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

2. 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 CMAJ Oct 2;184(14):E
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 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:
1. Yeung et al., CMAJ 2012: 184 (14): E / 2. Bhatia RS, et al. N Engl J Med. 2006;355(3): / 3. Jong P, et al. Circulation. 2003;108:

3. 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

4. Vicious Cycle of Congestion in Acute HF

5. Initial Management of a Patient With Acute HF

6. Patient With Acute HF

7. Goals of Treatment in Acute HF

8. After Initial Stabilization…What’s Next?

9. Neurohormonal Activation And Rationale For Standard Medical Therapy For Systolic HF

10. 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

11. 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

12. 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

13. 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

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

15. 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
1. McMurray et al. N Engl J Med 2014;371 (11):993–1004;

16. ESC Guidelines for HF: Patient With HFrEF

17. ESC Guidelines: Definition of the Type of HF

18. 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 Jul 20;355(3):260-9.
Bhatia S, Liu P, et al., N Engl J Med 2006; 355:260-9

19. How Do We Better Optimize Treatment?

20. 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.

21. 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) Jan-Feb;28(1): doi: /hlthaff
* p=0.06
** p=0.05
*** p<0.001
Sochalski J, et al. Health Aff (Millwood) Jan-Feb;28(1):

22. Conclusions

23. Abbreviations

24. Abbreviations (cont)

25. Abbreviations (cont)