1. To know more visit HeartFailure.com © 2016 Novartis Pharma AG, July 2016, GLCM/HTF/0028c HEART FAILURE DISEASE MANAGEMENT STANDARDS

2. Current standards in disease management What is heart failure and what are the treatment guidelines? ​ How is heart failure defined? According to European Society of Cardiology (ESC) guidelines, “HF is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and peripheral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.” 1 DEFINITIONS OF HFrEF, HFmrEF AND HFpEF 1 Type of HFHFrEFHFmrEFHFpEF CRITERIA 1 Symptoms  signs a 2LVEF <40%LVEF 40% to 49% LVEF  50% 3– 1.Elevated levels of natriuretic peptides b ; 2.At least one additional criterion: a. relevant structural heat disease (LVH and/or LAE), b. diastolic dysfunction 1.Elevated levels of natriuretic peptides b ; 2.At least one additional criterion: a. relevant structural heat disease (LVH and/or LAE), b. diastolic dysfunction a. Signs may not be present in the early stages of HF (especially in HFpEF) and in patients treated with diuretics. b. BNP >35 pg/mL and/or NT-proBNP >125 pg/mL. Adapted from Ponikowski P, et al. Eur Heart J. 2016 [Epub ahead of print] ESC = European Society of Cardiology; EF = ejection fraction; HFrEF = heart failure with reduced ejection fraction; HFmrEF = heart failure with mid-range ejection fraction; HFpEF = heart failure with preserved ejection fraction; LAE = left atrial enlargement; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; NT-proBNP = N-terminal pro-B type natriuretic peptide. 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 [Epub ahead of print]. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 3. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4-25.

3. Current standards in disease management What is heart failure and what are the treatment guidelines? ​ NEW YORK HEART ASSOCIATION (NYHA) CLASSES 1 NYHA class INYHA class IINYHA class IIINYHA class IV No limitation on physical activity No overt symptoms Slight limitation on physical activity Comfortable at rest, but ordinary physical activity causes symptoms of heart failure Marked limitation on physical activity Comfortable at rest, but less than ordinary activity causes symptoms of heart failure Inability to carry on any activity without symptoms Presence of symptoms even at rest Adapted from Ponikowski P, et al. Eur Heart J. 2016 [Epub ahead of print] NYHA= New York Heart Association. 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 [Epub ahead of print]. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 3. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4-25. NYHA classification is important for evaluating patient symptoms The New York Heart Association (NYHA) functional classification is widely used and accepted based on exercise capacity and symptoms of the disease. 1

4. Current standards in disease management What is heart failure and what are the treatment guidelines? ​ Recommended guidelines for care 1 The overall goals for chronic heart failure management, including patients with established HFrEF, “are to improve their clinical status, functional capacity and quality of life, prevent hospital admission and reduce mortality.” Recent studies have shown that including a focus on reducing hospitalisations can be highly important to patients and health care systems Treatment effectiveness at slowing or preventing progressive worsening of disease can be determined by reductions in the rates of both hospital admissions and mortality. 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 [Epub ahead of print]. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 3. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4-25. Green indicates a class I recommendation; yellow indicates a class IIa recommendation. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BNP = B-type natriuretic peptide; CRT = cardiac resynchronization therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; H-ISDN = hydralazine and isosorbide dinitrate; HR = heart rate; ICD = implantable cardioverter defibrillator; LBBB = left bundle branch block; LVAD = left ventricular assist device; LVEF = left ventricular ejection fraction; MR = mineralocorticoid receptor; NT- proBNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association; OMT = optimal medical therapy; VF = ventricular fibrillation; VT = ventricular tachycardia. a. Symptomatic = NYHA Class II–IV; b. HFrEF = LVEF 250 pg/mL or NTproBNP > 500 pg/mL in men and 750 pg/mL in women); f. With an elevated plasma natriuretic peptide level (BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization within recent 12 months plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL); g. In doses equivalent to enalapril 10 mg b.i.d; h. With a hospital admission for HF within the previous year; i. CRT is recommended if QRS ≥ 130 msec and LBBB (in sinus rhythm); j. CRT should/may be considered if QRS ≥ 130 msec with non-LBBB (in a sinus rhythm) or for patients in AF provided a strategy to ensure bi-ventricular capture in place (individualized decision). © European Society of Cardiology 2016 - All Rights Reserved

5. Current standards in disease management What is heart failure and what are the treatment guidelines? ​ Recommended treatment guidelines in patients with symptomatic (NYHA class II–IV) HFrEF a. Class of recommendation; b. Level of evidence; c. Or ARB, if ACEI is not tolerated/contraindicated Adapted from Ponikowski P, et al. Eur Heart J. 2016 [Epub ahead of print] ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; MRA = mineralocorticoid receptor *Level of evidence A represents data derived from multiple randomised clinical trials or meta-analyses. Level of evidence B however, includes data derived from a single randomised clinical trial or large non-randomised studies. Consensus of opinion of the experts and/or small studies, retrospective studies, and registries, are classified under level of evidence C. 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 [Epub ahead of print]. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 3. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4-25. PHARMACOLOGICAL TREATMENTS INDICATED IN POTENTIALLY ALL PATIENTS WITH SYMPTOMATIC (NYHA FUNCTIONAL CLASS II–IV) HFrEF* RecommendationsClass a Level b An ACEI c is recommended, in addition to a beta-blocker, for symptomatic patients with HFrEF to reduce the risk of HF hospitalisation and death IA A beta-blocker is recommended, in addition to an ACEI c for patients with stable, symptomatic HFrEF to reduce the risk of HF hospitalisation and death IA An MRA is recommended for patients with HFrEF, who remain symptomatic despite treatment with an ACEI c and a beta-blocker, to reduce the risk of HF hospitalisation and death IA

6. Current standards in disease management What is heart failure and what are the treatment guidelines? ​ Other recommended treatment guidelines in patients with symptomatic (NYHA class II–IV) HFrEF OTHER PHARMACOLOGICAL TREATMENTS RECOMMENDED IN SELECTED PATIENTS WITH SYMPTOMATIC (NYHA FUNCTIONAL CLASS II–IV) HFrEF* RecommendationsClass a Level b Diuretics Diuretics are recommended in order to improve symptoms and exercise capacity in patients with signs and/or symptoms of congestion IB Diuretics should be considered to reduce the risk of HF hospitalisation in patients with signs and/or symptoms of congestionIIaB ARNI Sacubitril/valsartan is recommended as a replacement for an ACEI to further reduce the risk of HF hospitalisation and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACEI, a beta-blocker and an MRA c IB If-channel inhibitor Ivabradine should be considered to reduce the risk of HF hospitalisation and cardiovascular death in symptomatic patients with LVEF ≤35%, in sinus rhythm and a resting heart rate ≥70 bpm despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACEI (or ARB), and an MRA (or ARB) IIaB Ivabradine should be considered to reduce the risk of HF hospitalisation and cardiovascular death in symptomatic patients with LVEF ≤35%, in sinus rhythm and a resting heart rate ≥70 bpm who are unable to tolerate or have contra-indications for a beta-blocker. Patients should also receive an ACEI (or ARB) and an MRA (or ARB) IIaC a. Class of recommendation; b. Level of evidence; c. Patient should have elevated natriuretic peptides (plasma BNP ≥ 150 pg/mL or plasma NT-proBNP ≥ 600 pg/mL, or if HF hospitalization within the last 12 months, plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL) and able to tolerate enalapril 10 mg b.i.d. Adapted from Ponikowski P, et al. Eur Heart J. 2016 [Epub ahead of print] ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BNP = B-type natriuretic peptide; bpm = beats per minute; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = N-terminal pro-B type natriuretic peptide; NYHA = New York Heart Association. *Level of evidence A represents data derived from multiple randomised clinical trials or meta-analyses. Level of evidence B however, includes data derived from a single randomised clinical trial or large non- randomised studies. Consensus of opinion of the experts and/or small studies, retrospective studies, and registries, are classified under level of evidence C. 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 [Epub ahead of print]. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 3. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4-25.

7. Current standards in disease management What is heart failure and what are the treatment guidelines? ​ Other recommended treatment guidelines in patients with symptomatic (NYHA class II–IV) HFrEF (cont’d) OTHER PHARMACOLOGICAL TREATMENTS RECOMMENDED IN SELECTED PATIENTS WITH SYMPTOMATIC (NYHA FUNCTIONAL CLASS II–IV) HFrEF* RecommendationsClass a Level b ARB An ARB is recommended to reduce the risk of HF hospitalisation and cardiovascular death in symptomatic patients unable to tolerate an ACEI (patients should also receive a beta-blocker and an MRA) IB An ARB may be considered to reduce the risk of HF hospitalisation and death in patients who are symptomatic despite treatment with a beta-blocker who are unable to tolerate an MRA IIbC Hydralazine and isosorbide dinitrate Hydrazine and isosorbide dinitrate should be considered in self-identified black patients with LVEF <35% or with an LVEF <45% combined with a dilated LV in NYHA Class III–IV despite treatment with an ACEI, a beta-blocker and an MRA to reduce the risk of HF hospitalisation and death IIaB Hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who can tolerate neither an ACEI nor an ARB (or they are contra-indicated) to reduce the risk of death IIbB a. Class of recommendation; b. Level of evidence. Adapted from Ponikowski P, et al. Eur Heart J. 2016 [Epub ahead of print] ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association. *Level of evidence A represents data derived from multiple randomised clinical trials or meta-analyses. Level of evidence B however, includes data derived from a single randomised clinical trial or large non-randomised studies. Consensus of opinion of the experts and/or small studies, retrospective studies, and registries, are classified under level of evidence C. 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 [Epub ahead of print]. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 3. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4-25.

8. Current standards in disease management What is heart failure and what are the treatment guidelines? ​ Benefits of a multidisciplinary approach to care During the management of heart failure, it is imperative to provide a system of care that ensures optimal management of every patient. Thus, a multifaceted approach to care – focused on holistic management, including exercise training and multidisciplinary management programmes, patient monitoring, and palliative care – can play an important role in the lives of heart failure patients. 1 Despite these treatment strategies, the survival rate for heart failure patients across the globe is poor. Continuing research and new pharmacological treatments are essential to addressing unmet needs in caring for patients with heart failure. 2,3 For further information regarding the quality of care measures recommended by ESC, please click here.click here 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 [Epub ahead of print]. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 3. Ponikowski P, Anker SD, AlHabib KF, et al. Heart failure: preventing disease and death worldwide. ESC Heart Failure. 2014;1(1):4-25.