Response to Sexton: Inhibiting the Renin–Angiotensin–Aldosterone System in Patients With Heart Failure and Renal Dysfunction
2014; Lippincott Williams & Wilkins; Volume: 7; Issue: 3 Linguagem: Inglês
10.1161/circheartfailure.113.000981
ISSN1941-3297
AutoresJaved Butler, Michael M. Givertz,
Tópico(s)Potassium and Related Disorders
ResumoHomeCirculation: Heart FailureVol. 7, No. 3Response to Sexton: Inhibiting the Renin–Angiotensin–Aldosterone System in Patients With Heart Failure and Renal Dysfunction Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBResponse to Sexton: Inhibiting the Renin–Angiotensin–Aldosterone System in Patients With Heart Failure and Renal DysfunctionCommon Sense or Nonsense? Javed Butler, MD, MPH and Michael M. Givertz, MD Javed ButlerJaved Butler From the Cardiology Division, Emory University, Atlanta, GA (J.B.); and Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.M.G.). and Michael M. GivertzMichael M. Givertz From the Cardiology Division, Emory University, Atlanta, GA (J.B.); and Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.M.G.). Originally published1 May 2014https://doi.org/10.1161/CIRCHEARTFAILURE.113.000981Circulation: Heart Failure. 2014;7:537–540IntroductionCommon sense is genius dressed in its working clothes. Ralph Waldo Emerson, American essayist (1803–1882)Modulation of the renin–angiotensin–aldosterone system (RAAS) has revolutionized the management of patients with heart failure and reduced ejection fraction (HFrEF) (Figure).1 Before clinical trials with angiotensin-converting enzyme (ACE) inhibitors, there were no therapies proven to improve survival in patients with HFrEF, barring cardiac transplantation in a small, select group of patients with advanced HF. Subsequent studies with both ACE inhibitors and angiotensin receptor blockers (ARB), as well as β-blockers and mineralocorticoid receptor antagonists (MRA), have shown significant reduction in morbidity and mortality in patients with HFrEF across the spectrum of pathogenesis (ischemic and nonischemic) and functional class.Download figureDownload PowerPointFigure. Pathophysiology of the renin–angiotensin–aldosterone system and therapeutic targets in heart failure. Modified from Ref. 1. AT1 indicates angiotensin type 1; ACE, angiotensin-converting enzyme; EDHF, endothelium-derived hyperpolarizing factor; and SNS, sympathetic nervous system. Asterisk indicates investigational.Despite impressive benefits across multiple trials, the use of RAAS antagonists in clinical practice poses multiple challenges, as eloquently stated in this issue's Challenges for the Basis of Practice by Sexton.2 In particular, most pivotal studies did not include patients with moderate or severe chronic kidney disease (CKD), who now may comprise ≤50% of patients with ambulatory HF and two thirds of patients hospitalized with acute HF. Similarly, although evidence supports the use of ACE inhibitors or ARBs to slow progression of renal dysfunction in patients with diabetes mellitus and CKD, these studies excluded patients with HF in general. The interactive effect of RAAS antagonists on populations of patients with HF and CKD may be elucidated, in part, from post hoc analyses of pivotal studies (Table3–9), but ultimately individual patient decisions must be made by clinicians. Furthermore, these decisions are often made against a demographic backdrop of older age and greater comorbidities than observed in patients who participated in clinical trials, as well as uncertain patient adherence to pharmacological and nonpharmacological strategies. The challenge, as proposed by Stevenson,10 is "to make a good decision with flawed data, which includes unbiased trials with limited relevance and relevant experience with unlimited bias." Sexton2 raises 4 specific questions to be addressed in patients with HFrEF with renal dysfunction.Table. Interactive Effects of Neurohormonal Antagonists on Heart Failure and Renal DysfunctionStudyDrugEffect on Heart FailureEffect on Renal FunctionCIBIS3BisoprololPositiveCKD≈non-CKDUnknownMERIT-HF4Metoprolol succinatePositiveCKD>non-CKDUnknownSAVE5CaptoprilPositiveCKD>non-CKDUnknownSOLVD6EnalaprilPositiveCKD≈non-CKDNegativeRR of WRF 1.33*Val-HeFT7ValsartanPositiveCKD>non-CKDNegativemean eGFR ↓ 3.8RALES8SpironolactonePositiveCKD≈non-CKDUnknownEPHESUS9EplerenonePositiveNon-CKD>CKDUnknownCIBS indicates Cardiac Insufficiency Bisoprolol Study; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; EPHESUS, Eplerenone Post-AMI Heart Failure Efficacy and Survival; MERIT-HF, Metoprolol CR/XL Randomized Intervention Trial in Chronic HF; RALES, Randomized Aldactone Evaluation Study; RR, relative risk; SAVE, Survival And Ventricular Enlargement; Val-HeFT, Valsartan Heart Failure Trial; and WRF, worsening renal function.Is There Benefit to Improve Outcomes When RAAS Antagonists Are Used in Patients With Moderate to Severe Renal Dysfunction and Heart Failure With Low Ejection Fraction?There are only sparse data in general and no randomized controlled trial data to guide clinicians in this scenario. Furthermore, there is not a uniform definition of moderate to severe renal dysfunction in the setting of HF. Indeed, the term cardiorenal syndrome has been defined in both clinical and pathophysiological terms, and formal staging systems have been proposed. There are credible data, however, that show substantial benefit with RAAS antagonists in patients with HFrEF and with CKD, separately. Because the combination of these diseases puts patients at particularly high risk, especially after a HF admission, it is reasonable to assume that the use of RAAS antagonists will be beneficial in this cohort. Observational data and subgroup analyses (Table) support this assertion, but many questions remain, including:Because moderate to severe renal dysfunction still encompasses a relatively large population, is there a threshold that alters the balance between benefit and risk?Does it matter if the renal dysfunction is primary or secondary, reversible or irreversible?Are there subgroups within this population that are affected differently by the use of RAAS antagonists, such as those with diabetes mellitus or uncontrolled hypertension?When there is limited blood pressure to work with, should treatment with RAAS antagonists or β-blockers take precedence?In general, patients with HFrEF with moderate to severe renal dysfunction should be given a trial of ACE inhibitor or ARB therapy. Currently, MRAs are contraindicated in patients with an estimated glomerular filtration rate (GFR) 3.0 mg/dL (or GFR 2.5 to 3.0 mg/dL, especially among patients with systolic blood pressures 2.0 mg/dL and systolic blood pressure <110 mm Hg) warrant withdrawal of ACE inhibitor or ARB therapy deserves further study. Unless an MRA is needed for potassium retaining effects in patients undergoing aggressive intravenous diuresis, we recommend holding these agents as well along with the ACE inhibitor or ARB.As is evident, these recommendations are largely based on common sense, logic, and current medical practice. In Complications: A Surgeon's Notes on an Imperfect Science,19 Atul Gawande writes, "There is science in what we do, yes, but also habit, intuition, and sometimes plain old guessing." These tendencies are understandable, but fraught with miscalculations and highlight the gap between science and practice. There are numerous examples in clinical medicine where common sense was proven to be wrong, underscoring the importance of asking scientific questions and critically analyzing the data. Collecting data on how to best treat patients with HFrEF and renal dysfunction and what benefits (versus risks) to expect is imperative because this patient population continues to grow and is a major burden on the healthcare economy. Moreover, the advent of novel RAAS antagonists (eg, selective nonsteroidal aldosterone blockers), better tolerated potassium binding polymers, and improved understanding of cardiorenal physiology may all affect successful treatment of this challenging patient population.DisclosuresDr Butler reports research funding from the National Institutes of Health, European Union, Health Resource Services Administration, Food and Drug Administration and consulting relationship with Amgen, Bayer, BG Medicine, Cardiocell, Celladon, Covis, Gambro, GE Healthcare, Janssen, Medtronic, Novartis, Ono Pharmaceutical, Relypsa, Trevena, and Takeda. Dr Givertz reports research funding from the National Institutes of Health.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Javed Butler, MD, MPH, Emory Clinical Cardiovascular Research Institute, 1462 Clifton Rd NE, Suite AT 504, Atlanta, GA 30322. E-mail [email protected]; or Michael M. Givertz, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail [email protected]References1. Givertz MM. Manipulation of the renin-angiotensin system.Circulation. 2001; 104:E14–E18.LinkGoogle Scholar2. Sexton DJ. How should we modify recommended renin–angiotensin–aldosterone system inhibition when facing the cardiorenal syndrome?Circ Heart Fail. 2014; 7:536.LinkGoogle Scholar3. Castagno D, Jhund PS, McMurray JJ, Lewsey JD, Erdmann E, Zannad F, Remme WJ, Lopez-Sendon JL, Lechat P, Follath F, Höglund C, Mareev V, Sadowski Z, Seabra-Gomes RJ, Dargie HJ. Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial.Eur J Heart Fail. 2010; 12:607–616.CrossrefMedlineGoogle Scholar4. Ghali JK, Wikstrand J, Van Veldhuisen DJ, Fagerberg B, Goldstein S, Hjalmarson A, Johansson P, Kjekshus J, Ohlsson L, Samuelsson O, Waagstein F, Wedel H; MERIT-HF Study Group. The influence of renal function on clinical outcome and response to beta-blockade in systolic heart failure: insights from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF).J Card Fail. 2009; 15:310–318.CrossrefMedlineGoogle Scholar5. Tokmakova MP, Skali H, Kenchaiah S, Braunwald E, Rouleau JL, Packer M, Chertow GM, Moyé LA, Pfeffer MA, Solomon SD. Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarction: the Survival And Ventricular Enlargement (SAVE) study.Circulation. 2004; 110:3667–3673.LinkGoogle Scholar6. Bowling CB, Sanders PW, Allman RM, Rogers WJ, Patel K, Aban IB, Rich MW, Pitt B, White M, Bakris GC, Fonarow GC, Ahmed A. Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: insights from the SOLVD Treatment trial.Int J Cardiol. 2013; 167:151–156.CrossrefMedlineGoogle Scholar7. Anand IS, Bishu K, Rector TS, Ishani A, Kuskowski MA, Cohn JN. Proteinuria, chronic kidney disease, and the effect of an angiotensin receptor blocker in addition to an angiotensin-converting enzyme inhibitor in patients with moderate to severe heart failure.Circulation. 2009; 120:1577–1584.LinkGoogle Scholar8. 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.CrossrefMedlineGoogle Scholar9. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman 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.CrossrefMedlineGoogle Scholar10. Stevenson LW. Challenges for the basis of practice in heart failure.Circ Heart Fail. 2008; 1:81–83.LinkGoogle Scholar11. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 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.Circulation. 2013; 128:e240–e319.LinkGoogle Scholar12. Shah SJ, Heitner JF, Sweitzer NK, Anand IS, Kim HY, Harty B, Boineau R, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Lewis EF, Markov V, O'Meara E, Kobulia B, Shaburishvili T, Solomon SD, Pitt B, Pfeffer MA, Li R. Baseline characteristics of patients in the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial.Circ Heart Fail. 2013; 6:184–192.LinkGoogle Scholar13. Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Rydén L, Thygesen K, Uretsky BF. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.Circulation. 1999; 100:2312–2318.LinkGoogle Scholar14. Konstam MA, Neaton JD, Dickstein K, Drexler H, Komajda M, Martinez FA, Riegger GA, Malbecq W, Smith RD, Guptha S, Poole-Wilson PA; HEAAL Investigators. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.Lancet. 2009; 374:1840–1848.CrossrefMedlineGoogle Scholar15. Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators.Circulation. 1996; 94:2807–2816.LinkGoogle Scholar16. Butler J, Ezekowitz JA, Collins SP, Givertz MM, Teerlink JR, Walsh MN, Albert NM, Westlake Canary CA, Carson PE, Colvin-Adams M, Fang JC, Hernandez AF, Hershberger RE, Katz SD, Rogers JG, Spertus JA, Stevenson WG, Sweitzer NK, Tang WH, Stough WG, Starling RC. Update on aldosterone antagonists use in heart failure with reduced left ventricular ejection fraction. Heart Failure Society of America Guidelines Committee.J Card Fail. 2012; 18:265–281.CrossrefMedlineGoogle Scholar17. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.N Engl J Med. 1991; 325:303–310.CrossrefMedlineGoogle Scholar18. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).N Engl J Med. 1987; 316:1429–1435.CrossrefMedlineGoogle Scholar19. Gawande A. Complications: A Surgeon's Notes on an Imperfect Science. New York, NY: Henry Holt and Company; 2002.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Younis A, Goldenberg I, Goldkorn R, Younis A, Peled Y, Tzur B and Klempfner R (2017) Elevated Admission Potassium Levels and 1-Year and 10-Year Mortality Among Patients With Heart Failure, The American Journal of the Medical Sciences, 10.1016/j.amjms.2017.07.006, 354:3, (268-277), Online publication date: 1-Sep-2017. Sarwar C, Bhagat A, Anker S and Butler J (2017) Role of Hyperkalemia in Heart Failure and the Therapeutic Use of Potassium Binders Heart Failure, 10.1007/164_2017_25, (537-560), . Sarwar C, Papadimitriou L, Pitt B, Piña I, Zannad F, Anker S, Gheorghiade M and Butler J (2016) Hyperkalemia in Heart Failure, Journal of the American College of Cardiology, 10.1016/j.jacc.2016.06.060, 68:14, (1575-1589), Online publication date: 1-Oct-2016. May 2014Vol 7, Issue 3 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.113.000981PMID: 24847130 Manuscript receivedDecember 6, 2013Manuscript acceptedFebruary 3, 2014Originally publishedMay 1, 2014 Keywordsangiotensin-converting enzyme inhibitorsheart failurerenin–angiotensin systemmineralocorticoid receptor antagonistsangiotensin receptor antagonistshypotensionrenal insufficiencyPDF download Advertisement SubjectsCardiorenal SyndromeHeart FailurePharmacology
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