Disruptive Treatment in HF: Combination

Disruptive Treatment in HF: Combination Therapies for the Home Run May 10, 2019 Faculty Peter Liu, MD, FRCPC (Co-chair) Chief Scientific Officer & Vice President, Research University of Ottawa Heart Institute Professor of Medicine, University of Ottawa Ottawa, ON Jonathan Howlett, MD, FRCPC, FACC Clinical Professor of Medicine Libin Cardiovascular Institute of Alberta University of Calgary Past President CHFS Calgary, AB Nadia Giannetti, MD, FRCPC (Co-chair) Associate Professor, Department of Medicine Medical Director, Heart Failure and Heart Transplant Program Chief, Division of Cardiology McGill University Health Centre Montreal, QC Kim Connelly, MBBS, FRACP, PhD Assistant Professor of Medicine, Department of Medicine, St. Michael’s Hospital University of Toronto Toronto, ON John Klein Montreal, QC 2 Speaker Disclosures Dr. Nadia Giannetti • Consulting Fees/Honoraria: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS/Pfizer Alliance, Novartis, Servier • Clinical Trials: Amgen, Boehringer Ingelheim, Merck, Novartis, Pfizer, Servier • Speaker Fees: • Other: 3 Speaker Disclosures Dr. Peter Liu • Consulting Fees/Honoraria: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Roche, Sanofi, Servier • Clinical Trials: Roche • Speaker Fees: • Other: 4 Speaker Disclosures Dr. Kim Connelly • Received honoraria, advisory board and/or grant support from Merck, Astra Zeneca, Boehringer Ingelheim, Janssen, Servier, Eli Lilly, Ferring and Novo Nordisk • Holds patent for linagliptin and HF 5 • Relationships with commercial interests: • Grants/Research Support: AstraZeneca, Merck, Servier, Pfizer, Novartis, Medtronic, Bayer • Speakers Bureau/Honoraria: Bayer, Servier, Boerhinger Ingleheim, Novartis • Consulting Fees: General Electric, Government of Canada and Alberta, Novo Nordisk, AstraZeneca, Merck, Servier, Pfizer, Novartis, St. Jude, Bayer • Medical Advisory Board: Cardiol Speaker Disclosure Dr. Jonathan Howlett 6 • Relationships with commercial interests: • Grants/Research Support: • Speakers Bureau/Honoraria: Servier • Consulting Fees: • Other: Speaker Disclosures Mr. John Klein 7 Learning Objectives • Reinforce the importance of in-hospital initiation of evidence- based therapies • Highlight the early impact of HR lowering on heart function • Recognize the benefits to patients of early optimization of evidence-based therapies in HF 8 Agenda Time Topic Presenter 11:55 am - 12:00 pm Welcome and Introduction Nadia Giannetti, MD 12:00 - 12:05 pm Call to Action John Klein 12:05 - 12:20 pm Optimizing HF Therapies as Early as Possible Jonathan Howlett, MD 12:20 - 12:25 pm Panel Discussion Nadia Giannetti, MD 12:25 - 12:45 pm Imaging the Heart: Early Impact of Lowering HR on Heart Function Kim Connelly, MD 12:45 - 12:50 pm Panel Discussion Nadia Giannetti, MD 12:50 - 12:55 pm Tying it all Together Peter Liu, MD 12:55 - 1:10 pm Questions and Answers ALL 1:10 pm Closing Remarks and Evaluations Peter Liu, MD 9 Question 1: Which of the following medical therapies have been shown to improve survival in patients with heart failure? 1. ACE-inhibitors 2. Beta-blockers 3. MRAs 4. ARNIs 5. Ivabradine 6. All of the above 7. 1,2,3 8. 1,2,3,4 10 Question 2: Which of the following is/are independent predictors of mortality? 1. NYHA class 2. Systolic BP 3. Creatinine 4. LVEF 5. Heart rate 6. All of the above 7. 1,2,3 8. 1,2,3,4 11 Question 3: What can be said that is true about recovery of LVEF in patients with HFrEF following ACE/BB/MRA? 1) Almost half exhibit some degree of improvement in LVEF 2) 30% will normalize EF 3) More than 70% will still have HFrEF even if they improve EF 4) Men have better EF recovery than women 5) EF improvement does not improve prognosis during the first year 12 Question 4: What statement best describes your understanding of initiation of in-hospital therapies for HFrEF (assume eligible for all therapies)? 1) Triple therapy should be optimized prior to initiation of any 'new' therapies such as ARNi or SNI 2) Patients should be started on ARNi while in hospital but not SNI 3) Patients should be started on both ARNi and SNI while in hospital 4) New therapies should only be started in outpatient population 13 Call to Action John Klein 14 Optimizing HF Therapies as Early as Possible or Why can’t HF treatment be more like cancer treatment? Jonathan Howlett MD, FRCPC, FACC Libin Cardiovascular Institute 15 Survival of New Onset HF in UK Crude CHF Deaths in Canada 180 280 380 480 580 J-81 J-83 J-85 J-87 J-89 J-91 J-93 J-95 J-97 J-99 J-01 J-03 J-05 Year Mortality for CHF 16 Year of diagnosis Angiotensin Neprilysin Inhibition with LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the Renin- Angiotensin System 17 One year NNT is 18 One year NNT is 46 18 Swedberg et al. Lancet 2010; 376: 875-85; Krum & Sindone. Heart Lung Circ 2013; 22: s87-8. Therapeutic Approach to Patients With HFrEF 19 Chronic Underdosing of Medications Following HF Discharge 20 In Contemporary Clinical Practice, Only 15–30% of Patients Are Able to Reach the BB Target Dose 21 Target dose as defined by landmark BB clinical trials ¥ as background therapy Target Doses of EBMT in the CHECK HF Registry 22 Poghni A. Peri-Okonny et al. JCHF 2019;j.jchf.2018.11.011 2018 American College of Cardiology Foundation Heart Rate Remains Relatively High in Recent Heart Failure Trials and Heart Failure Registries 23 Recent Heart Failure Clinical Trials Recent Heart Failure Registries Heart rate, bpm (mean/median) 73 87 86 71 75 71 77 80 80 80 72 78 60 65 70 75 80 85 90 STAMINA (US) OPTIMIZE Hospital Cohort (US) OPTIMIZE Follow-up Cohort (US) IMPROVE-HF (US) EuroHeart Failure (Europe) ESC-HF (W. Europe) ESC-HF (E. Europe) SHIFT (Ivabradine) EVEREST (Tolvaptan) PROTECT (Rolofylline) EMPHASIS (Eplerenone) ASTRONAUT (Aliskiren) RED-HF (Darbepoetin alfa) Median Mean PARADIGM-HF (LCZ696) 72 73 24 Vs. • Hosp. represents failure of Rx • Bests evidence for rapid med change in hospital • Give decongesting drug when congested • Give HR lowering drug when HR elevated • There is no evidence • It is not safe • It will prolong hospitalization • The old ways are best • We have time after hospitalization to do this UK HF Audit: Risk of Death or Hospitalization Starting at Discharge 25 Early Benefit of Treatment on Hospitalization for Heart Failure 26 Endpoint – hospitalization for HF Hospitalization for HF begins to diverge as quickly as 2 weeks. HR, 0.60 (95% CI: 0.38–0.94) p =0.027 Days after randomization Kaplan-Meier estimate of cumulative rate 0 1.5 1.0 0.5 0 10 3020 Enalapril (N = 4212) Sacubitril/valsartan (N = 4187) Early treatment with IVA reduces readmission for HF in SHIFT trial. The curves begin to diverge at 2 weeks for those hospitalized for HF. Cumulative incidence of all-cause hospitalizations following first hospitalization for heart failure (mean number of events/patient) IRR = 0.70 (0.50–1.00) Placebo IRR = 0.75 (0.58–0.98) IRR = 0.79 (0.63–0.99) Time (months) 0 0 0.1 0.2 0.3 0.4 0.5 1 2 3 Ivabradine Early Co-administration of Ivabradine and b-blockers During Hospitalization May Reduce Mortality 27 Probability of survival BBs and ivabradine BBs 1.0 Cumulative survival Time (days) 0.8 0.6 0.4 0.2 0 0 100 200 300 400 HR=0.41 (95% CI, 0.29-0.57) P<0.0001 A retrospective analysis on 370 hospitalized HF patients with heart rate ≥70 bpm (150 BB + ivabradine, 220 BB alone) in the Optimize Heart Failure Care Program from 8 countries (2015-2016) Lopatin et al Int. J Cardiol 2018, 260, 113-117 PIONEER-HF 28 Exploratory Serious Clinical Composite Endpoint HR = 0.54; 95% CI 0.37-0.79 P = 0.001 NNT= 13 20 KM estimate of event rate (%) 10 0 0 7 Sacubitril/Valsartan N=440 Enalapril N=441 14 24 28 35 42 49 56 Days since randomization Composite of death, HF re-hospitalization, LVAD, listing for transplant • Exploratory Serious Clinical Composite endpoint was driven by the reduction of risk of death and HF re-hospitalizations Velazquez EJ et al. nejm.org/doi/full/10.1056/NEJMoa1812851 29 “de novo” HF can be as old as 3 years 48.3 52 44.5 64.3 63.1 79.8 59.6 36.5 53 49.5 54.8 43.2 86.2 50 20.6 12.6 33.9 28.1 34.4 14.5 63.5 65 94.2 77 80.2 86.5 71.3 41 64 96.3 71.8 61.4 93.6 61.5 31 35.1 55.3 47.5 61.8 21.7 0 10 20 30 40 50 60 70 80 90 100 ADHERE-I N=10171 OPTIMIZE-HF N=48612 GWTG-HF N=158922 ESC-HF Long term N=5039 EHFS II N=3580 IMPROVE-HF N=34810 IMPACT-HF N=567 Patients treated with evidence-based drug (%) Hospitalization Provides an Opportunity for HF Treatment Optimization ACEi/ARB Beta-blocker MRA ACEi/ARB Beta-blocker MRA At admission At discharge Significant increase in the prescription of evidence-based disease-modifying therapies at discharge compared to pre-hospitalization1-7 Asia Pacific US Europe 30 ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; HF, heart failure; MRA, mineralocorticoid receptor antagonist 1. Atherton et al. J Card Fail 2012;18:82–8; 2. O'Connor et al. Am Heart J 2008;156:662–73; 3. Allen et al. Circulation 2015;132:1347–53; 4. Maggioni et al Eur J Heart Fail 2013;15:1173–84; 5. Nieminen et al. Eur Heart J 2006;27:2725–36; 6. Fonarow et al. Circulation 2010;122:585–96; 7. O'Connor et al. J Card Fail 2005;11:200–5 This is a 16% absolute increase over 20 years which is 50% more than HF increase in similar time Impact of National Cancer Policies on Cancer Survival Trends and Socioeconomic Inequalities in England, 1996–2013: Population-based Study 31 Therapeutic Approach to Patients with HFrEF 32 Breast Cancer vs. Heart Failure • Similarities: • Common • Life threatening • Poor quality of life • Early treatment improves mortality • Improving mortality rates • Highest long term risk for mortality in those surviving 2 yrs is CV death • Differences: • Malignant vs. degenerative • Well organized advocacy groups • Combination therapy upfront • Early access to treatment • National reporting strategy • Dedicated formulary committee 33 34 THE MANY Nearly 75% will need consideration of new therapies when finished titration, however long it takes THE FEW Only 25% possibly could have avoided ARNi and SNI LVEF Trends Following Initial Diagnosis of HF Median Time to Maximal EF Change 14 Months 35 Gianluigi Savarese et al. JCHF 2019;j.jchf.2018.11.019 Early Survival Benefit How well would this go over? • You have breast cancer • We will start with some old drugs and see how you do. • We will see you every couple of months • We may have to try several times to ensure you are on the highest drug dose of each • If THAT does not work, we will have to make sure we have done everything we can about you being on all of the other drugs at their optimal levels. • If you do not respond well to this, we will see if you qualify for 1 or both of 2 newer drugs. • Once that is done, we will see about getting another drug, but we need to do 3 separate visits first while on the older drugs to see if you qualify. • If you are hospitalized in the meantime, we might have to start over again as someone might stop one or more of your older drugs… 37 Time for a Disruption in HF Treatment: Cluster Titration (CT) for HFrEF Encounter 3 & ongoing (whenever feasible) Diuretic titration Easiest cluster B titration Alternate Cluster C titration Encounter 2 (whenever feasible) Start 2nd med Cluster A Start 2nd med Cluster B Start 2nd med Cluster B Encounter 1 Start 1st Med Cluster A Start 1st med Cluster B Start 1st med Cluster C Cluster A: Diuretic & SGLTi Cluster B: ARNi & MRA Cluster C: BB & SNI 38 Three Disruptions for the Treatment of Acute HF Problem: 1) SLOW uptake and use of EBMT 2) LONG titration even when it happens leaving complications in its wake 3) HIGH hospital readmission and poor patient experience Disruption: a) STOP ACE, GET BNP and LVEF on admission b) Start ALL medical therapies upfront with Cluster titration Pragmatic, easiest titration c) EARLY follow up with PCP and specialist – 7 days (one or the other) 39 Let the Hospital be Your Friend… 40 Imaging the Heart: Early Impact of Lowering HR on Heart Function Kim Connelly MBBS, FRACP, PhD 41 • Discuss HR as an independent risk factor for adverse CV outcomes • Review impact of HR modulation upon cardiac functional outcomes • Discuss potential mechanism behind beneficial effects Objectives 42 Hazard ratio for all-cause mortality All p<0.001 Heart Rate is Independently Linked to a Significant Increase in All-cause Mortality 43 Modifiable risk factors out of the top ten factors associated with increased mortality Ford et al. Int J Cardiol 2015;184: 163-9 (Shift sub-analysis). Böhm et al. Lancet 2010; 376: 886-94. Lowering Heart Rate Impacts on Prognosis Outcomes based on the HR achieved after 28 days of treatment with ivabradine Patients with CV death or HF hospitalization, % ≥ 75 bpm 70 - < 75 bpm 60 - < 65 bpm 65 - < 70 bpm < 60 bpm Months 0 6 12 18 24 30D28 50 40 30 20 10 0 p<0.0001 No. at risk ≥ 75 bpm 70 to < 75 bpm 65 to < 70 bpm 60 to < 65 bpm < 60 bpm 527 344 444 605 1 192 451 314 404 556 1 132 376 276 358 488 1 004 291 221 287 407 842 141 116 149 176 414 47 41 62 59 162 44 McMurray, NEJM, 2014, 371, 993-1004 Castagno D, et al. Poster presented at Heart Failure, May 21–24, 2016, Florence, Italy Independent Risk Factor: Prognostic of Heart Rate from the PARADIGM-HF Study 45 Adjusted hazard ratio Tertile 1- Reference Group ( 66 bpm) Tertile 2 (67-76 bpm) Tertile 3 (≥ 77 bpm) Primary endpoint 1.00 1.19 1.05-1.35 1.24 1.09-1.43 CV Death 1.00 1.19 1.01-1.40 1.24 1.04-1.47 Heart failure hospitalizations 1.00 1.18 0.99-1.39 1.37 1.15-1.63 All-cause Mortality 1.00 1.23 1.07-1.42 1.27 1.08-1.48 8399 patients from Paradigm-HF • Baseline HR: 72bpm • End of study HR: 72bpm Ivabradine: Heart Rate Reduction and Benefits on Mortality/Morbidity 46 DiFrancesco & Camm. Drugs 2004; 64 (16): 1757-65. Colin et al. Am J Physiol Heart Circ Physiol 2002; 282: H672-9 Reil JC et al. JACC 2013, 62, 1977-1985 Ivabradine MOA and Physiological Effect 47 R R If current Ivabradine HR reduction Slows diastolic depolarization slope ΔRR Sinus node Atenolol Systolic time Diastolic time 700 100 200 300 4000 Time (ms) Ivabradine 1 cardiac cycle 450 200 -50 Left ventricle wall stress (g/cm2) contraction relaxation Background • Cardiac remodeling is central to the pathophysiology of heart failure (HF) and is a prognostic factor in patients with HF • Left ventricular (LV) enlargement and reduced ejection fraction are powerful predictors of outcomes in heart failure • Therapeutic effects of drugs and devices on LV remodeling are associated with their longer-term effects on mortality Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com 48 Sub-study Population Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com 49 Excluded (N=96) 52: Poor quality of echo recording 19: No baseline and/or 8-month recording 8: Non-matching biplane or 4-chamber views 13: Withdrawn due to death 4: Consent withdrawn Excluded (N=104) 208 patients Ivabradine Median follow-up after 8-month echocardiogram: 16.1 months 52: Poor quality of echo recording 15: No baseline and/or 8- month recording 1: Non-matching biplane or 4-chamber views 23: Withdrawn due to death 13: Consent withdrawn 611 patients included from 89 centers in 21 countries 304 patients Ivabradine 307 patients Placebo 203 patients Placebo Baseline Characteristics Ivabradine N=304 Placebo N=307 Mean age, years 60 59 Male, % 80 82 Mean BMI, kg/m2 28 28 Mean HF duration, years 4 4 HF ischaemic cause, % 67 65 NYHA class II, % 48 46 NYHA class III, % 51 53 Mean LVEF, % 32 32 Mean HR, bpm 78 79 Mean systolic BP, mm Hg 121 119 Mean diastolic BP, mm Hg 75 75 50Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com Baseline Background Treatment 51 Ivabradine N=304 Placebo N=307 Beta-blocker, % 92 92 ACE inhibitor, % 80 83 ARB, % 17 12 Diuretic (excludes antialdo), % 87 87 Aldosterone antagonist, % 74 71 Digitalis, % 27 32 Devices, % 3 4 LVESVI > 59 mL/m2 LVESVI < 59 mL/m2 HR 1.62, p=0.04 Patients with primary composite endpoint, % 60 40 20 LV End-systolic Volume Index and Outcome in the Placebo Group 52Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com Left ventricular end-systolic volume index 0 50 75 70 65 60 55 mL/m2 65.2±29.1 58.2±28.3 63.6 ±30.1 62.8 ±28.7 D - 7.0 ± 16.3 D - 0.9 ± 17.1 ∆ -5.8, P<0.001 Ivabradine (n=208) Placebo (n=203) Baseline 8 months Baseline 8 months Primary Endpoint: Change in LVESVI from Baseline to 8 Months 53Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com 0 75 100 95 90 85 80 mL/m2 93.9 ±32.8 85.9 ±30.9 90.8 ±33.1 89.0±31.6 D -7.9 ± 18.9 D -1.8 ± 19.0 Ivabradine (n=204) Placebo (n=199) Baseline 8 months Baseline 8 months ∆ -5.5, P=0.002 Left ventricular end-diastolic volume index Secondary Endpoint: Change in LVEDVI from Baseline to 8 Months 54Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com M008 32.3±9.1 34.7±10.2 31.6 ±9.3 31.5±10.0 D 2.4 ± 7.7 D - 0.1 ± 8.0 Ivabradine (n=204) Placebo (n=199) Baseline 8 months Baseline 8 months ∆ + 2.7, P<0.001Left ventricular ejection fraction Secondary Endpoint: Change in LVEF from Baseline to 8 Months 55Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com Summary of Changes in HR, LV End-Systolic/End-Diastolic Volume Indexes Ivabradine n=304 Placebo n=307 P Change in resting HR at 8 months, bpm - 14.7 - 5.8 <0.001 Change in LVESVI at 8 month, mL/m2 - 7.0 - 0.9 <0.001 Change in LVEDVI at 8 month, mL/m2 - 7.9 - 1.8 0.002 56 Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com SHIFT Compared to Prior Echo HF Studies 57 Impact of Evidence-based Therapies on LVEF Number of Studies (n) ∆EF (IC 95%) Mean Follow-up (weeks) Bisoprolol 1 (28) 12,0 (4,4-19,6) 52 Metoprolol CR 4 (587) 4,5 (1,8-7,1) 25,5 Enalapril 6 (431) 3,7 (1,5-5,9) 24 Spironolactone 3 (185) 3,0 (1,9-4,1) 25,7 CRT 4 (1052) 2,7 (1,9-3,5) 21 Ivabradine 1 (411) 2.7 (1.3-4.2) 35 58 • Heart rate reduction with ivabradine reverses left ventricular remodeling in patients with heart failure and LV systolic dysfunction: • Marked reductions of LV volumes • Significant improvement of LV ejection fraction • These results suggest that ivabradine modifies disease progression in patients with HF receiving background therapy Conclusions 59 Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com But what about mechanism? 60 Better Filling Increases Contractility 61 Healthy heart Failing heart Muscle length Developed force Holubarsch C. et al. Circulation 1996 Link Between Afterload and Aortic Elastance • Afterload has two principal components: • Fixed component: total peripheral resistance = Pam/Qc • Pulsatile component: arterial compliance 62 As Heart Rate Increases, Arterial Compliance Decreases Reil J-C al. JACC 2013 63 Cross-Over Study in Permanently Paced Systolic Heart Failure Patients Logeart D et al. Eur J HF 2009 64 Logeart D et al. Eur J HF 2009 65 Ivabradine Force-frequency relationship Improved myocardial perfusion Maintained contractility Decreased afterload Decreased post- systolic contraction Better LV filling Increased SV Improved renal and peripheral perfusion Decrease in deleterious hormone release Catecholamines, ACE Reverse remodelling 66 How could reducing heart rate improve arterial elastance? Placebo ↑ number of contraction/relaxation cycles ↑ muscle tone (↓ elasticity) ↑ afterload ↓ stroke volume Arterial wall Systole Diastole Ivabradine ↓ number of contraction/relaxation cycles ↓ muscle tone (↑ elasticity) ↓ afterload ↑ stroke volume 67 Ivabradine Infusion Leads to an Immediate Increase in Stroke Volume 68 10 severe heart failure patients (NYHA III), with advanced systolic dysfunction (Mean LVEF 21%) and HR ≥ 80 bpm treated with ACE I and beta-blockers → In severe systolic heart failure patients IV administration of ivabradine leads to a significant 51% increase in stroke volume. Ferrari GM et al. Eur J Heart Failure 2008 Acute Effects: 9 Days Post-IVA Administration... EF= <25% SV= 46ml EF= ~25% SV= 58ml 26% increase in SV 69 Vol (ml) SV 100 200 300 TDV TSV HF Vol (ml) SV 100 200 300 TDV TSV Beta-blocker: HR and inotropic reduction Ivabradine: Pure HR reduction Immediate Effects on Stroke Volume HF 70 Beta-blocker Infusion Has No Effect on Stroke Volume 24 patients with heart failure (FEVG < 40%), beta-blocker infusion IV SVI: Stroke Volume Index (Volume d’éjection systolique) Haber HL et al. Circulation 1993 71 Increased Stroke Volume Persists Over the Long Term Echocardiography study in 275 heart failure patients from the SHIFT trial (Baseline to 8 months) Reil J-C al. JACC 2013 72 Conclusions • Elevated HR is an adverse prognostic factor • Pure HR reduction improves outcomes • Reducing HR results in reverse remodeling • Effects are independent of and additive to neurohormonal blockade • Ivabradine is safe and well tolerated • Ivabradine is indicated by CCS guidelines for HFrEF patients in SR 73 Tying it all Together Peter Liu MD, FRCPC 74 High Mortality in Hospitalized HF Patient – the “Vulnerable Paradox” 75 High Mortality in Hospitalized HF Patient – the “Vulnerable Paradox” 76 1 0-1 No. of deaths 63 6386 94 130 150 1233 Time after discharge from hospital (months) 1-3 3-6 6-12 12-24 24+ 6 7 4 2 3 5 8 Hazard ratio No HF hospitalization Solomon et al. Circulation 2007;116:1482-87 Acute HFrEF Rx: Reproducing History of Medicine • Diuretics [1962], ACEi [1980], Beta Blocker [1990] 77 0 500 1000 1500 2000 2500 3000 3500Pro-BNP (pg/mL) Days Since Admission Pro-BNP Modern evidence- based therapy Recurrent Hospitalization Improvement as Outpatient 1 32 4 5 6 7 12 45 6015 18 21 30 90 NT-proBNP Levels During & Post Discharge for ADHF Diuretic 78 Benefits of Combinatorial Rx for HFrEF 79 79• Komajda M, et al. Eur J Heart Fail 2018 All-cause Mortality Cardiovascular Mortality Activation of three major neurohormonal systems Decline in systolic function Complementarity Between the HF Treatments Neurohormonal + Physiological, Rapid + Chronic Natriuretic peptide system Renin angiotensin aldosterone system Sympathetic nervous system Heart rate Direct determinant of heart function NEUROHORMONAL CHRONIC PHYSOLOGICAL RAPID + CHRONIC 80 Time for a Disruption in HF Treatment: Cluster Titration (CT) for HFrEF Encounter 3 & ongoing (whenever feasible) Diuretic titration Easiest cluster B titration Alternate Cluster C titration Encounter 2 (whenever feasible) Start 2nd med Cluster A Start 2nd med Cluster B Start 2nd med Cluster B Encounter 1 Start 1st Med Cluster A Start 1st med Cluster B Start 1st med Cluster C Cluster A: Diuretic & SGLTi Cluster B: ARNi & MRA Cluster C: BB & SNI 81 Ivabradine in Hospitalized HF Patients •Effect of ivabradine on stroke volume in failing heart is immediate •Effect of ivabradine on the failing heart in HFrEF is sustained: •Decreases LV volumes •Improves LV ejection fraction •Reduces NTproBNP over time •Reduces mortality •Combines well with other treatment “clusters” in HFrEF 82 For the Patient Admitted with HFrEF •Rapid symptom relief and volume optimization •Assess patient risk for rehospitalization •Hold ACEi and consider sacubitril/valsartan if no contraindication (BP, Creatinine) •If HR>77/minute, consider adding ivabradine to beta blockade •Patient education, community/family support •Timely follow-up as outpatient 83 Question 5: What statement best describes your understanding of initiation of in-hospital therapies for HFrEF (assume eligible for all therapies)? 1) Triple therapy should be optimized prior to initiation of any 'new' therapies such as ARNi or SNI 2) Patients should be started on ARNi while in hospital but not SNI 3) Patients should be started on both ARNi and SNI while in hospital 4) New therapies should only be started in outpatient population 84 Thank you! 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