The Gap to Fill: Rationale for Rapid Initiation and Optimal Titration of Comprehensive Disease-modifying Medical Therapy for Heart Failure with Reduced Ejection Fraction

Nicholas K Brownell, Boback Ziaeian, Gregg C Fonarow, Nicholas K Brownell, Boback Ziaeian, Gregg C Fonarow

Abstract

There are gaps in the use of therapies that save lives and improve quality of life for patients with heart failure with reduced ejection fraction, both in the US and abroad. The evidence is clear that initiation and titration of guideline-directed medical therapy (GDMT) and comprehensive disease-modifying medical therapy (CDMMT) to maximally tolerated doses improves patient-focused outcomes, yet observational data suggest this does not happen. The purpose of this review is to describe the gap in the use of optimal treatment worldwide and discuss the benefits of newer heart failure therapies including angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter 2 inhibitors. It will also cover the efficacy and safety of such treatments and provide potential pathways for the initiation and rapid titration of GDMT/CDMMT.

Keywords: Heart failure; comprehensive disease-modifying medical therapy; cost benefits; early treatment initiation; guideline-directed medical therapy; rates of use.

Conflict of interest statement

Disclosure: GCF reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck and Novartis. All other authors have no conflicts of interest to declare.

Copyright © 2021, Radcliffe Cardiology.

Figures

Figure 1:. Simultaneous/Rapid Sequence Initiation and Optimal…
Figure 1:. Simultaneous/Rapid Sequence Initiation and Optimal Titration of Comprehensive Disease-modifying Medical Therapy
Figure 2:. Reasons for Underuse of Comprehensive…
Figure 2:. Reasons for Underuse of Comprehensive Disease-modifying Medical Therapy and Potential Interventions for Improvement

References

    1. Virani SS, Alonso A, Benjamin EJ et al. Heart disease and stroke statistics — 2020 update: a report from the American Heart Association. Circulation. 2020;141:e139–596. doi: 10.1161/CIR.0000000000000757.
    1. Heidenreich PA, Albert NM, Allen LA et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606–19. doi: 10.1161/HHF.0b013e318291329a.
    1. Shah KS, Xu H, Matsouaka RA et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017;70:2476–86. doi: 10.1016/j.jacc.2017.08.074.
    1. Taylor CJ, Ord ez-Mena JM, Roalfe AK et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000 2017: population based cohort study. BMJ. 2019;364:l223. doi: 10.1136/bmj.l223.
    1. Greene SJ, Butler J, Fonarow GC. Simultaneous or rapid sequence initiation of quadruple medical therapy for heart failure – optimizing therapy with the need for speed. JAMA Cardiol. 2021;6:743–4. doi: 10.1001/jamacardio.2021.0496.
    1. DeVore AD, Thomas L, Albert NM et al. Change the management of patients with heart failure: rationale and design of the CHAMP-HF registry. Am Heart J. 2017;189:177–83. doi: 10.1016/j.ahj.2017.04.010.
    1. Greene SJ, Butler J, Albert NM et al. Medical therapy for heart failure with reduced ejection fraction. J Am Coll Cardiol. 2018;72:351–66. doi: 10.1016/j.jacc.2018.04.070.
    1. Maddox TM, Song Y, Allen J et al. Trends in US ambulatory cardiovascular care 2013 to 2017. J Am Coll Cardiol. 2020;75:93–112. doi: 10.1016/j.jacc.2019.11.011.
    1. Food & Drug Administration. FDA approves new treatment for a type of heart failure. 5 May 2020. (accessed 24 October 2021)
    1. Zelniker TA, Wiviott SD, Raz I et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31–9. doi: 10.1016/S0140-6736(18)32590-X.
    1. McMurray JJV, Solomon SD, Inzucchi SE et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303.
    1. Maddox TM, Januzzi JL, Allen LA et al. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction. J Am Coll Cardiol. 2021;77:772–810. doi: 10.1016/j.jacc.2020.11.022.
    1. McDonagh TA, Metra M, Adamo M et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726. doi: 10.1093/eurheartj/ehab368.
    1. Vaduganathan M, Fonarow GC, Greene SJ et al. Contemporary treatment patterns and clinical outcomes of comorbid diabetes mellitus and HFrEF. JACC Heart Fail. 2020;8:469–80. doi: 10.1016/j.jchf.2019.12.015.
    1. Packer M, Poole-Wilson PA, Armstrong PW et al. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation. 1999;100:2312–8. doi: 10.1161/01.CIR.100.23.2312.
    1. Konstam MA, Neaton JD, Dickstein K et al. 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;374:1840–8. doi: 10.1016/S0140-6736(09)61913-9.
    1. Bristow MR, Gilbert EM, Abraham WT et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation. 1996;94:2807–16. doi: 10.1161/01.CIR.94.11.2807.
    1. Fonarow GC, Albert NM, Curtis AB et al. Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the registry to improve the use of evidence-based heart failure therapies in the outpatient setting (IMPROVE HF). Circulation. 2010;122:585–96. doi: 10.1161/CIRCULATIONAHA.109.934471.
    1. Greene SJ, Fonarow GC, DeVore AD et al. Titration of medical therapy for heart failure with reduced ejection fraction. J Am Coll Cardiol. 2019;73:2365–83. doi: 10.1016/j.jacc.2019.02.015.
    1. Komajda M, Anker SD, Cowie MR et al. Physicians – adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey: adherence to heart failure guidelines. Eur J Heart Fail. 2016;18:514–22. doi: 10.1002/ejhf.510.
    1. Maggioni AP, Anker SD, Dahlstrm U et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long-term registry. Eur J Heart Fail. 2013;15:1173–84. doi: 10.1093/eurjhf/hft134.
    1. Ouwerkerk W, Voors AA, Anker SD et al. 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;38:1883–90. doi: 10.1093/eurheartj/ehx026.
    1. Savarese G, Bodegard J, Norhammar A et al. Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden). Eur J Heart Fail. 2021;23:1499–511. doi: 10.1002/ejhf.2271.
    1. Fonarow GC, Albert NM, Curtis AB et al. Incremental reduction in risk of death associated with use of guideline-recommended therapies in patients with heart failure: a nested case-control analysis of IMPROVE HF. J Am Heart Assoc. 2012;1:16–26. doi: 10.1161/JAHA.111.000018.
    1. Komajda M, Schpe J, Wagenpfeil S et al. Physicians guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry. Eur J Heart Fail. 2019;21:921–9. doi: 10.1002/ejhf.1459.
    1. Butler J, Yang M, Manzi MA et al. Clinical course of patients with worsening heart failure with reduced ejection fraction. J Am Coll Cardiol. 2019;73:935–44. doi: 10.1016/j.jacc.2018.11.049.
    1. Vaduganathan M, Claggett BL, Jhund PS et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020;396:121–8. doi: 10.1016/S0140-6736(20)30748-0.
    1. Fonarow GC, Yancy CW, Hernandez AF et al. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J. 2011;161:1024–30. e3. doi: 10.1016/j.ahj.2011.01.027.
    1. Fonarow GC, Hernandez AF, Solomon SD, Yancy CW. Potential mortality reduction with optimal implementation of angiotensin receptor neprilysin inhibitor therapy in heart failure. JAMA Cardiol. 2016;1:714–7. doi: 10.1001/jamacardio.2016.1724.
    1. Bassi NS, Ziaeian B, Yancy CW, Fonarow GC. Association of optimal implementation of sodium-glucose cotransporter 2 inhibitor therapy with outcome for patients with heart failure. JAMA Cardiol. 2020;5:948–51. doi: 10.1001/jamacardio.2020.0898.
    1. Fonarow GC, Albert NM, Curtis AB et al. Associations between outpatient heart failure process-of-care measures and mortality. Circulation. 2011;123:1601–10. doi: 10.1161/CIRCULATIONAHA.110.989632.
    1. McEwan P, Darlington O, McMurray JJV et al. Cost-effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health-economic analysis of DAPA-HF. Eur J Heart Fail. 2020;22:2147–56. doi: 10.1002/ejhf.1978.
    1. Gandjour A, Ostwald DA. Sacubitril/valsartan (LCZ696): a novel treatment for heart failure and its estimated cost effectiveness, budget impact, and disease burden reduction in Germany. Pharmacoeconomics. 2018;36:1285–96. doi: 10.1007/s40273-018-0688-4.
    1. McMurray JJV, Trueman D, Hancock E et al. Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction. Heart. 2018;104:1006–13. doi: 10.1136/heartjnl-2016-310661.
    1. Gaziano TA, Fonarow GC, Claggett B et al. Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol. 2016;1:666–72. doi: 10.1001/jamacardio.2016.1747.
    1. Anderson JL, Heidenreich PA, Barnett PG et al. ACC/AHA statement on cost/value methodology in clinical practice guidelines and performance measures: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures and Task Force on Practice Guidelines. Circulation. 2014;129:2329–45. doi: 10.1161/CIR.0000000000000042.
    1. Fonarow GC. Utilization of current GDMT: closing the gap. Presented at: ACC21 Scientific Sessions, online, 15 May 2021
    1. Banka G, Heidenreich PA, Fonarow GC. Incremental cost-effectiveness of guideline-directed medical therapies for heart failure. J Am Coll Cardiol. 2013;610:1440–6. doi: 10.1016/j.jacc.2012.12.022.
    1. Fonarow GC. GDMT implementation is challenging. Presented at: HFSA 2021 Annual Scientific Meeting, Denver, CO, US, 11 September 2021
    1. DeJong C, Kazi DS, Dudley RA et al. Assessment of national coverage and out-of-pocket costs for sacubitril/valsartan under Medicare part D. JAMA Cardiol. 2019;4:828–30. doi: 10.1001/jamacardio.2019.2223.
    1. Luo J, Feldman R, Rothenberger SD et al. Coverage, formulary restrictions, and out-of-pocket costs for sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists in the Medicare part D program. JAMA Netw Open. 2020;3:e2020969. doi: 10.1001/jamanetworkopen.2020.20969.
    1. Hauptman PJ, Goff ZD, Vidic A et al. Variability in retail pricing of generic drugs for heart failure. JAMA Intern Med. 2017;177:126–8. doi: 10.1001/jamainternmed.2016.6955.
    1. American Medical Association. Prior authorization and utilization management reform principles. 2017. (accessed 24 October 2021)
    1. Krum H, Roecker EB, Mohacsi P et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS study. JAMA. 2003;289:712–8. doi: 10.1001/jama.289.6.712.
    1. Gottlieb SS, Fisher ML, Kjekshus J et al. Tolerability of β-blocker initiation and titration in the metoprolol cr/xl randomized intervention trial in congestive heart failure (MERIT-HF). Circulation. 2002;105:1182–8. doi: 10.1161/hc1002.105180.
    1. Zannad F, McMurray JJV, Krum H et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21. doi: 10.1056/NEJMoa1009492.
    1. McMurray JJV, Packer M, Desai AS et al. Angiotensin neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. doi: 10.1056/NEJMoa1409077.
    1. Khariton Y, Fonarow GC, Arnold SV et al. Association between sacubitril/valsartan initiation and health status outcomes in heart failure with reduced ejection fraction. JACC Heart Fail. 2019;7:933–41. doi: 10.1016/j.jchf.2019.05.016.
    1. Packer M, Anker SD, Butler J et al. Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-reduced trial. Circulation. 2021;143:326–36. doi: 10.1161/CIRCULATIONAHA.120.051783.
    1. Packer M, Anker SD, Butler J et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–24. doi: 10.1056/NEJMoa2022190.
    1. Berg DD, Jhund PS, Docherty KF et al. Time to clinical benefit of dapagliflozin and significance of prior heart failure hospitalization in patients with heart failure with reduced ejection fraction. JAMA Cardiol. 2021;6:499–507. doi: 10.1001/jamacardio.2020.7585.
    1. Packer M, Coats AJS, Fowler MB et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–8. doi: 10.1056/NEJM200105313442201.
    1. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13. doi: 10.1016/S0140-6736(98)11181-9.
    1. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001–7. doi: 10.1016/S0140-6736(99)04440-2.
    1. Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349–55. doi: 10.1056/NEJM199605233342101.
    1. Gattis WA, O'Connor CM, Gallup DS et al. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure. J Am Coll Cardiol. 2004;43:1534–41. doi: 10.1016/j.jacc.2003.12.040.
    1. Sanam K, Bhatia V, Bajaj NS et al. Renin-angiotensin system inhibition and lower 30-day all-cause readmission in Medicare beneficiaries with heart failure. Am J Med. 2016;129:1067–73. doi: 10.1016/j.amjmed.2016.05.008.
    1. Ferreira JP, Santos M, Almeida S et al. Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failure. Eur J Int Med. 2014;25:67–72. doi: 10.1016/j.ejim.2013.08.711.
    1. Butler J, Anstrom KJ, Felker GM et al. Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial. JAMA Cardiol. 2017;2:950–8. doi: 10.1001/jamacardio.2017.2198.
    1. Fonarow GC, Abraham WT, Albert NM et al. Influence of beta-blocker continuation or withdrawal on outcomes in patients hospitalized with heart failure. J Am Coll Cardiol. 2008;52:190–9. doi: 10.1016/j.jacc.2008.03.048.
    1. Hernandez AF, Hammill BG, O'Connor CM et al. Clinical effectiveness of beta-blockers in heart failure. J Am Coll Cardiol. 2009;53:184–92. doi: 10.1016/j.jacc.2008.09.031.
    1. Gilstrap LG, Fonarow GC, Desai AS et al. Initiation, continuation, or withdrawal of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction. J Am Heart Assoc. 2017;6:e004675. doi: 10.1161/JAHA.116.004675.
    1. Lam PH, Dooley DJ, Inampudi C et al. Lack of evidence of lower 30-day all-cause readmission in Medicare beneficiaries with heart failure and reduced ejection fraction discharged on spironolactone. Int J Cardiol. 2017;227:462–6. doi: 10.1016/j.ijcard.2016.11.006.
    1. Hamaguchi S, Kinugawa S, Tsuchihashi-Makaya M et al. Spironolactone use at discharge was associated with improved survival in hospitalized patients with systolic heart failure. Am Heart J. 2010;160:1156–62. doi: 10.1016/j.ahj.2010.08.036.
    1. Hernandez AF, Mi X, Hammill BG et al. Associations between aldosterone antagonist therapy and risks of mortality and readmission among patients with heart failure and reduced ejection fraction. JAMA. 2012;308:2097. doi: 10.1001/jama.2012.14795.
    1. Krantz MJ, Ambardekar AV, Kaltenbach L et al. Patterns and predictors of evidence-based medication continuation among hospitalized heart failure patients (from Get With the Guidelines Heart Failure). Am J Cardiol. 2011;107:1818–23. doi: 10.1016/j.amjcard.2011.02.322.
    1. Velazquez EJ, Morrow DA, DeVore AD et al. Angiotensin neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380:539–48. doi: 10.1056/NEJMoa1812851.
    1. Morrow DA, Velazquez EJ, DeVore AD et al. Clinical outcomes in patients with acute decompensated heart failure randomly assigned to sacubitril/valsartan or enalapril in the PIONEER-HF trial. Circulation. 2019;139:2285–8. doi: 10.1161/CIRCULATIONAHA.118.039331.
    1. Wachter R, Senni M, Belohlavek J et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail. 2019;21:998–1007. doi: 10.1002/ejhf.1498.
    1. Bhatt DL, Szarek M, Steg PG et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384:117–28. doi: 10.1056/NEJMoa2030183.
    1. Tromp J, Ponikowski P, Salsali A et al. Sodiumglucose co-transporter 2 inhibition in patients hospitalized for acute decompensated heart failure: rationale for and design of the EMPULSE trial. Eur J Heart Fail. 2021;23:826–34. doi: 10.1002/ejhf.2137.
    1. Bhagat AA, Greene SJ, Vaduganathan M et al. Initiation, continuation, switching, and withdrawal of heart failure medical therapies during hospitalization. JACC Heart Fail. 2019;7:1–12. doi: 10.1016/j.jchf.2018.06.011.
    1. Desai AS, Vardeny O, Claggett B et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. 2017;2:79. doi: 10.1001/jamacardio.2016.4733.
    1. Allen LA, Venechuk G, McIlvennan CK et al. An electronically delivered patient-activation tool for intensification of medications for chronic heart failure with reduced ejection fraction: the EPIC-HF trial. Circulation. 2021;143:427–37. doi: 10.1161/CIRCULATIONAHA.120.051863.
    1. Balakumaran K, Patil A, Marsh S et al. Evaluation of a guideline directed medical therapy titration program in patients with heart failure with reduced ejection fraction. Int J Cardiol Heart Vasc. 2019;22:1–5. doi: 10.1016/j.ijcha.2018.10.003.
    1. Thibodeau JT, Gorodeski EZ. Telehealth for uptitration of guideline-directed medical therapy in heart failure. Circulation. 2020;142:1507–9. doi: 10.1161/CIRCULATIONAHA.120.050582.
    1. Kao DP, Trinkley KE, Lin C-T. Heart failure management innovation enabled by electronic health records. JACC Heart Fail. 2020;8:223–33. doi: 10.1016/j.jchf.2019.09.008.
    1. Koehler F, Koehler K, Deckwart O et al. Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): a randomised, controlled, parallel-group, unmasked trial. Lancet. 2018;392:1047–57. doi: 10.1016/S0140-6736(18)31880-4.
    1. Schulz M, Griese-Mammen N, Anker SD et al. Pharmacy-based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM-CHF randomized controlled trial. Eur J Heart Fail. 2019;21:1012–21. doi: 10.1002/ejhf.1503.

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