldosteronism. In this patient population, aldosterone levels increase paradoxically with glomerular filtration rate. For this reason, the mechanism of MRAs render the class an attractive option in these patients. Patients with ESRD, as we know, are at an increased risk for hyperkalemia, which is another concern for the addition of spironolactone. However, small studies have shown a reduction in CV mortality and hospitalization with spironolactone in patients with ESRD on hemodialysis (HD) without an increase in hyperkalemia.14-15 It is important to note, though, that most of these studies were performed in anuric patients, who no longer have the renal ability to retain potassium. The risk of hyperkalemia would likely be increased in oliguric patients, especially between HD sessions, due to remaining renal mechanisms that cause potassium retention. Currently, the ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST), a randomized, controlled trial, is recruiting and will further evaluate the use of MRAs in this patient population.16
Aside from hyperkalemia and renal dysfunction, it is widely accepted that spironolactone increases the risk of sexual side effects including menstrual irregularities and gynecomastia.17 This is a result of the nonselectivity of spironolactone for the mineralocorticoid receptor, with additional effects on androgen and progesterone receptors. This nonselectivity, however, is also responsible for spironolactone’s efficacy in a wide array of non-cardiac indications, including acne, hirsutism, ascites and cirrhosis, hypokalemia, and primary aldosteronism. Conversely, eplerenone exhibits increased selectivity for the mineralocorticoid receptor and can be utilized in patients who experience this adverse effect. Cost has been a major limiting factor for eplerenone in the past, but the cost differential between the two agents has narrowed over the past few years.
Not only are MRAs beneficial in HF and myocardial infarction, but they are an attractive option when it comes to resistant hypertension as well; significant reductions in BP can be seen as early as 6 weeks. Despite the overwhelming evidence to suggest their use in the CV disease realm, MRAs remain an untapped and underutilized drug class, likely due to the AEs associated with the agents. The take-home message for this two-part series in terms of the effects of MRAs is this: the opportunity to improve outcomes with use of MRAs without compromising safety, especially in HF patients, is tightly coupled to appropriate patient selection, individualized drug dosing, and attentive monitoring in accordance with established guidelines.
Kristin Watson, PharmD, BCPS-AQ Cardiology
Stormi Gale, PharmD
Jeannie L. Poon, PharmD
- Calhoun DA, Jones D, Textor S et al. Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117(25):e510-e526.
- James P, Oparil S, Carter B et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
- Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003;16(11 Pt 1):925-30.
- Dahlof B, Sever PS, Poulter NR et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895-906.
- Chapman N, Dobson J, Wilson S et al. Effect of Spironolactone on Blood Pressure in Subjects With Resistant Hypertension. Hypertension. 2007;49:839-845.
- Václavík J, Sedlák R, Plachy M, et al. Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. 2011;57:1069–75.
- Williams B, MacDonald T, Morant S et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386:2059-68.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-17.
- Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-1321.
- Juurlink, D, Mamdani M, Lee D et al. Rates of Hyperkalemia after Publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351:543-51.
- Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239.
- Aldactone (spironolactone) [prescribing information]. New York, NY: Pfizer Inc; October 2014.
- Bomback et al. Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease: Efficacy and Safety. Blood Purif. 2016;41:166–170.
- Matsumoto Y, Kageyama S, Yakushigawa T et al. Long-term low-dose spironolactone therapy is safe in oligoanuric hemodialysis patients. 2009;114:32–38.
- Matsumoto Y, Mori Y, Kageyama S, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014;63:528–536.
- ALdosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST). (2016). Retrieved from http://clinicaltrials.gov/ct2 (Identification No. NCT01848639).
- Struthers A, Krum H, Williams HG, et al. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol. 2008;31(4):153-8.
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