Known Actions of Digoxin

Known Actions of Digoxin Hemodynamic effects in heart failure Increases cardiac output, no effect on blood pressure Decreases PCWP Increases LVEF (<5%, mild inotrope) Neurohormonal effects Vagomimetic action Improves baroreceptor sensitivity Decreases serum norepinephrine concentration Decreases activation of renin-angiotensin system Direct sympathoinhibitory effect Decreases cytokine concentrations Increases release of ANP and BNP Electrophysiological effects S-A node: slowing of the sinus rate independent of vagal influence Atrium: no effect or decreased refractory period AV node: slows conduction Ventricle and Purkinje fibers: practically no electrophysiological effects at low therapeutic doses Toxic/proarrhythmic-- may be caused by calcium-dependent after-potentials Gheorghiade2006 doi: 10.1161/CIRCULATIONAHA.105.560110

Controversy Ongoing. 210 years later ACC/AHA GUIDELINE 1995 Heart Failure is no longer considered just an edematous state responsive to diuretic therapy Digoxin: Class I, Level of Evidence A Digoxin use in patients with heart failure due to systolic dysfunction not adequately responsive to ACE inhibitors and diuretic drugs Digoxin use in pts with atrial fibrillation and rapid ventricular rates Digoxin is an effective treatment in many patients with moderate to severe heart failure, but there is uncertainty regarding its influence on mortality. JF Williams, et al. JACC (26) 5, 1376-1398

DIG TRIAL (NHLBI and DVA) 6800 patients with HFand LVEF 0.45, in sinus rhythm Randomly assignedto digoxin or placebo, double-blind fashion The placebo groupreceiveddiuretics (82%) andace-i (95%) The digoxin group received digoxin, diuretics (81%), and ACE-I (94%). Included 302 centers in the United States and Canada Duration: 31.5 month recruitment, minimum 28 month followup Primary Endpoint: All-causemortality & HospitalizationforHF Ancillary Trial Total of 988 patients with HF and LVEF >0.45 who were randomly assigned to digoxin or placebo Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997; 336: 525

DIG TRIAL Primary endpoint CUMULATIVE PROBABILITY OF DEATH OR HOSPITALIZATION DUE TO WORSENING HEART FAILURE Garg R., Gorlin R., Smith T. N Engl J Med 1997; 336:525-533 4

DIG TRIAL All Cause Mortality Heart Failure Mortality p=0.80 p=0.06 Digitalis Investigation Group. N Engl J Med. 1997; 336: 525

DIG TRIAL Cumulative Probability of Death or Hospitalization due to Heart Failure Hospitalization for worsening HF (P<0.001) Death caused by worsening HF (P=0.06) Benefits were incremental to use of diuretic and ACE-inhibitors Digitalis Investigation Group. N Engl J Med. 1997; 336: 525

DIG TRIAL HF-rEF High Risk pre-specified subgroup analysis NYHA class III IV LVEF < 25 % CTR > 55 % Gheorghiade M, et al. European Journal of Heart Failure 2013; 15: DOI: 10.1093/eurjhf/hft010

Controversy Over!?. 216 years later ACC/AHA GUIDELINES 2001 Digoxin: Class I, Level of Evidence A Digitalis is recommended for the treatment of symptoms of HF (NYHA classes II-IV) in patients with LV systolic dysfunction, unless contraindicated. Not for Asx HF-rEF pts in SR. II A (A). Digitalis to control the ventricular response in patients with HF and atrial fibrillation. II B (C). Digitalis to minimize symptoms of HF in patients with HF-pEF Hunt, SA et al. 2001 ACC/AHA Heart Failure Guideline

Pharmacological Treatment for Stage C HF With Reduced EF Ivabradine COR LOE Recommendations IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDEM*, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest. Comment/ Rationale NEW: New clinical trial data. *In other parts of the document, the term GDMT has been used to denote guideline-directed management and therapy. In this recommendation, however, the term GDEM has been used to denote this same concept in order to reflect the original wording of the recommendation that initially appeared in the 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.

Yancy CW et al. 2013 ACC/AHA Heart Failure Guideline Controversy Over!. 230 years hence! ACC/AHA GUIDELINES 2013 7.3.2.7. Digoxin: Class IIa, Level of Evidence: B Digoxin can be beneficial in patients with HF-rEF, unless contraindicated, to decrease hospitalizations for HF. Therapy with digoxin is commonly initiated and maintained at a dose of 0.125 to 0.25 mg daily. Low doses (0.125 mg daily or every other day) should be used initially if the patient is >70 years of age, has impaired renal function, or has a low lean body mass. There is no reason to use loading doses of digoxin to initiate therapy in patients with HF. Doses of digoxin that achieve a plasma concentration of drug in the range of 0.5 to 0.9 ng/ml are suggested, given the limited evidence currently available

2014 AHA/ACC/HRS atrial Fibrillation Guidelines Recommendations 2006 2014 In the absence of pre-excitation, intravenous digoxin or amiodarone is recommended to control heart rate acutely in patients with HF. Digoxin is effective to control resting heart rate in patients with HF with reduced EF. Class I LOE: B Class I LOE: C Class I LOE: B Class I LOE: C January C.T., et al. J Am Coll Cardiol. 2014; 64(21):2246-2280. Fuster V., et al. J Am Coll Cardiol. 2006; 48(4):854-906. 12

Timeline: enthusiasm for DIGOXIN 1993 PROVED 1993 RADIANCE AHA/ACC TREATMENT GUIDELINES 1997 DIG 2002 AFFIRM 2006 DIG post-hoc 1995 2001 2005 2013 2013 AFFIRM post-hoc 2014 TREAT-AF

A NEVER - ENDING STORY? Digoxin Reduces 30-day All-cause Hospital Admission in Older Patients with Chronic Systolic Heart Failure n = 3405 Age 65 years (mean age, 72 yr) 25% women; 11% nonwhite Bourge, R et al. Am J Med. 2013; 126(8): 701 708. doi:10.1016/j.amjmed.2013.02.001.

WHY WON T DIG WHITHER? Clinical Significance! According to the new United States health care reform law, starting October 2012, hospitals are being penalized for higher than expected 30-day all-cause hospital readmissions for older patients with heart failure. We have limited therapies for patients with advanced heart failure In these patients we are frequently reducing or withdrawing efficacious therapies due to intolerance, renal dysfunction Reducing or stopping ACE/ARB and Beta Blockers reflects very high risk patients Bourge, R et al. Am J Med. 2013; 126(8): 701 708. doi:10.1016/j.amjmed.2013.02.001.

Resting Heart Rate and CV Outcomes in Patients with HF Retrospective analysis of 7,599 symptomatic HF* patients from the CHARM studies, who were followed for a median of 38 months to determine the relationship between resting heart rate at baseline and all-cause mortality, and fatal and nonfatal CV outcomes. Tertile 1: Median heart rate 60 bpm Tertile 2: Median heart rate 72 bpm Tertile 3: Median heart rate 85 bpm 0.4 All-Cause Mortality p<0.001 0.4 CV Death or WHFH p<0.001 Probability 0.3 0.2 0.1 0.3 0.2 0.1 0 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Months Months Heart rate is an important predictor of mortality and CV outcomes in patients with HF WHFH = worsening heart failure hospitalization; *symptomatic HF defined as NYHA functional Class II to IV. Adapted from: Castagno D, et al. J Am Coll Cardiol. 2012;59:1785-1795.

Ivabradine Specific inhibitor of the I f current in SA node This so-called funny current controls the rate of spontaneous activity of SA node myocytes Reduces the slope for diastolic depolarization Prolongs diastolic duration à slows heart rate No action on other cardiac channels Does not modify cardiac contractility DiFrancesco D. Pharmacol Res. 2006;53(5):399-406. Savelieva I, Camm AJ. Drug Saf. 2008;31(2):95-107.

Objective of the SHIFT Study To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with: 1. Moderate to severe chronic HF 2. Left ventricular EF 35% 3. Heart rate 70 bpm, and 4. Recommended therapy Swedberg K, et al. Lancet. 2010;376:875-885.

Inclusion Criteria: SHIFT Study: Design 18 years; symptomatic HF NYHA Class II to IV; ischemic/non-ischemic etiology LV systolic dysfunction (EF 35%); heart rate 70 bpm; sinus rhythm Documented hospital admission for worsening HF 12 months Ivabradine 5 mg bid, titrate to 7.5 mg bid on D14, adjust dose to 7.5/5/2.5 mg bid according HR and tolerability n=3241 D 0 D 14 7,411 Screened HF Patients (n=6,558) R Median follow-up 22.9 months n=3264 D 0 D 14 Placebo bid Primary endpoint: CV death or hospitalization for worsening HF Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Baseline Characteristics Ivabradine (n=3241) Placebo (n=3264) Mean heart rate (bpm) 79.7 80.1 Mean LVEF (%) 29.0% 29.0% NYHA Class II /III (%) 49%/ 50% 49%/ 50% Mean SBP, mm Hg 122.0 121.4 egfr, ml/min/1.73 m 2 74.6 74.8 Beta-blocker (%) 89% 90% ACE inhibitor/arb (%) 79%/ 14% 78%/ 14% Diuretics (%) 84% 83% Aldosterone antagonist (%) 61% 59% Digitalis (%) 22% 22% CRT/ ICD (%) 1%/ 3% 1%/ 4% Swedberg K, et al. Lancet. 2010;376:875-885.

Background Beta-Blocker Treatment 100 90 80 89 90 Ivabradine Placebo 70 Patients (%) 60 50 40 30 56 56 26 26 20 10 0 BB at Randomization At Least 50% Target Daily Dose Target Daily Dose Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Primary Endpoint of CV Death or Hospitalization for Worsening HF 40 Ivabradine (n=3241) Patients with Primary Endpoint (%) 30 20 10 Placebo (n=3264) Placebo 937 events (29%) Ivabradine 793 events (24%) 18% 0 HR 0.82 (95% CI, 0.75 0.90) p<0.0001 ARR = 5%, NNT = 20 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Mean Heart Rate Mean ivabradine dose was 6.4 mg bid at 1 month and 6.5 mg bid at 1 year 90 Ivabradine Placebo Heart Rate (bpm) 80 70 60 80 75 64 75 67 50 HR reduction: Ivabradine HR 10.9 bpm at day 28, 9.1 bpm at 1 year, and 8.1 at study end vs. placebo. 0 2 weeks 1 4 8 12 16 20 24 28 32 Months Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Cardiovascular Death 30 Ivabradine Placebo Patients with Event (%) 20 10 Placebo 491 events (15%) Ivabradine 449 events (14%) 0 HR 0.91, p=0.128 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Hospitalization for Worsening HF Patients with First Hospitalization for Worsening HF (%) 30 20 10 0 Ivabradine Placebo Placebo 672 events (21%) HR 0.74 (95% CI, 0.66-0.83) p<0.0001 NNT = 20 0 6 12 18 24 30 Months Ivabradine 514 events (16%) 26% Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Effect of Ivabradine on Outcomes Endpoint Ivabradine (n=3241) Placebo (n=3264) HR p-value Primary endpoint 24% 29% 0.82 <0.0001 All-cause mortality 16% 17% 0.90 0.092 Death from HF 3% 5% 0.74 0.014 All-cause hospitalization 38% 42% 0.89 0.003 Any CV hospitalization 30% 34% 0.85 0.0002 CV death, hospitalization for worsening HF, or hospitalization for non-fatal MI 25% 30% 0.82 <0.0001 Swedberg K, et al. Lancet. 2010;376:875-885.

SHIFT Study: Effect of Ivabradine in Prespecified Subgroups Age <65 years 65 years Sex Male Female Beta-blockers No Yes Aetiology of heart failure Non-ischaemic Ischaemic NYHA Class NYHA Class II NYHA Class III or IV Diabetes No Yes Hypertension No Yes Baseline heart rate <77 bpm 77 bpm Test for Interaction p=0.099 p=0.260 p=0.103 p=0.059 p=0.793 p=0.861 p=0.779 p=0.029 Swedberg K, et al. Lancet. 2010;376:875-885. 0.5 1.0 Hazard Ratio Favors Ivabradine Favors Placebo 1.5

SHIFT Study: Effect of Ivabradine in Patients at 50% BB Target Dose (n=3181) Ivabradine Placebo Hazard Ratio p-value Primary composite endpoint 330 (11.9 PY) 362 (13.3 PY) 0.90 ns Cardiovascular death 176 (5.9 PY) 175 (5.9 PY) 1.00 ns Hospitalization for worsening HF 213 (7.7 PY) 260 (9.6 PY) 0.81 p=0.021 0.5 Favors Ivabradine 1.0 Hazard Ratio Favors Placebo 1.5 Swedberg K, et al. J Am Coll Cardiol. 2012;59(22):1938-1945.

SHIFT Study: Effect on Recurrence of Hospitalizations for Worsening HF Ivabradine (n=3241) Placebo (n=3264) Hazard Ratio p-value First hospitalization 514 (16%) 672 (21%) 0.75 p<0.001 Second hospitalization 189 (6%) 283 (9%) 0.66 p<0.001 Third hospitalization 90 (3%) 128 (4%) 0.71 p=0.012 0.4 0.6 0.8 Favors Ivabradine 1.0 Hazard Ratio 1.2 Favors Placebo Broer JS, et al. Eur Heart J. 2012;33(22):2813-2820.

SHIFT Study: Incidence of Selected Adverse Events Endpoint Ivabradine (n=3241) Placebo (n=3264) p-value All serious adverse events 45% (1450) 48% (1553) 0.025 All adverse events 75% (2439) 74% (2423) 0.303 Heart failure 25% (804) 29% (937) 0.0005 Symptomatic bradycardia 5% (150) 1% (32) <0.0001 Asymptomatic bradycardia 6% (184) 1% (48) <0.0001 Atrial fibrillation 9% (306) 8% (251) 0.012 Phosphenes 3% (89) 1% (17) <0.0001 Blurred vision 1% (17) <1% (7) 0.042 Phosphenes are luminous phenomena; bradycardia is defined here as resting heart rate was lower than 50 bpm or the patient had signs or symptoms related to bradycardia. Swedberg K, et al. Lancet. 2010;376:875-885.

Effect of Ivabradine on Outcomes according to HR Achieved at 28 Days Patients with Primary Composite Endpoint (%) 40 30 20 10 75 bpm 70 to <75 bpm 65 to <70 bpm 60 to <65 bpm <60 bpm 0 0 D 28 6 12 18 24 Time (months) Böhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22.

Effect of Ivabradine on Outcomes according to Magnitude of HR Reduction Patients with Primary Composite Endpoint (%) 40 30 20 10 0 bpm 10 to <0 bpm > 10 bpm 0 0 D 28 6 12 18 24 Time (months) Böhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22.

SHIFT Echo Substudy: Change in LVEF from Baseline to 8 mos (Secondary Endpoint) +2.7, p=0.0003 Left Ventricular Ejection Fraction (%) 40 35 30 25 20 15 10 5 0 32.3 ± 9.1 2.4 ± 7.7 0.1 ± 8.0 34.7 ± 10.2 Ivabradine (n=204) 31.6 ± 9.3 31.5 ± 10.0 Baseline 8 Months Baseline 8 Months Placebo (n=199) LVESVI = left ventricular end-systolic volume index. Tardif JC, et al. Eur Heart J. 2011;32(20):2507-2515.

Pooled Analysis of BEAUTIFUL and SHIFT Reduced EF, Heart Rate 75 bpm (N=7632) Fox K. Eur Heart J. 2013

FDA-Approved Ivabradine Ivabradine Brand name Indication Dosage Contraindications Side effects Corlanor To reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF with LVEF 35% who are in sinus rhythm with resting HR 70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. Start with 5 mg twice daily. After 2 weeks of treatment, adjust dose based on HR. Max is 7.5 mg twice daily. In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, start with 2.5 mg twice daily. Acute decompensated HF; BP <90/50 mmhg; sick sinus syndrome or third-degree AV block, unless a functioning demand pacemaker is present; resting HR < 60 bpm prior to treatment; severe hepatic impairment; pacemaker dependence. WARNING fetal toxicity. Occurring in 1% of patients are bradycardia, hypertension, atrial fibrillation, and luminous phenomena (phosphenes). http://www.pdr.net/full-prescribing-information/corlanor?druglabelid=3713. Accessed October 20, 2015.

Practical Points on Use of Ivabradine Starting dose is 5 mg twice daily Target HR is 50-60 bpm After 2 weeks: If HR >60 bpm: Increase dose to 7.5 mg twice daily (Max dose) If HR 50-60 bpm: Maintain initial dose If HR <50 bpm or symptomatic bradycardia: Lower dose to 2.5 mg twice daily If HR <50 bpm or symptomatic bradycardia and dose is 2.5 mg twice daily: Discontinue

2016 ACC/AHA/HFSA Heart Failure Guideline Update Pharmacological Treatment for Stage C HFrEF COR = class of recommendation; LOE = level of evidence. Reference: Yancy et al. Circulation. 2016;134:[ePub ahead of print].

Potential Candidates for Ivabradine Therapy Patients with stable symptomatic chronic heart failure with LVEF 35% in sinus rhythm receiving standard therapy with resting heart rate 70 bpm Taking maximally tolerated doses of beta-blockers Common reasons for not taking maximally tolerated dose Hypotension CorlanorPrescribing Information, Amgen Fatigue Contraindicated to beta-blocker use Common reasons for not receiving any dose COPD Hypotension Severe Asthma

Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030. Evidence-Based HFrEF Therapies Guideline Relative Risk Number Needed NNT for Mortality Relative Risk Recommended Reduction in to Treat for (standardized to Reduction in HF Therapy Mortality Mortality 36 months) Hospitalizations ACEI/ARB 17% 22 over 42 months 26 31% ARNI 16% 36 over 27 months 27 21% Beta-blocker 34% 28 over 12 months 9 41% Aldosterone Antagonist 30% 9 over 24 months 6 35% Hydralazine/Nitrate 43% 25 over 10 months 7 33% CRT 36% 12 over 24 months 8 52% ICD 23% 14 over 60 months 23 NA Ivabradine NA NA NA 26%

Potential Impact of Optimal Implementation of Evidence-Based HFrEF Therapies on Mortality Guideline Recommended HF Patient Current HF Potential Lives Potential Lives Therapy Population Population Saved per Year Saved per Year Eligible for Eligible and (Sensitivity Range*) Treatment, n* Untreated, n (%) ACEI/ARB 2,459,644 501,767 (20.4) 6516 (3336-11,260) Beta-blocker 2,512,560 361,809 (14.4) 12,922 (6616-22,329) Aldosterone Antagonist 603,014 385,326 (63.9) 21,407 (10,960-36,991) Hydralazine/Nitrate 150,754 139,749 (92.7) 6655 (3407-11,500) CRT 326,151 199,604 (61.2) 8317 (4258-14,372) ICD 1,725,732 852,512 (49.4) 12,179 (6236-21,045) Total - - 67,996 (34,813-117,497) ARNI (replacing ACEI/ARB) 2,287,296 2,287,296 (100) 28,484 (18,230-41,017) Updated from Fonarow GC, et al. Am Heart J 2011;161:1024-1030. and JAMA Cardiology 2016