The burden Of heart failure © 2015 Novartis Pharma AG, May 2015, GLCM/HTF/0027a

Heart Failure is a complex syndrome involving multiple organ systems and is associated with a high mortality and morbidity burden Heart failure (HF) is a chronic condition, punctuated by acute episodes Each acute event results in further organ damage: myocardial and renal damage occurring during such episodes may contribute to progressive left ventricular and/or renal dysfunction Increasing frequency of acute events with disease progression leads to higher rates of hospitalization and increased risk of mortality Chronic decline Cardiac function and quality of life Hospitalisations for acute decompensation episodes Disease progression Adapted from Gheorghiade et al. Am J Cardiol 2005;96:11–17; Gheorghiade and Pang. J Am Coll Cardiol 2009;53:557–73

Heart failure is a major and growing public health problem Prevalence1 Incidence2–4 new cases per 100,000 per year Growth5 2% 219 HF Prevalence of the population in Europe have HF1 130 70‡ Increasing prevalence of risk factors5,6 Aging population5 Improved post-MI survival5 As many as 1 in 5 people aged 70–80 years have HF1 MI=myocardial infarction; ‡Calculated using the incidence rate of HF in 1997 for the population in Hong Kong and applying it to the Chinese population 1. Dickstein et al. Eur Heart J 2008;29:2388–442; 2. Go et al. Circulation 2013;127:e6–e245; 3. Allender et al. Coronary Heart Disease Statistics 2008; 4. Hung et al. Hong Kong Med J 2000;6:159–62; 5. Hunt et al. J Am Coll Cardiol 2009;53:e1–90; 6. Kearney et al. Lancet 2005; 365:217–23

Morbidity and mortality in Heart failure HF is associated with significant mortality 30 days 1 year 5 years Hospital post-diagnosis 4-7% in-hospital mortality rate‡1–3 ~10% mortality after 30 days†4 ~20% mortality after 1 year‡5 Up to 50% mortality after 5 years§6-8 HF=heart failure ‡Data from European patients hospitalized for heart failure in the European Society of Cardiology Heart Failure (ESC-HF) Pilot study and EuroHeart Failure Survey (EHFS) II †Analysis of HF data from 1,282 incident cases of HF in the Atherosclerosis Risk in Communities (ARIC) population-based study of n=15,792 individuals from four communities in the USA (1987–2002) §Reported rates vary but some publications include rates up to 50%68 1.Maggioni et al. Eur J Heart Fail 2010;12:1076–84; 2. Nieminen et al. Eur Heart J 2006;27:2725–36; 3. Cleland et al. Eur Heart J 2003;24:442–636; 4. Loehr et al. Am J Cardiol 2008;101:1016–22; 5. Maggioni et al. Eur J Heart Fail 2013;15:808–17; 6. Roger et al. JAMA 2004;292:344–50; 7. Levy et al. N Engl J Med 2002;347:1397–402; 8. Askoxylakis et al. BMC Cancer 2010;10:105

Morbidity and mortality in Heart failure HF with reduced EF and HF with preserved EF are associated with high levels of morbidity and mortality HF with reduced EF and HF with preserved EF are associated with high levels of mortality1 The prognosis for patients with chronic HF and preserved EF is substantially worse than that for patients with other conditions that increase CV risk‡2 40 HFrEF 30 Mortality (%) 20 HFpEF No therapies are proven to reduce morbidity and mortality in chronic HF with preserved EF3 10 1 2 3 Years ‡Based on data comparing mortality and HF hospitalization rates from clinical trials in patients with HFpEF (n=3 trials) with similar data from clinical trials in patients of without HF but who were of a similar age, comorbidity profile and had other conditions that increase CV risk (stable angina pectoris [n=1 trial], diabetes [n=1 trial] or hypertension [n=5 trials]) CV=cardiovascular; EF=ejection fraction; HF=heart failure; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction; LVEF=left ventricular ejection fraction 1.Meta-Analysis Global Group In Chronic heart failure (MAGGIC). Eur Heart J 2012;33:1750–7; 2. Campbell et al. J Am Coll Cardiol 2012;60:2349–56; 3. McMurray et al. Eur Heart J 2012;33:1787–847

Heart failure has a significant impact on quality of life Quality of life among patients with HF compared with the general population and other chronic conditions* General population General population aged 65-74 CARE-HF (Chronic heart failure) Type II diabetes Moderate motor neurone disease Parkinson's disease Non-small cell lung cancer 0.0 0.2 0.4 0.6 0.8 1.0 EQ-5Dindex score *Data from patients receiving optimal medical therapy with chronic heart failure due to left ventricular systolic dysfunction and dysynchrony enrolled in the CARE-HF trial EQ-5D™ is a standardized instrument for use as a measure of health outcome, providing a simple descriptive profile and a single index value for health status Reprinted from the European Journal of Heart Failure, 7(2), Calvert MJ, et al. The impact of chronic heart failure on health-related quality of life data acquired in the baseline phase of the CARE-HF study, 243–51, Published on behalf of the European Society of Cardiology. All rights reserved, Copyright (2005) the authors, with permission of John Wiley & Sons, Inc. CARE-HF=CArdiac REsynchronisation in Heart Failure; HF=heart failure Calvert et al. Eur J Heart Fail 2005;7:243–51

Heart failure imposes a significant economic burden on the healthcare system 70% of the cost of HF is due to hospitalizations1 ~2% of the total healthcare budget in many countries is spent on the treatment of HF1 ~10% of the cost of HF is due to pharmacological treatment2 Due to an ageing population, the total cost of HF in the USA alone is expected to increase ~127% 2030 by ‡3 ‡USA estimate includes direct costs (total annual medical spending) and indirect costs (lost productivity due to morbidity and mortality) 1. Dickstein et al. Eur Heart J 2008;29:2388–442; 2. Hunt et al. J Am Coll Cardiol 2009;53:e1–90; 3. Heidenreich et al. Circulation 2013 [epub ahead of print]

Unmet therapeutic need in acute Heart failure: Many patients are discharged with unresolved congestion, which is associated with poor long-term outcomes Persistent congestion after hospitalization for HF predicts poor survival‡2 Number of signs of congestion after discharge from hospital‡ 2-year mortality rate 24% 13% 1–2 33% of patients hospitalized for HF in Europe have signs of congestion at discharge1 3–5 59% ‡Patients with New York Heart Association class IV heart failure (HF; n=146) were re-assessed for signs of congestion 4–6 weeks after discharge. Criteria for congestion were orthopnea, raised jugular venous pressure, the need to increase the dose of diuretic during the past week, attending staff assessment of weight, and peripheral edema 1. Maggioni et al. Eur J Heart Fail 2010;12:1076–84; 2. Lucas et al. Am Heart J 2000;140:840–7

Unmet therapeutic need in chronic Heart failure HFrEF mortality remains high despite the introduction of new therapies that improve survival HFrEF survival rates have improved over time with the introduction of new therapies ACEI* ARB* β-blocker* MRA* 16% 17% Reduction in relative risk of mortality vs placebo 4.5% ARR; mean follow up of 41.4 months SOLVD1 3.0% ARR; median follow-up of 33.7 months CHARM-Alternative2 30% 34% 11.0% ARR; mean follow up of 24 months RALES4 5.5% ARR; mean follow up of 1.3 years CIBIS-II3 However, significant mortality remains5 *On top of standard therapy at the time of study (except in CHARM-Alternative where background ACEI therapy was excluded). Patient populations varied between trials and as such relative risk reductions cannot be directly compared. SOLVD (Studies of Left Ventricular Dysfunction), CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and RALES (Randomized Aldactone Evaluation Study) enrolled chronic HF patients with LVEF≤35%. CHARM-Alternative (Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity) enrolled chronic HF patients with LVEF≤40%. ARR=absolute risk reduction; HF=heart failure; MRA=mineralocorticoid receptor antagonist; RRR=relative risk reduction 1. SOLVD Investigators. N Engl J Med 1991;325:293–302; 2. Granger et al. Lancet 2003;362:772–6; 3. CIBIS-II Investigators. Lancet 1999;353:9–13; 4. Pitt et al. N Engl J Med 1999;341:709-17; 5. Roger et al. JAMA 2004;292:344–50

Summary Heart failure (HF) is a chronic condition, punctuated by acute episodes, which may affect multiple organ systems HF is associated with high morbidity and mortality and place a significant economic burden on healthcare systems Unresolved congestion at discharge is associated with poor long- term outcomes No therapies are proven to reduce morbidity and mortality in chronic HF with preserved EF The evidence base supporting long-term benefits of current treatments for acute HF is limited Early treatment with a therapy that targets the underlying pathophysiology of acute HF may improve long-term outcomes There is a need for therapeutic advances in HF