HEART FAILURE: NEW HORIZONS IN CLINICAL PRACTICE Hussein Fadlallah MD, MSc, FRCPc Cardiologist, Interventional Cardiology Assistant professor of medicine University of Montreal

HF: The Fastest Rising Cardiovascular Condition In Canada Depending on the severity of symptoms, heart dysfunction, age and other factors, HF can be associated with an annual mortality of between 5% and 50%1-3 Up to 40% to 50% of people with congestive heart failure die within five years of diagnosis References: Yeung DF, Boom NK, Guo H, et al. Trends in the incidence and outcomes of heart failure in Ontario, Canada: 1997 to 2007. CMAJ. 2012 Oct 2;184(14):E765-73. Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006 Jul 20;355(3):260-9. Jong P, Gong Y, Liu PP, et al. Care and outcomes of patients newly hospitalized for heart failure in the community treated by cardiologists compared with other specialists. Circulation. 2003;108:184-191. 1. Yeung et al., CMAJ 2012: 184 (14): E765-773 / 2. Bhatia RS, et al. N Engl J Med. 2006;355(3):260-9. / 3. Jong P, et al. Circulation. 2003;108:184-191.

Current Challenges Associated With HF Care In Canada HF cannot be “cured” by relieving symptoms Often progresses without signs or symptoms Clinical focus has been to control symptoms Patients discharged are often unprepared and unsupported Patients unable to self-manage – information overload Frequent returns to emergency 30-day readmission rates are high

Vicious Cycle of Congestion in Acute HF

Initial Management of a Patient With Acute HF

Patient With Acute HF

Goals of Treatment in Acute HF

After Initial Stabilization…What’s Next?

Neurohormonal Activation And Rationale For Standard Medical Therapy For Systolic HF

HF SYMPTOMS & PROGRESSION Decline In Systolic Function Leads To Activation Of Three Major Neurohormonal Systems Sympathetic nervous system Epinephrine Norepinephrine α1, β1, β2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility Natriuretic peptide system Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy NPRs NPs HF SYMPTOMS & PROGRESSION Renin angiotensin aldosterone system Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis Ang II AT1R Ang=angiotensin; AT1R=angiotensin II type 1 receptor; HF=heart failure; NPs=natriuretic peptides; NPRs=natriuretic peptide receptors; RAAS=renin-angiotensin-aldosterone system Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte. Cardiovascular Pathology 2012;365–371; Schrier & Abraham. N Engl J Med 2009;341:577–85

Sustained Activation Of The RAAS Has A Detrimental Effect In HF Cardiac dysfunction leads to RAAS activation… …sustained activation puts further strain on the weakened heart, creating a vicious cycle RAAS suppression as an effective strategy in treating HF Hypertrophy Fibrosis Cardiac remodeling Myocyte necrosis Heart rate Contractility ACEIs Sympathetic tone ACE Sodium and water retention Blood volume ACEIs ARBs MRAs Angiotensinogen Ang I Ang II Aldosterone Adrenal gland Direct renin inhibitors* Renin Vasoconstriction Hypertrophy Blood pressure ADH secretion Pituitary gland Water absorption Blood volume *Studies ongoing; not approved for treatment of HF ACE=angiotensin-converting enzyme; ACEI=angiotensin-converting-enzyme inhibitor; ADH=antidiuretic hormone; ARB=angiotensin receptor blocker; Ang=angiotensin; HF=heart failure; MRA=mineralocorticoid receptor antagonist; RAAS=renin-angiotensin-aldosterone system Zaman et al. Nat Rev Drug Discov 2002;1:621–36; Schrier, Abraham. N Engl J Med 1999;341:577–85; Brewster et al. Am J Med Sci 2003;326:15–24; Schmeider. Am J Hypertens 2005;18:720–30; McMurray et al. Eur Heart J 2012;33:1787–847

The Cardiovascular And Renal Effects Of The NP System Oppose Those Of The RAAS Signalling cascades GTP cGMP Internalization Inactive peptides Receptor recycling Inactive NP fragments Ang II AT1 receptor NPR-C ANP/CNP/BNP NPR-B CNP NPR-A ANP BNP Neprilysin ANP CNP Gene expression; protein synthesis; cell proliferation Vasodilation Cardiac fibrosis/hypertrophy Natriuresis/diuresis Vasoconstriction Cardiac fibrosis/hypertrophy Sodium/water retention ANP=atrial natriuretic peptide; Ang=angiotensin; AT1 = angiotensin II type 1; BNP=B-type natriuretic peptide; cGMP=cyclic guanosine monophosphate; CNP=C-type natriuretic peptide; GTP=guanosine triphosphate; NP=natriuretic peptide; NPR=natriuretic peptide receptor; RAAS=renin-angiotensin-aldosterone system Levin et al. N Engl J Med 1998;339;321–8; Gardner et al. Hypertension 2007;49:419–26; Molkentin. J Clin Invest 2003;111:1275–77; Nishikimi et al. Cardiovasc Res 2006;69:318–28; Guo et al. Cell Res 2001;11:165–80; Von Lueder et al. Circ Heart Fail 2013;6:594–605; Yin et al. Int J Biochem Cell 2003;35:780–3; Mehta and Griendling. Am J Physiol Cell Physiol 2007;292:C82–97

Simultaneous Inhibition Of Neprilysin And Suppression Of The RAAS With LCZ696 (ENTRESTO) Has Complementary Effects LCZ696 Enhancing cGMP-mediated effects of natriuretic peptides Vasodilation Natriuretic and diuretic effects Proliferation Hypertrophy SNS outflow/sympathetic tone Aldosterone secretion Detrimental effects of vascular remodeling Suppressing RAAS-mediated effects Vasoconstriction Sodium and water retention Ventricular hypertrophy/remodeling Aldosterone secretion Cardiac fibrosis Sympathetic tone Systemic vascular resistance Wrap-up slides where the dual role of LCZ696 in promoting beneficial NPs and stopping deleterial RAAS overactivation can be described. LCZ696 simultaneously inhibits neprilysin and the renin-angiotensin-aldosterone system (RAAS): Inhibition of neprilysin, the enzyme responsible for the breakdown of natriuretic peptides (NPs), leads to increased levels of NPs, which mediate their effects via cyclic guanosine monophosphate. Suppression of RAAS by the valsartan moiety complements the physiological effects of the natriuretic peptide system. Key message: With its unique dual inhibition role, LCZ696 will favour beneficial NPs effects and will suppress RAAS deleterious effects. cGMP=cyclic guanosine monophosphate; RAAS=renin-angiotensin-aldosterone system; SNS=sympathetic nervous system Levin et al. N Engl J Med 1998;339:321–8 Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42 Schrier & Abraham. N Engl J Med 2009;341:577–85 Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131–9

PARADIGM-HF Primary Results: Significant Reduction in Primary Endpoints, CV Death, and All-Cause Mortality

PARADIGM-HF: Conclusions LCZ696 was more effective than enalapril in: Reducing the risk of CV death and HF hospitalization Reducing the risk of CV death Reducing the risk of HF hospitalization Reducing all-cause mortality Incrementally improving symptoms and physical limitations LCZ696 was better tolerated than enalapril: Less likely to cause cough, hyperkalemia or renal impairment Less likely to be discontinued due to an adverse event More hypotension, but no increased discontinuations Not more likely to cause serious angioedema Interpretation The effect of LCZ696 to stabilize the course of heart failure is likely to have important ramifications for both quality of life and resource utilization in this disorder Abbreviations BNP=B-type natriuretic peptide; cGMP=cyclic guanosine monophosphate; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure; NT-proBNP=N-terminal pro-B-type natriuretic peptide; NYHA=New York Heart Association References 1. McMurray et al. N Engl J Med 2014;371:993–1004 2. Packer et al. Circulation 2014; epub ahead of print: DOI:0.1161/CIRCULATIONAHA.114.013748 1. McMurray et al. N Engl J Med 2014;371 (11):993–1004;

ESC Guidelines for HF: Patient With HFrEF

ESC Guidelines: Definition of the Type of HF

Reduced EF: Different Diseases With The Same Prognosis? 100 95 90 85 80 75 70 50 150 200 250 300 350 400 Survival (%) Days Preserved ejection fraction Reduced ejection fraction Adjusted Survival Curves for Patients with Heart Failure with Reduced or Preserved Ejection Fraction during the Year after the First Hospital Admission. HTN DM Preserved EF or Diast HF Reduced EF or Syst HF The importance of heart failure with preserved ejection fraction is increasingly recognized. This study evaluated the epidemiologic features and outcomes of patients who had heart failure with preserved ejection fraction and compared the findings with those from patients who had heart failure with reduced ejection fraction. From April 1, 1999 through March 31, 2001, we studied 2802 patients admitted to 103 hospitals in the province of Ontario, Canada, with a discharge diagnosis of heart failure whose ejection fraction had also been assessed. The patients were categorized into three groups: those with an ejection fraction of less than 40 percent (heart failure with reduced ejection fraction), those with an ejection fraction of 40 to 50 percent (heart failure with borderline ejection fraction) and those with an ejection fraction of more than 50 percent (heart failure with preserved ejection fraction). Two groups were studied in detail: those with an ejection fraction of less than 40 percent and those with an ejection fraction of more than 50 percent. The main outcome measures were death within one year and readmission to the hospital for heart failure. RESULTS: Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P=0.08) and at 1 year (22 percent vs. 26 percent, P=0.07). The adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P=0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups. CONCLUSIONS: Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction Reference: Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006 Jul 20;355(3):260-9. Bhatia S, Liu P, et al., N Engl J Med 2006; 355:260-9

How Do We Better Optimize Treatment?

Multidisciplinary Approach To HF Management Patient Cardiologists Caregivers Nurses Primary care physicians Pharmacists Internists Dieticians Other specialists Physio- therapists Psychological support Heart failure is a complex condition to manage, placing significant demands on: Patients Their families and caregivers Health care system HCP who provide their care HF patients often need frequent follow up (every 2-4 weeks), especially if the condition is more severe and accompanied with comorbidities. HF management has been a target of organizational and quality improvement interventions aimed at: Increasing adherence to evidence-based guidelines Improving patient outcomes Increasing the efficiency of care delivery. As a result, there is clear evidence available on how to optimally manage HF from a clinical and organizational standpoint.

Team Approaches And In-Person Communication Reduce HF Readmissions -0.4 -1.8** Hospital readmissions per month Hospital readmissions days per month -2.9** -1.5 -4.3* -6.4*** Single heart failure expert and telephone communication Single heart failure expert and in-person communication Team and in-person communication Reference: Sochalski J, Jaarsma T, Krumholz HM, et al. What works in chronic care management: the case of heart failure. Health Aff (Millwood). 2009 Jan-Feb;28(1):179-89. doi: 10.1377/hlthaff.28.1.179. * p=0.06 ** p=0.05 *** p<0.001 Sochalski J, et al. Health Aff (Millwood). 2009 Jan-Feb;28(1):179-189.

Conclusions

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