Chronic Heart Failure Therapies: Transforming the Landscape

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1 Chronic Heart Failure Therapies: Transforming the Landscape Dr. Nadia Giannetti Chief of Cardiology Medical Director, Heart Failure and Heart Transplant Program McGill University Health Center

2 Conflict of Interest Received grants or honoraria from: Novartis, Servier, Pfizer, Amgen, HeartWare, Astra 2

3 Agenda Review the Pathophysiology of Heart Failure and the burden on society Explore the need to act Introduce the new data supporting the role of newer drugs therapies Discuss the Role of family practitioners in the treatment of Heart Failure 3 MED/ENT/0149

4 What is the prevalence of HF in Canada? 4

5 HF: The Fastest Rising Cardiovascular Condition in Canada The prevalence of HF has increased over the past few decades 1 An estimated 600,000 Canadians are living with HF and 50,000 new patients are diagnosed each year million hospital days per year 1. Johansen H, et al. Can J Cardiol. 2003;19(4): / 2. Ross H, et al. Can J Cardiol. 2006;22(9): Heart and Stroke Foundation, the Burden of Heart Failure, report on health of Canadians

6 Heart Failure is the Fastest Rising Cardiovascular Condition in Canada Actual and Projected Incidence of HF in Canada 1 >750,000 people in Canada will have Heart Failure in MED/ENT/ Management of Heart Failure Patients in Ontario: Recommendations from Best Practice, April 2013, *Ross et al. Treating the right patient at the right time; Access to HF care, CJC Blais C et all, Assesing HF in Canada CJC 2014; 30: ; Statistic Canada Ross H et al. Can J Cardiol 2006: 22(9); Cook C, Cole G, Asaria P, Jabbour R, Francis DP. The annual global economic burden of heart failure. Int J Cardiol 2014;171(3):

7 Heart Failure Mortality Exceeds that of Most Cancers All patients with a first administration to any Scottish Hospital in 1991 for HF, MI or the four most common types of cancer specific to men and women were identified, an 5-year survival rates compared MED/ENT/ Stewart et al. Eur J Heart Fail 2001;3:315-22

8 8

9 The Burden of Heart failure in Canada 9

10 Canadian Landscape Large country with large rural population Mostly family MD provided care with consultative support by specialists Care is fragmented and variable across the country Only 15% access HF clinic or Disease management programs These are mostly younger patients About 2/3 of HF diagnosed in clinics About 1/3 in ER 50% of HF admissions are de novo Gravely S, Can J Cardiol 2012;28:483-9.

11 Current Challenges Associated With HF Care In Canada Differential HF clinic access for patients remains a problem Rural HF care lacks support Heart and Stroke Foundation s 2014 Report on the Health of Canadians More people are surviving heart attacks and strokes, but they face challenges and lack support to thrive to the fullest Heart and Stroke Foundation 2014 Report on the Health of Canadians Creating_Survivors.htm

12 Four Key Emerging Themes Challenging HF Care in Canada Hayes et al. BMC Health Services Research (2015) 15:290

HF is a Progressive Condition with High Morbidity and Mortality With each acute event, myocardial injury may contribute to progressive LV dysfunction 2 Increasing frequency of acute events with

$slope; intermittent exacerbations of HF that respond to rescue efforts Stage D HF, with refractory symptoms and limited function End of life Death Time Dotted lines represent sudden cardiac death$

13 HF is a Progressive Condition with High Morbidity and Mortality With each acute event, myocardial injury may contribute to progressive LV dysfunction 2 Increasing frequency of acute events with disease progression leads to high rates of hospitalization and increased risk of mortality 2 Excellent Phase 1 Initial symptoms of HF develop and HF treatment is initiated 3 Physical Function Phase 2 Phase 3 Phase 4 Phase 5 Plateau of variable length reached with initial medical management, or following mechanical support or heart transplant Functional status decline with variable slope; intermittent exacerbations of HF that respond to rescue efforts Stage D HF, with refractory symptoms and limited function End of life Death Time Dotted lines represent sudden cardiac death that can occur anytime during the trajectory Sudden Death Event Transplant or Ventricular Assist Device 13 MED/ENT/ Roger VL et al. JAMA 2004;292: Gheorghiade & Pang. J Am Coll Cardiol 2009;53: Goodlin SJ. J Am Coll Cardiol Jul 28;54(5):

Heart Failure: The Abnormality of Cardiac Structure and/or Function HEART FAILURE Inability for the heart to deliver sufficient

Heart Failure With Reduced Ejection Fraction The heart is too weak or too stiff to maintain circulation without running the risk

Failure is a clinical diagnosis and doesn't suggest a cause or underlying pathological state CARDIOMYOPATHY Disease of the heart

14 Heart Failure: The Abnormality of Cardiac Structure and/or Function HEART FAILURE Inability for the heart to deliver sufficient blood/oxygen to meet the demands of the peripheral tissues, or to do so at abnormally high filling pressures, or both Normal Heart Heart Failure With Reduced Ejection Fraction The heart is too weak or too stiff to maintain circulation without running the risk of congestion Characterized by signs and symptoms of decreased cardiac output and/or volume overload Weakened heart muscle Heart Failure is a clinical diagnosis and doesn't suggest a cause or underlying pathological state CARDIOMYOPATHY Disease of the heart muscle due to any number of causes Clinically characterized by heart failure 1 MED/ENT/01494 McMurray et al. Eur Heart J 2012;33:

15 What is the difference between systolic and diastolic HF? 15

$Heart Failure with reduced ejection fraction (systolic) and preserved ejection fraction (diastolic) Heart Failure with reduced ejection$ volume overload 1. Characterized by eccentric hypertrophy 2.

volume overload 1. Characterized by eccentric hypertrophy 2.

Characterized by concentric hypertrophic growth 2.

16 Heart Failure with reduced ejection fraction (systolic) and preserved ejection fraction (diastolic) Heart Failure with reduced ejection fraction - EF 35 40% Heart Failure with preserved ejection fraction - EF>40 50% Systolic dysfunction Diastolic dysfunction A condition of volume overload 1. Characterized by eccentric hypertrophy 2. Results in globular heart with thinning of LV walls, decreased systolic function and enlarged LV volume A condition of pressure overload 1. Characterized by concentric hypertrophic growth 2. Results in normal sized LV cavity with thickened walls and preserved systolic function 1 6 MED/ENT/ Aurigemma. Circulation 2006;113; , 2. Paulus et al. Eur Heart J 2007;28: , 3. Colucci (Ed.). Atlas of Heart Failure, 5 th ed. Springer 2008, 4. McMurray et al. Eur Heart J 2012;33:

and Gilbert. Lancet 2003;362:147 58; Colucci (Ed.).

17 Main causes of Heart Failure Coronary artery disease Valvular disease Cardiomyopathy Hypertension Diabetes 17 MED/ENT/0149 Krum and Gilbert. Lancet 2003;362:147 58; Colucci (Ed.). Atlas of Heart Failure, 5th ed. Springer 2008; Dickstein et al. Eur Heart J 2008;29:

18 Heart Failure triggers the activation of Endogenous Compensatory Mechanisms Risk factors Myocardial injury to the heart Initial fall in left ventricle performance Activation of RAAS: Vasoconstriction necessary to keep enough volume of circulating blood Activation of SNS: Sympathetic tone discharge Natriuretic Peptides: Natural compensatory system to protect the heart 18 MED/ENT/0149 RAAS: renin-angiotensin-aldosterone system, SNS: sympathetic nervous system Krum H, Abraham WT. Lancet. 2009;373: ; Khan MG. Cardiac Drug Therapy. 6th ed. Philadelphia: WB Saunders; 2003.

Signs and Symptoms of Heart Failure Symptoms Breathlessness Orthopnea Paroxysmal Nocturnal Dyspnea Reduced exercise tolerance Fatigue Ankle swelling Pumping action of the heart grows weaker Pleural

19 Signs and Symptoms of Heart Failure Symptoms Breathlessness Orthopnea Paroxysmal Nocturnal Dyspnea Reduced exercise tolerance Fatigue Ankle swelling Pumping action of the heart grows weaker Pleural effusion Tiredness Shortness of breath Coughing Fluid retention Signs Elevated jugular venous pressure Hepato-jugular reflux Third heart sound Laterally displaced apical impulse Cardiac murmur Early signs of HF: Swelling of feet, ankles, abdomen and lower back area Walking less with shortness of breath Palpitation Pulmonary edema 19 McMurray et al. Eur Heart J 2012;33: MED/ENT/0149

20 Symptomatic Severity of Heart Failure New York Heart Association functional classification Based on severity of symptoms and impact on physical activity Clear relationship between severity of symptoms and survival NYHA Class I II Functional Capacity Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitations, or shortness of breath. Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitations, or shortness of breath. III IV Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitations, or shortness of breath. Patients with cardiac disease resulting in the inability to carry on any physical activity without discomfort. Symptoms of HF may be present even at rest. If any physical activity is undertaken, discomfort increases. Among 411 outpatients total mortality during a follow-up of 1.4 years was: NYHA Class II: 7.1% NYHA Class II: 15% NYHA Class IV: 28% 2 0 MED/ENT/ Muntwyler et al. Eur Heart J 2002;23:1861 6; Yeung DF, Boom NK, Guo H, Lee DS, Schultz SE, Tu JV. CMAJ Oct 2;184:E Levy D, Kenchaiah S, Larson MG et al. N Engl J Med 2002;347(18):

21 What are the goals of therapy? 21

22 Goals of Therapy Relieve symptoms and improve QOL Decrease hospitalizations Slow disease progression Prolong life Is there room for improvement? Definitely! 22

23 HFrEF until recently Life-style modificationmo Devices

Heart Failure Is A State Of Neurohormonal Imbalance As HF advances, the RAAS becomes the predominantly activated neurohormonal system Until recently, drugs target only the RAAS system However, the NP

24 Heart Failure Is A State Of Neurohormonal Imbalance As HF advances, the RAAS becomes the predominantly activated neurohormonal system Until recently, drugs target only the RAAS system However, the NP system is counter-regulatory to the RAAS system in HF Physiological response NP system RAAS Pathophysiological response NPs Ang II Vasodilation Inactive fragments AT 1 receptor Vasoconstriction BP BP Sympathetic tone Aldosterone Fibrosis Hypertrophy HF symptoms/ progression Sympathetic tone Aldosterone Fibrosis Hypertrophy Natriuresis/diuresis Ang=angiotensin; AT1=angiotensin type 1; BP=blood pressure; NP=natriuretic peptide; RAAS=renin-angiotensin-aldosterone system Ferro et al. Circulation 1998;97: ; Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier et al. Kidney Int 2000;57: ; Schrier & Abraham. N Engl J Med 1999;341:577 85

25 Evidence Behind ACE Inhibitors These trials form the basis of ACE inhibitors use in HF with LVEF < 40% and/or post-mi with reduced LVEF and/or HF CONSENSUS Cumulative probability of death* SOLVD Treatment** SAVE, AIRE and TRACE Placebo Cumulative probability of death Placebo Enalapril Mortality (%) Placebo Enalapril Cumulative mortality (%) Enalapril 0 p= Months Months p= p= Years *CONSENSUS Trial. N Engl J Med 1987;316: / **SOLVD Investigators. N Engl J Med 1991;325: / ***Flather MD et al. Lancet 2000;355: Arnold JMO, Liu P et al. Can J Cardiol 2006;22(1):23-45.

26 New therapy: Sacubitril/Valsartan Canadian Cardiovascular Society Recommendations For HFrEF: Jan 2015 We recommend that in patients with mild to moderate HF, an EF < 40%, an elevated NP level or hospitalization for HF in the past 12 months, a serum potassium < 5.2 mmol/l and an egfr 30 ml/min and treated with appropriate doses of guideline-directed medical therapy, they should be treated with LCZ696 in place of an ACE inhibitor or an angiotensin receptor blocker, with close surveillance of serum potassium and creatinine (Conditional Recommendation, High-Quality Evidence) 1 Health Canada approved indication: Oct 2015 Treatment of heart failure with reduced ejection fraction (HFrEF) in patients with NYHA Class II or III, to reduce the incidence of cardiovascular death and heart failure hospitalisation 2 26 MED/ENT/ G. Moe, 2014 CCS HF Management Guidelines Focus up-date: CJC 31 (2015): J.G. Howlett, The Canadian Cardiovascular Society HF companion; CJC 2015: 1-15

27 Sacubitril/Valsartan as a new Alternative to an ACEI or ARBs in Patients with HFrEF SNS β-blockers NP system Neprilysin inhibitors HF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy INACTIVE FRAGMENTS Sacubitril/Valsartan RAAS Ang II AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) Sacubitril/Valsartan: Increase level of natriuretic peptide and other vasoactive peptides, with simultaneous RAAS suppression 27 MED/ENT/0149 Figure references: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012; ; Schrier & Abraham N Engl J Med 2009;341:577 85

28 PARADIGM-HF 1 : The largest mortality-morbidity trial in patients with HFrEF 10,000 9,000 N=8442 8,000 Number of patients 7,000 6,000 5,000 4,000 3,000 2,000 N=2569 N=2548 N=3834 N=1798 N=6505 N=2737 1,000 0 SOLVD-T CHARM-Added HEAAL RAFT SHIFT EMPHASIS-HF PARADIGM-HF Recruitment CHARM-Added=Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-added trial; EMPHASIS-HF=Eplerenone in Mild Patients Hospitalization And Survival study in Heart Failure; HEAAL=Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan; HFrEF=heart failure with reduced ejection fraction; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; RAFT=Resynchronization/Defibrillation for Ambulatory Heart Failure Trial; SHIFT=Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial; SOLVD-T=Studies of Left Ventricular Dysfunction Treatment trial 28 MED/ENT/0149 McMurray et al. Eur J Heart Fail 2014;16:817 25

29 PARADIGM-HF: Study Design Single-blind active run-in period Randomization n=8442 Double-blind Treatment period Sacubitril/Valsartan 97.2/102.8 mg BID Enalapril 10 mg BID* Sacubitril/ Valsartan 48.6/51.48 mg BID Sacubitril/ Valsartan 97.2/102.8 mg BID Enalapril 10 mg BID 2 Weeks 1 2 Weeks 2 4 Weeks Median of 27 months follow-up On top of standard HFrEF therapy (excluding ACEIs and ARBs) *Enalapril 5 mg BID (10 mg TDD) for 1 2 weeks followed by enalapril 10 mg BID (20 mg TDD) as an optional starting run-in dose for those patients who are treated with ARBs or with a low dose of ACEI; 200 mg TDD; 400 mg TDD; 20 mg TDD. McMurray et al. Eur J Heart Fail. 2013;15: ; McMurray et al. Eur J Heart Fail. 2014;16:817 25; McMurray et al. N EnglJ Med 2014;371 (11):

30 PARADIGM-HF: Key Inclusion Criteria Chronic HF NYHA FC II IV with LVEF 40%* BNP (or NT-proBNP) levels as follows: 150 (or 600 pg/ml), or 100 (or 400 pg/ml) and a hospitalization for HFrEF within the last 12 months 4 weeks stable treatment with an ACE inhibitor or an ARB #, and a β-blocker Aldosterone antagonist should be considered for all patients (with treatment with a stable dose for 4 weeks, if given) *The ejection fraction entry criteria was lowered to 35% in a protocol amendment #Dosage equivalent to enalapril 10 mg/day McMurray et al. Eur J Heart Fail. 2013;15:

31 PARADIGM-HF: Key exclusion criteria History of angioedema egfr <30 ml/min/1.73 m 2 at screening, end of enalapril run-in or randomization, or a >35% decrease in egfr between screening and end of enalapril run-in or between screening and randomization Serum potassium >5.2 mmol/l at screening OR >5.4 mmol/l at the end of the enalapril run-in or end of the LCZ696 run-in Requirement for treatment with both ACEI and ARBs Symptomatic hypotension, SBP <100 mmhg at screening, OR SBP <95 mmhg at end of enalapril run-in or at randomization Current acute decompensated HF History of severe pulmonary disease Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other major CV surgery, PCI, or carotid angioplasty within the 3 months prior to screening McMurray et al. Eur J Heart Fail. 2013;15:

32 PARADIGM-HF: Summary of Baseline Characteristics: 70% were NYHA Class II Sac/Val Enalapril Characteristic* (n=4187) (n=4212) Age, years 63.8 ± ± 11.3 Women, n (%) 879 (21.0) 953 (22.6) Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1) LV ejection fraction, % 29.6 ± ± MED/ENT/0149 NYHA functional class, n (%) II III 2998 (71.6) 969 (23.1) 2921 (69.3) 1049 (24.9) SBP, mmhg 122 ± ± 15 Heart rate, beats/min 72 ± ± 12 NT pro-bnp, pg/ml (IQR) 1631 ( ) 1594 ( ) BNP, pg/ml (IQR) 255 ( ) 251 ( ) History of diabetes, n (%) 1451 (34.7) 1456 (34.6) Treatments at randomization, n (%) Diuretics 3363 (80.3) 3375 (80.1) Digitalis 1223 (29.2) 1316 (31.2) β-blockers 3899 (93.1) 3912 (92.9 Mineralocorticoid antagonists 2271 (54.2) 2400 (57.0) ICD 623 (14.9) 620 (14.7) CRT 292 (7.0) 282 (6.7) *mean ± standard deviation, unless stated McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

Sacubitril/Valsartan Reduced Death from CV Causes or First Hospitalization for HF by 20% Compared to Enalapril 1.0 Cumulative probability 0.6 0.4 0.2 Enalapril Sacubitril/Valsartan Hazard ratio = 0.

at risk 4187 3922 3663 3018 2257 1544 896 249 Sacubitril/Valsartan 4212 3883 3579 2922 2123 1488 853 236 Enalapril Outcome, n % Sac/Val (n=4,187) Enalapril (n=4,212) Hazard ratio* (95% CI) p value

33 Sacubitril/Valsartan Reduced Death from CV Causes or First Hospitalization for HF by 20% Compared to Enalapril 1.0 Cumulative probability Enalapril Sacubitril/Valsartan Hazard ratio = 0.80 (95% CI: ) p<0.001 NNT to prevent one primary event: ,080 1,260 Days since randomization No. at risk Sacubitril/Valsartan Enalapril Outcome, n % Sac/Val (n=4,187) Enalapril (n=4,212) Hazard ratio* (95% CI) p value Death from CV causes or first hospitalization for worsening of HF 914 (21.8) 1,117 (26.5) 0.80 ( ) <0.001 Death from CV causes 558 (13.3) 693 (16.5) 0.80 ( ) <0.001 First hospitalization for worsening of HF 537 (12.8) 658 (15.6) 0.79 ( ) < MED/ENT/0149 McMurray et al. Eur J Heart Fail 2014;16:817 25

34 Cumulative probability Superiority of Sacubitril/Valsartan was Demonstrated in all Secondary Endpoints First hospitalization for HF Hazard ratio = 0.80 (95% CI: ) p< Death from CV causes Hazard ratio = 0.80 (95% CI: ) p<0.001 NNT: 32 Enalapril Sac/Val Death from any cause 1.5 Heart Failure Hospitalization within 30 days Cumulative probability Hazard ratio = 0.84 (95% CI: ) p< Hazard ratio = 0.60 (95% CI: ) p= Days since randomization Days since randomization 34 MED/ENT/0149 McMurray et al. Eur J Heart Fail 2014;16:817 25

35 Sacubitril/valsartan significantly reduced the number of sudden cardiac deaths compared with enalapril Cumulative probability of event Enalapril LCZ696 Hazard ratio = ) p=0.008 (95% CI: ,080 1,260 Days since randomization No. at risk LCZ696 4,187 3,891 2,478 1,005 Enalapril 4,212 3,860 2, Resuscitated sudden deaths* occurred in 16 patients receiving LCZ696 versus 28 patients receiving enalapril (HR 0.57, 95% CI: , p=0.07). Further, LCZ696 significantly reduced the risk of combined resuscitated and non-resuscitated sudden deaths by 22% when compared with enalapril (HR 0.78, 95% CI: , p=0.002) *Resuscitated sudden deaths were defined as successful resuscitation following cardiac arrest CI=confidence interval; HR=hazard ratio Desai et al. Eur Heart J 2015; epub ahead of print: DOI: /eurheartj/ehv186; Data on file. Clinical Study Protocol CLCZ696B MDL167E

36 Effect of Sacubitril/Valsartan in Secondary Endpoints Outcome Sac/Val (n=4187) Enalapril (n=4212) Hazard ratio* or difference (95% CI) p-value Death from any cause, n (%) 711 (17.0) ) 0.84 ( ) <0.001 Change in KCCQ clinical summary score at 8 months, mean ± SD ± ± ( ) New onset atrial fibrillation, n (%) 84 (3.1) 83 (3.1) 0.97 ( ) 0.83 Decline in renal function, n (%) 94 (2.2) 108 (2.6) 0.86 ( ) 0.28 *Calculated with the use of stratified cox proportional-hazard models Two-sided p-values calculated by means of a stratified log-rank test without adjustment for multiple comparisons KCCQ scores range from 0 to 100 higher scores indicate fewer symptoms and physical limitations associated with HF 2670 patients in the LCZ696 and 2638 in the enalapril group who did not have atrial fibrillation at randomization were evaluated Defined as: (a) 50% decline in egfr from randomization; (b) > 30 ml/min/1.73 m 2 decline in egfr from randomization or to a value of <60 ml/min/1.73 m 2, or (c) progression to end-stage renal disease 36 McMurray et al. Eur J Heart Fail 2014;16: MED/ENT/0149

37 Sacubitril/Valsartan Increase the Effect on CV Death of Current Standard of care (ACEis/ARBs) 0% Angiotensin receptor blocker1 ACE inhibitor Angiotensin neprilysin inhibition % Decrease in CV Mortality 10% 20% 30% 40% 15% 17% 20% Effect of ARB vs placebo derived from CHARM-Alternative trial Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial Effect of Sacubitril/Valsartan vs ACE inhibitor derived from PARADIGM-HF trial 37 MED/ENT/0149 McMurray et al. Eur Heart J 2015;36(7):

38 Fewer Patients in the Sacubitril/Valsartan Group Stopped Study Medication Because of an Adverse Events Event, n (%) Hypotension Sacubitril/ Valsartan (n=4,187) Enalapril (n=4,212) p value Symptomatic 588 (14.0) 388 (9.2) <0.001 Symptomatic with SBP <90 mmhg 112 (2.7) 59 (1.4) <0.001 Elevated serum creatinine 2.5 mg/dl 139 (3.3) 188 (4.5) mg/dl 63 (1.5) 83 (2.0) 0.10 Elevated serum potassium >5.5 mmol/l 674 (16.1) 727 (17.3) 0.15 >6.0 mmol/l 181 (4.3) 236 (5.6) Cough 474 (11.3) 601 (14.3) <0.001 Angioedema (adjudicated by a blinded expert committee) No treatment or use of antihistamines only 10 (0.2) 5 (0.1) 0.19 Catecholamines or glucocorticoids without hospitalization 6 (0.1) 4 (0.1) 0.52 Hospitalized without airway compromise 3 (0.1) 1 (<0.1) 0.31 Airway compromise 0 0 Fewer patients in the sacubitril/valsartan group than in the enalapril group stopped their study medication because of an Adverse Events (10.7 vs. 12.3%, p=0.03) 38 MED/ENT/0149 McMurray et al. N Engl J Med 2014;371:

Initiating and titrating Sacubitril/Valsartan to target dose Stop ACE inhibitor therapy for a 36-hour wash out Sacubitril/Valsartan must not be started until 36 hours have passed following

(Child-Pugh B) Patients with: Prior ACE inhibitor or ARB at guidelinesrecommended doses Sacubitipril/Valsartan should only be initiated in clinically stable patients whose baseline systolic blood

39 Initiating and titrating Sacubitril/Valsartan to target dose Stop ACE inhibitor therapy for a 36-hour wash out Sacubitril/Valsartan must not be started until 36 hours have passed following discontinuation of ACE inhibitor therapy Patients with: Prior ACE inhibitor or ARB at less than guidelines-recommended doses Risk for hypotension ( 75 years old, low SBP) Moderate hepatic impairment (Child-Pugh B) Patients with: Prior ACE inhibitor or ARB at guidelinesrecommended doses Sacubitipril/Valsartan should only be initiated in clinically stable patients whose baseline systolic blood pressure, serum potassium and renal function are at acceptable levels. If patients experience tolerability issues, e.g. symptomatic hypotension or hyperkalemia, consideration should be given to temporary down-titration or treatment interruption of Sacubitipril/Valsartan 39 MED/ENT/0149 Entresto TM Product Monograph

40 Conclusion PARADIGM-HF 40

41 Ivabradine 41

42 SHIFT-Trial B- Lancet Sep 11;376(9744):

43 SHIFT Trial: Design And Follow Up 7,411 screened 6,558 randomized 3,268 to ivabradine 3,290 to placebo Excluded: 27 Excluded: 26 3,241 analysed 2 lost to follow-up 3,264 analysed 1 lost to follow-up Median study duration: 22.9 months; maximum: 41.7 months Swedberg K, et al. SHIFT Investigators. Lancet. 2010;376(9744):

44 SHIFT Trial: Mean Heart Rate Reduction 90 HR = 0.82 ( ) p< Heart rate (bpm) Placebo Ivabradine Mean ivabradine dose: 6.4 mg bid at 1 month 6.5 mg bid at 1 year weeks Months Böhm M, et al. Lancet ;376(9744):

45 SHIFT Trial: Primary Endpoint CV Death Or Hospital Admission For Worsening CHF Cumulative frequency (%) HR = 0.82 ( ) p< Placebo Ivabradine 18% RRR Months Swedberg K, et al. SHIFT Investigators. Lancet. 2010;376(9744):

46 PARADIGM-HF: Primary Endpoint: Death From CV Causes Or First Hospitalization For HF Cumulative probability Hazard ratio = 0.80 (95% CI: ) p<0.001 NNT to prevent one primary event: 21 HR: 20% difference favoring sacubitril/valsartan 0.2 Enalapril 0 Sacubitril/Valsartan Days since randomization No. at risk Sacubitril/Valsartan Enalapril *The numbers of patients who would need to have been treated (NNT) to prevent one primary event was evaluated over the duration of the trial McMurray et al. N Engl J Med 2014;371 (11):

47 SHIFT Trial: Ivabradine Reduces The Risk Of Death For Heart Failure Patients with death from heart failure (%) 10 5 Heart rate 75 bpm n=4150 p<0.006 Placebo Ivabradine 39% Time (months) Böhm M et al. Clin Res Cardiol. 2012;102(1): Ivabradine or placebo is given on top of guideline-recommended therapy including ACE inhibitor, β-blocker, mineralocorticoid receptor antagonist

48 AE And Those Leading To Definitive Withdrawal Of Study Drug Ivabradine group (n=3232) Patients with an adverse event Placebo group (n=3260) p value Ivabradine group (n=3232) Patients with an adverse event leading to drug withdrawal Placebo group (n=3260) p value All 2439 (75%) 2423 (74%) (14%) 416 (13%) Heart failure 804 (25%) 937 (29%) (2%) 82 (3%) Symptomatic bradycardia 150 (5%) 32 (1%) < (1%) 5 (<1%) Asymptomatic bradycardia 184 (6%) 48 (1%) < (1%) 5 (<1%) < Atrial fibrillation 306 (9%) 251 (8%) (4%) 113 (3%) Phosphenes* 89 (3%) 17 (1%) < (<1%) 3 (<1%) Blurred vision 17 (1%) 7 (<1%) (<1%) 1 (<1%) Data are number of patients (%). Patients included in this safety analysis are those who had taken at least one dose of study drug. p values are calculated on the basis of number of patients. *Transient enhanced brightness in a restricted area of the visual field.

49 Conclusion SHIFT Trial findings should be interpreted as the effects of ivabradine in addition to normal clinical practice in the specific population of patients with heart failure and heart rates of 70 bpm or higher, who are unlikely to tolerate the highest dose of β blocker. Our results support the importance of heart-rate reduction with ivabradine for improvement of clinical outcomes in heart failure and confirm the important role of heart rate in the pathophysiology of heart failure Swedberg, Lancet Vol 376 September 11,

50 CCS HF Algorithm: Therapeutic Approach To Patients With CHF And Reduced Ejection Fraction Patient with LVEF <40% Diuretics to relieve congestion Titrated to minimum effective dose to maintain euvolemia NYHA I Continue triple therapy NYHA I or LVEF <35% Continue present management Triple Therapy ACEi (or ARB if ACEi intolerant), BB, MRA Titrate to target doses or maximum tolerated evidence-based dose Reassess Symptoms NYHA II-IV SR, HR 70 bpm* ADD Ivabradine and SWITCH ACEi or ARB to LCZ696 for eligible patients** Reassess Symptoms and LVEF NYHA I-III and LVEF 35% refer to ICD/CRT algorithm NYHA II-IV SR with HR 70 bpm or AF or pacemaker SWITCH ACEi or ARB to LCZ696 for eligible patients** NYHA IV Consider: Hydralazine/nitrates Referral for advanced HF therapy (mechanical circulatory support/transplant) Advance HF referral Non-pharmacologic therapies (teaching self care, exercise) Advance Care Plan and Documentation of Goals of Care Reassess every 1-3 years or with clinical status change Consider LVEF reassessment every 1-5 years Reassess as needed according to clinical status

51 Effectiveness Of Multidisciplinary Heart Failure Clinics HF clinics with greater frequency of visits (>4 contacts of significant duration for 6 months) were associated with lower mortality (hazard ratio, 0.14; p<0.0001) and hospitalization (hazard ratio, 0.69; p=0.039) More intensive medication management was associated with lower all-cause (hazard ratio, 0.46; p<0.001) and HF readmission (hazard ratio, 0.42; p<0.001). Wijeysundera HC, et al. Circ Heart Fail. 2013;6(1):68-75.

52 CCS HF Algorithm Recommended Initial Referral And Wait Time Routine, Elective Referral Chronic HF disease management NYHA II NYHA I minimal or no symptoms See within 12 weeks, ideally within 6 Initial Referral Situational wait time benchmarks Initial Referral Urgency Semi-Urgent, Intermediate Risk New diagnosis of HF, stable, compensated NYHA II/III Worsening HF on therapy Mild symptoms with valvular or renal disease or hypotension Urgent New diagnosis of HF, not improving on therapy (unstable, decompensated) Progression to NYHA IV HF Post-hospitalization or ER visit for HF Severe HF with valvular or renal disease or hypotension Post myocardial infarction HF Emergent Acute severe myocarditis Rapidly progressive heart failure/cardiogenic shock Heart failure with ACS or MI Transplant and device evaluation of unstable patients New-onset acute pulmonary edema See within 4 weeks, ideally within 2 See within 4 weeks, ideally within 2 See within 24 hours Heart Failure Care Howlett JG et al. The Canadian Cardiovascular Society Heart Failure Companion: Bridging Guidelines to Your Practice. CJC 2015;1-15.

53 CCS HF Algorithm Recommended Follow-up Frequency Follow-up Frequency* High Risk Individual NYHA IIIb or IV symptoms Recent HF hospitalization During titration of HF medications New onset heart failure Complications of HF therapy (rising creatinine, hypotension) Need to down-titrate or discontinue beta-blockers or ACEi/ARB Severe concomitant and active illness (e.g. COPD, frailty) Frequent ICD firings (1 month) Intermediate Risk Individual No clear features of high or low risk. Low Risk Individual NYHA I or II No hospitalization in past year No recent changes in medications Receiving optimal medical/device HF therapies Follow-up every 1-4 weeks or as clinically indicated (remote monitoring possible for some titrations) Follow-up every 1-6 months Follow-up every 6-12 months Heart Failure Care Make inactive or consider for discharge from HF clinic if a minimum of 2 of the following characteristics are present: Stable NYHA I or II for 6-12 months On optimal therapies Reversible causes of HF fully controlled Having access to General Practitioner with expertise in management of HF Stable adherence to optimal HF therapy No hospitalization for >1 year LVEF >35% (consistently shown if more than one recent EF measurement) Primary care provider has access to urgent specialists reassessment *Visit frequency may increase during medication titration Howlett JG et al. The Canadian Cardiovascular Society Heart Failure Companion: Bridging Guidelines to Your Practice. CJC 2015;1-15.

54 Heart Failure Patient Stratification And Care Provision Level of Care Patient Status Care Provision Primary care (Level 1) Intermediate care (Level 2) Specialist support (Level 3) Less complexity NYHA I-II Intermediate complexity NYHA II-III Unable to stabilize at Level 1 High complexity NYHA III-IV Unable to stabilize at Level 2 Optimal prescription of pharmacological and nonpharmacological therapy, patient and caregiver self-care education and support. Consultation by Level 2 HF team. Patient stabilization, review of therapies and recommendations for changes. Discharge back to Level 1 when stable. Consultation with and involvement of Level 3 specialized HF team until patient stabilizes sufficiently for transfer to Level 2 care. 54 MED/ENT/0149 Brand C, et al. Intern Med J 2007; 37(9):

55 What is the role of the primary care physician in HF management? 55

56 Primary care physician s Role in the management of HFrEF patients Prevalence of patients with HFrEF is rising as population is aging In many regions of Canada, about 50% of HF patients are being followed by GPs/FPs 1 Even patients with mild symptoms have a high risk of heart failure hospitalization and cardiovascular death NYHA Class II patients are mainly followed and treated by FPs Sacubiril/valsartan was shown to be superior to ACEi in Class II patients (70% of PARADIGM-HF trial population) on CV mortality and HF hospitalization Asking the right questions for a better diagnostic of disease progression Co-management (family practitioners & specialists) of patients with HFrEF has been demonstrated to be the most efficient approach to manage this disease FPs are the ones who follow most of the HF patients Early identification of signs and symptoms of the patients Identify early signs and adjust medication before patients decompensate MED/ENT/ Tu K et al. Can J Cardiol. 2004; 20:282-91

57 Model For Future Disease Management Of HF From this To this! Heart Failure Clinic Heart Failure Clinic Patient with Heart Failure Other Care Provider HF Patient Family and community Primary Care Provider Primary Care Provider

58 Summary Heart Failure: 50% of patients will die within 5 years 1 The leading cause of hospitalization for patients >65 years of age Approx. 50% of patients with HFrEF are seeing by GPs/FPs in Canada 2 HF burden on patients, families and society 1.4 million hospital days per year The Estimated direct cost of heart Failure in Canada in 2012 was $2.9 billions New therapies are available to decrease risk of CV death and heart failure hospitalization in heart failure patients with reduced EF: Sacubitril/Valsartan Ivabradine The role of GPs/FPs in HFrEF patients treatment optimization is critical: Asking the right questions Increase survival Reduce hospitalization 58 MED/ENT/ Roger VL et al. JAMA 2004;292: Tu K et al. Can J Cardiol. 2004; 20: McMurray et al. N Engl J Med 2014;371: Packer et al. Circulation 2014

59 Summary Heart failure is on the rise and a growing burden to our society and our health care resources Evidence-based medical therapy can improve quality of life, morbidity and mortality in our patients Access to care and optimization of therapy is essential to improve the future of heart failure 59

Sacubitril/Valsartan in HFrEF for All Protagonist View George Honos MD FRCPC FCCS FACC

Sacubitril/Valsartan in HFrEF for All Protagonist View George Honos MD FRCPC FCCS FACC Head of Cardiology Medical Manager / CV Program CHUM Disclosure Statement Within the past two years: I have had an