Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease

Bertram Pitt, David A Bushinsky, Dalane W Kitzman, Frank Ruschitzka, Marco Metra, Gerasimos Filippatos, Patrick Rossignol, Charles Du Mond, Dahlia Garza, Lance Berman, Mitja Lainscak, Patiromer-204 Investigators, Bertram Pitt, David A Bushinsky, Dalane W Kitzman, Frank Ruschitzka, Marco Metra, Gerasimos Filippatos, Patrick Rossignol, Charles Du Mond, Dahlia Garza, Lance Berman, Mitja Lainscak, Patiromer-204 Investigators

Abstract

Aims: Hyperkalaemia risk precludes optimal renin-angiotensin-aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium-free, non-absorbed potassium (K+ )-binding polymer approved for the treatment of hyperkalaemia. In PEARL-HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone.

Methods and results: This open-label 8-week study enrolled 63 patients with CKD, serum K+ 4.3-5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0-5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48-4.70 mEq/L during treatment. Serum K+ of 3.5-5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0-5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients].

Conclusions: In this open-label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well tolerated, with a low incidence of hyperkalaemia, hypokalaemia, and hypomagnesaemia.

Trial registration: ClinicalTrials.gov NCT01130597.

Keywords: Chronic kidney disease; Heart failure; Mineralocorticoid receptor antagonist; Patiromer; Potassium-binding polymer.

© 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Proportion of patients with serum K+ in the range of 3.5–5.5 mEq/L and 4.0–5.1 mEq/L by study visit. ET, end of treatment; K+, potassium.
Figure 2
Figure 2
Serum K+ before and after an uptitration or downtitration. *Total number of titrations during the study. K+, potassium; SD, standard deviation.

References

    1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. 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: 709–717.
    1. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleinman J, Gatlin M, 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.
    1. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, EMPHASIS‐HF Study Group . Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364: 11–21.
    1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2017; 70: 776–803.
    1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PE, Stevenson LW, Westlake C. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol 2016; 27: 1476–1488.
    1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez‐Juanaty JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GP, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force Members; Document Reviewers . ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016; 18: 891–975.
    1. Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, Weir MR, Fink JC. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009; 169: 1156–1162.
    1. Jain N, Kotla S, Little BB, Weideman RA, Brilakis ES, Reilly RF, Banerjee S. Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol 2012; 109: 1510–1513.
    1. Lainscak M, Cleland JG, Lenzen MJ, Follath F, Komajda M, Swedberg K. International variations in the treatment and co‐morbidity of left ventricular systolic dysfunction: data from the EuroHeart Failure Survey. Eur J Heart Fail 2007; 9: 292–299.
    1. Veltassa (patiromer) for oral suspension [package insert]. Relypsa, Inc. ; 2016.
    1. Li L, Harrison SD, Cope MJ, Park C, Lee L, Salaymeh F, Madsen D, Benton WW, Berman L, Buysse J. Mechanism of action and pharmacology of patiromer, a nonabsorbed cross‐linked polymer that lowers serum potassium concentration in patients with hyperkalemia. J Cardiovasc Pharmacol Ther 2016; 21: 456–165.
    1. European Medicines Agency . Veltassa. (9 January 2018).
    1. Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, Stasiv Y, Zawadski R, Beerman L, Bushinsky DA, AMETHYST‐DA Investigators . Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST‐DN randomized clinical trial. JAMA 2015; 314: 151–161.
    1. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ‐Schmidt H, Berman L, Pitt B, OPAL‐HK Investigators . Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 2015; 372: 211–221.
    1. Pitt B, Bakris GL, Bushinsky DA, Garza D, Mayo MR, Stasiv Y, Christ‐Shmidt H, Berman L, Weir MR. Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail 2015; 17: 1057–1065.
    1. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ, PEARL‐HF Investigators . Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double‐blind, placebo‐controlled study in patients with chronic heart failure (the PEARL‐HF) trial. Eur Heart J 2011; 32: 820–828.
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–470.
    1. Bushinsky DA, Spiegel DM, Gross C, Benton WW, Fogli J, Hill Gallant KM, Du Mond C, Block GA, Weir MR, Pitt B. Effect of patiromer on urinary ion excretion in healthy adults. Clin J Am Soc Nephrol 2016; 11: 1769–1776.
    1. Epstein M, Pitt B. Recent advances in pharmacological treatments of hyperkalemia: focus on patiromer. Expert Opin Pharmacother 2016; 17: 1435–1448.
    1. Weir MR, Bakris GL, Gross C, Mayo MR, Garza D, Stasiv Y, Yuan J, Berman L, Williams GH. Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin–angiotensin system inhibitors. Kidney Int 2016; 90: 696–704.
    1. Weir MR, Mayo MR, Garza D, Arthur SA, Berman L, Bushinsky D, Wilson DJ, Epstein M. Effectiveness of patiromer in the treatment of hyperkalemia in chronic kidney disease patients with hypertension on diuretics. J Hypertens 2017; 35: S57–S63.
    1. Zannad F, Alla F, Dousset B, Perez A, Pitt B, RALES Investigators . Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Circulation 2000; 102: 2700–2706.
    1. RALES Investigators . Effectiveness of spironolactone added to an angiotensin‐converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996; 78: 902–907.
    1. Hensen J, Abraham WT, Durr JA, Schrier RW. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991; 11: 441–446.
    1. Perazella MA. Drug‐induced hyperkalemia: old culprits and new offenders. Am J Med 2000; 109: 307–314.
    1. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin–angiotensin–aldosterone system. N Engl J Med 2004; 351: 585–592.
    1. Maggioni AP, Anker SD, Dahlstrom U, Filippatos G, Ponikowski P, Zannad F, Amir O, Chioncel O, Leiro MC, Drozdz J, Erglis A, Fazlibegovic E, Fonseca C, Fruhwald F, Gatzov P, Goncalvesova E, Hassanein M, Hradec J, Kavoliunine A, Lainscak M, Logeart D, Merkley B, Metra M, Persson H, Seferovic P, Temizhan A, Tousoulis D, Tavazzi L, Heart Failure Association of the ESC . Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12440 patients of the ESC Heart Failure Long‐Term Registry. Eur J Heart Failure 2013; 15: 1173–1184.
    1. Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P, Hillege HL, Lang CC, Ter Maaten JM, Ng LL, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zannad F, Metra M, Zinderman AH. Determinants and clinical outcome of uptitration of ACE‐inhibitors and beta‐blockers in patients with heart failure: a prospective European study. Eur Heart J 2017; 38: 1883–1890.
    1. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Causell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM, TOPCAT Investigators . Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014; 370: 1383–1392.
    1. Pitt B, Gheorghiade M. Geographic variation in heart failure trials: time for skepticism? Eur J Heart Fail 2014; 16: 601–602.
    1. Pfeffer MA, Claggett B, Assmann S, Boineua R, Anand IS, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Heitner JF, Lewis EF, O'Meara E, Rouleau JL, Probstfield JL, Shaburishvili T, Sha SJ, Solomon SD, Sweitzer NK, McKinlay SM, Pitt B. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation 2015; 131: 34–42.

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