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Author: Sandeep Devabhakthuni, PharmD, BCCP
Cardiovascular morbidity and mortality is exceptionally high in patients with end stage renal disease (ESRD) with a 5-year survival rate of 45%.1 Up to 70% of patients with ESRD have concomitant heart failure.2,3 Pharmacotherapeutic strategies for treating patients with heart failure with reduced ejection fraction (HFrEF) are the same for those with or without ESRD. The use of renin-angiotensin-aldosterone system (RAAS) inhibitors have been shown to decrease the risk of death, heart failure (HF) hospitalization among other outcomes in patients with HFrEF. 4 The presence of renal impairment raises special considerations for use with the aldosterone receptor antagonists (ARAs). This creates a dilemma in patients with HFrEF, who would derive the greatest benefit from ARA therapy, but have ESRD undergoing dialysis, which puts them at higher risk for hyperkalemia. Current HF guidelines caution against the use of aldosterone antagonists in patients with advanced renal disease (estimated glomerular filtration rate < 30 mL/min/1.73m2), which may have limited use in this population.5,6,20
Numerous studies have shown that elevated levels of aldosterone leads to profound cardiovascular disease despite RAAS blockade with angiotensin converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs).7-10 Even with RAAS inhibition from ACE inhibitors or ARBs, 30-50% of patients on long-term therapy have elevations of serum aldosterone levels.7-10 This breakthrough may explain the mortality benefit of aldosterone blockade as add-on therapy to ACE inhibitors or ARBs in heart failure.11 Also, aldosterone levels increase as creatinine clearance declines so patients with chronic kidney disease (CKD) or ESRD have relative hyperaldosteronism.12 Thus, in patients with advanced renal disease, aldosterone breakthrough may be particularly noxious, and use of ARAs may be needed in addition to ACE inhibitors or ARBs for maximal RAAS inhibition.
Efficacy of ARAs in Patients with HFrEF and ESRD Undergoing Dialysis
Aldosterone receptor antagonists have become mainstays in treating HFrEF due to large clinical trials – RALES and EMPHASIS-HF.11,13 However, these landmark trials excluded patients with ESRD undergoing dialysis. The ARAs have been shown to be safe in proteinuric CKD management, but evidence is based on small studies, and most were uncontrolled.14,15 There is modest literature for the use of ARAs in patients with ESRD undergoing dialysis.16-18 Patients with ESRD typically have left ventricular hypertrophy and elevated aldosterone levels.16 A recent study of 328 patients undergoing hemodialysis who were euvolemic revealed a median serum aldosterone level of 18.4 ng/dL, and those with a level of > 28 ng/dL had a doubling of mortality and cardiovascular events. This suggests a role for ARA therapy in those with ESRD undergoing dialysis.16
While there are no trials that investigated clinical outcomes in HFrEF patients with ESRD undergoing dialysis yet, two trials have investigated the effect of spironolactone on left ventricular ejection fraction (LVEF). In a small double-blind, placebo-controlled, randomized-controlled trial of patients undergoing hemodialysis with HFrEF (LVEF < 45%), those given spironolactone 25 mg three times weekly after dialysis for 6 months had a significant improvement in LVEF (mean absolute increase 6% vs. no change with placebo, p = 0.046).17 In another small, randomized, placebo-controlled study in 18 patients with HFrEF undergoing peritoneal dialysis, those who received spironolactone 25 mg every other day for 6 months had a significant improvement in LVEF compared to placebo (33.3 ± 7.8 vs. 25.7 ± 7.3, p = 0.002).18 There is an ongoing randomized clinical trail, the Aldosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST), of spironolactone in HFrEF patients undergoing hemodialysis that should provide more clarity regarding efficacy and safety.19
Safety of ARAs in Patients with HFrEF and ESRD Undergoing Dialysis
Exclusion of patients with an eGFR < 30 mL/min/1.73m2 from RALES and EMPHASIS trials limit the use of ARAs in patients with ESRD.11,13 One of the major concerns for using ARAs in patients with ESRD undergoing dialysis is the risk of hyperkalemia. The other major adverse effect associated with ARAs is worsening renal function; spironolactone is also associated with increased incidence of gynecomastia and menstrual irregularities. However, incidence of these risks are not higher in the ESRD population undergoing dialysis.20 Although serum potassium levels rise with ARA administration in patients undergoing dialysis, only rarely does therapy lead to clinically meaningful hyperkalemia requiring medication or dialysate adjustments.21 Hyperkalemia is actually less concering in ESRD patients who are anuric because serum potassium concentrations are regulated by dialysis treatments rather than by renal tubular function.22 Patients with HFrEF undergoing peritoneal dialysis have also been shown to tolerate spironolactone without significant hyperkalemia.22
Numerous studies in the general ESRD population undergoing dialysis have determined that spironolactone can be used safely without significant risk of hyperkalemia.20,21 Eplerenone has not yet been evaluated in HFrEF patient undergoing dialysis; however, there are no data to refute that these medications are comparable in terms of effect on potassium.20 One randomized, placebo-controlled trial investigated the safety of spironolactone in patients with HFrEF undergoing hemodialysis.17 Sixteen patients with HFrEF (LVEF < 45%) and on chronic hemodialysis were randomized to placebo or spironolactone 25 mg three times weekly. Those enrolled were receiving an ACE inhibitor or ARB and had a potassium < 5.5 mEq/L.. Baseline serum potassium concentrations in the placebo group were higher than the spironolactone group (4.66 vs. 3.86 mEq/L, p = 0.001). However, at six months, there was no difference in the serum potassium concentration between the two groups (4.74 mEq/L vs. 4.88 mEq/L; p not reported). One patient in the placebo group developed hyperkalemia (potassium > 5.5 mEq/L) and was treated successfully with sodium polystyrene sulfonate.
The safety of spironolactone has also been evaluated in 18 patients with HFrEF undergoing continuous ambulatory peritoneal dialysis.18 This study included 18 patients who were on treatment with ACE inhibitor or ARB and had serum potassium level ≤ 5.5 mEq/L at baseline. Rise in serum potassium levels was similar, at six months, in those who received spironolactone 25 mg every other day or placebo. Only one patient in the spironolactone group had a serum potassium level of 5.7 mEq/L at the end of the second month of study.
It is important to note that the majority of ESRD patients undergoing dialysis in these small studies were anuric, and therefore no longer had the renal ability to retain potassium. The risk of hyperkalemia would likely be increased in oliguric patients due to residual renal function allowing for potassium retention between hemodialysis sessions.21 In patients with residual renal function experiencing hyperkalemia on RAAS inhibitors, clinicians could consider the use of a cation exchange polymer (e.g., patiromer) to control serum potassium levels.23 In a small study of patients with CKD and HF who were hyperkalemic and on RAAS inhibitors, 4 weeks of patiromer led to a mean reduction of 1.06 ± 0.05 mEq/L in serum potassium levels and lower rates of recurrent hyperkalemia compared to placebo.23 However, the role of pharmacological control of potassium levels on HF and CKD outcomes remains unclear.
Given the increased risk of mortality and morbidity in patients with HFrEF and ESRD undergoing dialysis, there is a strong rationale for adding ARAs to maximize RAAS blockade in these patients. Extending the use of these medications to the dialysis population appears beneficial from small-scale studies. Of equal importance, these studies have provided reassuring data about safety of ARAs in dialysis patients, particularly those who are anuric. For ESRD patients with residual renal function, ARAs should be used cautiously with appropriate patient selection and attentive monitoring of potassium.
Sandeep Devabhakthuni, PharmD, BCCP
- Pippias M, Jager KJ, Kramer A, et al. The changing trends and outcomes in renal replacement therapy: data from the ERA-EDTA Registry. Neprhol Dial Transplant. 2016;31:831-41.
- National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Part 7 – stratification of risk for progression of kidney disease and development of cardiovascular disease. Am J Kidney Dis. 2002;39:S170-S212.
- Silverberg D, Wexler D, Blum B, et al. The association between congestive heart failure and chronic renal disease. Curr Opin Nephrol Hypertens. 2004;2:163-170.
- Damman K, Tang WH, Felker GM, et al. Current evidence on treatment of patients with chronic systolic heart failure and renal insufficiency: practical considerations from published data. J Am Coll Cardiol. 2014;63:853-71.
- Epstein M, Reaven NL, Funk SE, et al. Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors. Am J Manag Care. 2015;21:S212-S220.
- Rossignol P, Zannad F, Pitt B, et al. Time to retrieve the best benefits from renin angiotensin aldosterone system (RAAS) inhibition in heart failure patients with reduced ejection fraction: lessons from randomized controlled trials and registries. Int J Cardiol. 2014;177:731-33.
- Bomback AS, Rekhtman Y, Klemmer PJ, et al. Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy. J Am Soc Hypertens. 2012;6:338-45.
- Sato A, Hayashi K, Naruse M, Saruta T. Effectiveness of aldosterone blockade in patients with diabetic nephropathy. Hypertension. 2003;41:64-8.
- Horita Y, Taura K, Taguchi T, Furusu A, Kohno S. Aldosterone breakthrough during theirap with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy. Nephrology (Carlton). 2006;11:462-6.
- Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3:486-92.
- Pitt B, Zannad F, Remime 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;341:709-17.
- Berl T, Katz FH, Henrich WL, de Torrente A, Schrier RW. Role of aldosterone in the control of sodium excretion in patients with advanced chronic renal failure. Kidney Int. 1978;14:228-235.
- Pitt B, Remme W, Zannad P, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-21.
- Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis. 2008;51:199-211.
- Navaneethan SD, Nigwekar SU, Sehgal AR< Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2009;3:CD007004.
- Hung SC, Lin YP, Huang HL, Pu HF, Tarng DC. Aldosterone and mortality in hemodialysis patients: role of volume overload. PLoS One. 2013;8:e57511.
- Taheri S, Mortazavi M, Shahidi S, et al. Spironolactone in chronic hemodialysis patients improves cardiac function. Saudi J Kidney Dis Transpl. 2009;20:392-7.
- Taheri S, Mortazavi M, Pourmoghadas A, Seyrafian S, Alipour Z, Karimi S. A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis. Saudi J Kidney Dis Transpl. 2012;23:507-12.
- Aldosterone Antagonist Chronic HEModialysis Interventional Survival Trial (ALCHEMIST). 2016. Retrieved from http://clinicaltrials.gov/ct2 (NCT01848639).
- Yancy CW, Jessup M, Bozkurt B, et al. 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;62:e147-239.
- Chua D, Lo A, Lo C. Spironolactone use in heart failure patients with end-stage renal disease on hemodialysis: is it safe? Clin Cardiol. 2010;33:604-8.
- Hausmann MJ, Liel-Cohen N. Aldactone therapy in a peritoneal dialysis patient with decreased left ventricular function. Neprhol Dial Transplant. 2002;17:2035-36.
- Pitt B, Bakris GL, Bushinsky DA, et al. Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalemia in patients with heart failure and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail. 2015;17:1057-65.
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