4. Referral for ICD and CRT
When to refer for ICD/CRT in the current era of medical therapy for HFrEF
The decision regarding when and if an ICD should be implanted must include evaluation of the short- and long term risks of sudden death due to a ventricular arrhythmia and death from nonarrhythmic causes. This is often a complex assessment and must integrate many factors including the presence of ischemic heart disease, burden of scar, frailty, advancing dementia, comorbidities, and adequacy of background medical therapy. In addition to ICD considerations, CRT further improves mortality and reduces HHF in patients with HFrEF and dyssynchrony, particularly those with QRS 150 ms.
Most trials that have shown a mortality reduction for primary prevention ICD implantation or CRT were conducted in an era when conventional HFrEF therapy included β-blockers, RASi with ACEIs and ARBs, and MRAs. In the past decade, HFrEF therapies such as sacubitril-valsartan, ivabradine, SGLT2 inhibitor,, and vericiguat have also shown a reduction in CV death and worsening HF events in patients with HFrEF. In part, this might be because of the beneficial effects of these agents on ventricular function. For example, in the echocardiography substudy of the SHIFT trial (discussed previously), among the 411 patients who had paired baseline and 8-month follow-up echocardiography data, there was an increase in LVEF of 2.4% (SD, 7.7) in ivabradine-treated patients compared with a decrease of 0.1% (SD, 8.0%) in the placebo group (P < 0.001). Similarly, patients with NYHA II-IV symptoms and LVEF < 40% who were switched from an ACEI/ARB to an ARNI in the open-label, single-arm Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) study, there was an increase in LVEF by 4.9% (range, 4.5%-5.3%) at 6 months and 8.8% (range, 8.3%-9.3%) at 12 months. In a meta-analysis of 9 studies including 707 patients with HFrEF, the LVEF increased by 4.9% (range, 4.13%-5.65%) after patients were switched to treatment with an ARNI. Because of the demonstrated benefits of current HFrEF therapies to improve LVEF over time, it seems prudent to ensure that GDMT has been optimized before implanting primary prevention ICDs and CRT. However, it must be emphasized that there are no randomized controlled trial data on the risk/benefit of ICD implantation and CRT before vs after the initiation of newer HFrEF therapies. Every attempt should be made to initiate and titrate GDMT as quickly as feasible to avoid delays in referring suitable patients with persistently reduced LVEF for device therapy.
21. We recommend that after a diagnosis of HFrEF, standard medical therapy should be initiated and titrated to target or maximally tolerated doses with a repeat assessment of LVEF before referral for ICD or CRT (Strong Recommendation; Moderate-Quality Evidence).
Reassessment of ejection fraction should be performed 3 months after the achievement of target or maximally tolerated doses of GDMT.
An assessment of arrhythmic and non-arrhythmic sudden cardiac death (SCD) risk should be performed to estimate the risk/benefit of ICD implantation or CRT.
Specific HF therapies might contribute to improvements in LVEF and should be considered before referral for ICD implantation or CRT:
- For eligible patients, switching to ARNI therapy should be considered before referral for ICD or CRT.
- Additional use of ivabradine, where otherwise indicated after β-blocker optimization, should be considered before referral for ICD implantation or CRT.
Referral for ICD implantation or CRT should not be unduly delayed if timely titration of pharmacologic therapies is infeasible or impractical.
1. Ezekowitz JA, O’Meara E, McDonald MA, et al. 2017 Comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure. Can J Cardiol 2017;33:1342-433.
2. O’Meara E, McDonald M, Chan M, et al. CCS/CHFS heart failure guidelines: clinical trial update on functional mitral regurgitation, SGLT2 inhibitors, ARNI in HFpEF, and tafamidis in amyloidosis. Can J Cardiol 2020;36:159-69.
3. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-6.
4. 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.
5. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
6. 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.
7. Pascual-Figal D, Wachter R, Senni M, et al. NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction: TRANSITION study. JACC Heart Fail 2020;8:822-33.
8. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med 2019;380:539-48.
9. DeVore AD, Braunwald E, Morrow DA, et al. Initiation of angiotensin-neprilysin inhibition after acute decompensated heart failure: secondary analysis of the open-label extension of the PIONEER-HF trial. JAMA Cardiol 2020;5:202-7.
10. Berg DD, Braunwald E, DeVore AD, et al. Efficacy and safety of sacubitril/valsartan by dose level achieved in the PIONEER-HF trial. JACC Heart Fail 2020;8:834-43.
11. Grant ADM, Chew DS, Howlett JG, Miller RJH. Cost-effectivness of earlier transition to angiotensin receptor neprilysin inhibitor in patients with heart failure and reduced ejection fraction. CJC Open 2020;2: 447-53.
12. McKelvie RS, Moe GW, Ezekowitz JA, et al. The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure. Can J Cardiol 2013;29:168-81.
13. 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.
14. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557-73.
15. Greene SJ, Fonarow GC, Vaduganathan M, et al. The vulnerable phase after hospitalization for heart failure. Nat Rev Cardiol 2015;12:220-9.
16. Vaduganathan M, Butler J, Pitt B, Gheorghiade M. Contemporary drug development in heart failure: call for hemodynamically neutral therapies. Circ Heart Fail 2015;8:826-31.
17. Kane JA, Kim JK, Haidry SA, Salciccioli L, Lazar J. Discontinuation/dose reduction of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers during acute decompensated heart failure in African-American patients with reduced left-ventricular ejection fraction. Cardiology 2017;137:121-5.
18. 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.
19. Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.
20. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) study investigators. Lancet 1993;342:821-8.
21. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:1670-6.
22. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998;97:2202-12.
23. Dickstein K, Kjekshus J; OPTIMAAL Trial Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360:752-60.
24. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55.
25. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.
26. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000;283:1295-302.
27. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13.
28. Brophy JM, Joseph L, Rouleau JL. Beta-blockers in congestive heart failure. A Bayesian meta-analysis. Ann Intern Med 2001;134:550-60.
29. Gattis WA, O’Connor CM, Gallup DS, et al. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004;43:1534-41.
30. Bohm M, Link A, Cai D, et al. Beneficial association of beta-blocker therapy on recovery from severe acute heart failure treatment: data from the Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support trial. Crit Care Med 2011;39:940-4.
31. Jondeau G, Neuder Y, Eicher JC, et al. B-CONVINCED: Beta-blocker CONtinuation Vs. INterruption in patients with Congestive heart failure hospitalizED for a decompensation episode. Eur Heart J 2009;30:2186-92.
32. Fonarow GC, Abraham WT, Albert NM, et al. Influence of beta-blocker continuation or withdrawal on outcomes in patients hospitalized with heart failure: findings from the OPTIMIZE-HF program. J Am Coll Cardiol 2008;52:190-9.
33. Butler J, Young JB, Abraham WT, et al. Beta-blocker use and outcomes among hospitalized heart failure patients. J Am Coll Cardiol 2006;47:2462-9.
34. Gattis WA, O’Connor CM, Leimberger JD, et al. Clinical outcomes in patients on beta-blocker therapy admitted with worsening chronic heart failure. Am J Cardiol 2003;91:169-74.
35. Prins KW, Neill JM, Tyler JO, Eckman PM, Duval S. Effects of beta-blocker withdrawal in acute decompensated heart failure: a systematic review and meta-analysis. JACC Heart Fail 2015;3:647-53.
36. Greene SJ, Butler J, Albert NM, et al. Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry. J Am Coll Cardiol 2018;72:351-66.
37. 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;341:709-17.
38. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.
39. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.
40. 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.
41. 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;413:326-36.
42. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014;370:1383-92.
43. Solomon SD, Claggett B, Lewis EF, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J 2016;37:455-62.
44. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inibitors in patients with heart failure and reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819-29.
45. Martinez FA, Serenelli M, Nicolau JC, et al. Efficacy and saftey of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation 2020;141:100-11.
46. Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation 2020;142:1040-54.
47. Kosiborod MN, Jhund PS, Docherty KF, et al. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results fro the DAPA-HF trial. Circulation 2020;141:90-9.
48. Serenelli M, Bohm M, Inzucchi SE, et al. Effect of dapagliflozin according to baseline systolic blood pressure in the dapagliflozin and prevention of adverse outcomes in heart failure trial (DAPA-HF). Eur Heart J 2020;41:3402-18.
49. Jhund PS, Solomon SD, Docherty KF, et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure and reduced ejection fraction: results of DAPA-HF. Circulation 2021;143:298-309.
50. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.
51. Canadian Heart Failure Society: Practical approach to SGLT2 inhibitors for treatment of cardiovascular disease. Available at: https://heartfailure.ca/sites/default/files/chfs_practical_approach_algorithm_sglt2i_0.pdf. Accessed February 9, 2021.
52. Diaz A, Bourassa MG, Guertin MC, Tardif JC. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005;26:967-74.
53. Fox K, Ford I, Steg PG, et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372:817-21.
54. Docherty KF, Shen L, Castagno D, et al. Relationship between heart rate and outcomes in patients in sinus rhythm or atrial fibrillation with heart failure and reduced ejection fraction. Eur J Heart Fail 2020;22:528-38.
55. Laskey WK, Alomari I, Cox M, et al. Heart rate at hospital discharge in patients with heart failure is associated with mortality and rehospitalization. J Am Heart Assoc 2015;4:e001626.
56. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009;150:784-94.
57. Komajda M, Hanon O, Hochadel M, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J 2009;30:478-86.
58. Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008;101:865-9.
59. DiFrancesco D, Borer JS. The funny current: cellular basis for the control of heart rate. Drugs 2007;67(suppl 2):15-24.
60. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-85.
61. Bouabdallaoui N, O’Meara E, Bernier V, et al. Beneficial effects of ivabradine in patients with heart failure, low ejection fraction, and heart rate above 77 b. m. ESC Heart Fail 2019;6:1199-207.
62. Bohm M, Borer J, Ford I, et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol 2013;102:11-22.
63. 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. MOCHA Investigators. Circulation 1996;94:2807-16.
64. Metra M, Torp-Pedersen C, Swedberg K, et al. Influence of heart rate, blood pressure, and beta-blocker dose on outcome and the differences in outcome between carvedilol and metoprolol tartrate in patients with chronic heart failure: results from the COMET trial. Eur Heart J 2005;26:2259-68.
65. Das D, Savarese G, Dahlstrom U, et al. Ivabradine in heart failure: the representativeness of SHIFT (Systolic Heart Failure Treatment With the IF Inhibitor Ivabradine Trial) in a broad population of patients with chronic heart failure. Circ Heart Fail 2017;10:e004112.
66. Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): a randomised study. Int J Cardiol 2016;217:7-11.
67. Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to beta-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther 2015;32:108-19.
68. Barilla F, Pannarale G, Torromeo C, et al. Ivabradine in patients with ST-elevation myocardial infarction complicated by cardiogenic shock: a preliminary randomized prospective study. Clin Drug Investig 2016;36:849-56.
69. Mert KU, Mert GO, Morrad B, et al. Effects of ivabradine and beta-blocker therapy on dobutamine-induced ventricular arrhythmias. Kardiol Pol 2017;75:786-93.
70. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation 2007;116:1482-7.
71. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med 2020;382: 1883-93.
72. Teerlink JR, Diaz R, Felker M, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105-16.
73. Ezekowitz JA, O’Connor CM, Troughton RW, et al. N-terminal proB-type natriuretic peptide and clinical outcomes: vericiguat heart failure with reduced ejection fraction study. JACC Heart Fail 2020;8:931-9.
74. Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336:525-33.
75. Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ. Digitalis for treatment of heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2014;4:CD002901.
76. Malik A, Masson R, Singh S, et al. Digoxin discontinuation and outcomes in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol 2019;74:617-27.
77. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52.
78. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-10.
79. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049-57.
80. Tardif JC, O’Meara E, Komajda M, et al. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J 2011;32:2507-15.
81. Januzzi JL Jr, Prescott MF, Butler J, et al. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA 2019;322:1-11.
82. Wang Y, Zhou R, Lu C, et al. Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis. J Am Heart Assoc 2019;8:e012272.