1. EPIDEMIOLOGY AND HISTORY AHF/HF Disease Awareness

2. History of acute heart failure management Did you know? Despite having being used for decades, the effects of diuretics on mortality and morbidity have not been studied in patients with heart failure 7 1. Lechat et al. Eur Heart J Suppl 2006;8(Suppl C):C5–12; 2.Crawford et al. J Clin Invest 1925;1:333–58; 3. Davies et al. BMJ 2000;320:39–42; 4. Evans et al. Br Heart J 1941:3:112–20; 5. Judson et al. Circulation 1956;13:664–74; 6. http://fdazilla.com/drugs (Accessed 1 May 2013); 7. McMurray et al. Eur Heart J 2012;33:1787–847 Heart transplant image 1900–1970 Early models of heart failure focussed on hemodynamics, with edema as the key characteristic of the condition. This led to the widespread use of diuretics in patients with heart failure 1 The first half of the 20 th Century saw the introduction of mercurial diuretics for the treatment of congestive heart failure 2,3 The 1950’s saw the introduction of thiazide diuretics 3 and vasodilators such as hydralazine 5 The loop diuretic furosemide was approved by the Food and Drug Administration in 1966, 6 while in 1967, the first human-to-human heart transplant was performed. 3 Both of these are still used today in the management of heart failure 7 “... when heart failure occurs with normal rhythm, as in hypertension, mercurial diuretics usually prove more successful than digitalis in increasing the urinary output, in lessening pulmonary congestion, and in relieving dyspnoea” 4

3. History of acute heart failure management *A population-based study assessed survival rates for patients hospitalized for heart failure between 1987–2002 from four communities within the USA 1. McKee et al N Engl J Med 1971;285:1441–6; 2. http://fdazilla.com/drugs (Accessed 1 May 2013); 3. McMurray et al. Eur Heart J 2012;33:1787–847; 4. Loehr et al. Am J Cardiol 2008;101:1016–22 1970–1990 The Framingham heart study was published in 1971 showing high mortality in patients with heart failure:1 “Despite modern management, congestive heart failure proved to be extremely lethal. The probability of dying within five years from onset of congestive heart failure was 62% for men and 42% for women” During the 1970’s and 1980’s, inotropes and intravenous nitrates were approved for patients with acute heart failure.2 These were the first advances in therapy in over a decade – there have been relatively few advances since Although nitrates are still used in the management of acute heart failure today, there is no robust evidence that they relieve dyspnoea or improve other clinical outcomes Intravenous drip Did you know? Acute heart failure is still associated with high levels of mortality; 30-day, 1-year and 5-year mortality rates for patients hospitalized for acute heart failure are approximately 10%, 22% and 42%, respectively*4

4. History of acute heart failure management 1. http://fdazilla.com/drugs/application/020920 (Accessed 1 May 2013); 2. http://www.orion.fi/Documents/Publications%20and%20Media%20main%20file/Presentation%20materials%20PDF/ Simdax%20Fact%20Sheet.pdf (Accessed 1 May 2013); 3. Konstam et al. JAMA 2007;297:1319–31; 4. McMurray et al. JAMA 2007;298:2009–19; 5. Massie et al. N Engl J Med 2010;363:1419–28; 6. O’Connor et al. N Engl J Med 2011;365:32–43; 7. Cowie et al. Br J Cardiol 2013;20(suppl 2):S1–S11; 8. European Society of Cardiology Heart Failure Awareness Day http://www.escardio.org/communities/HFA/heart-failure-awareness-day-2013/Pages/european-heart-failure-awareness-day-2013.aspx (Accessed 29 April 2013); 9. British Heart Foundation ‘Mending Broken Hearts’ Appeal http://www.bhf.org.uk/mending-broken-hearts-appeal.aspx#&panel1-1 (Accessed 29 April 2013); 10. Ezekowitz. Curr Cardiol Rep 2013;15:329; 11. McMurray et al. Eur Heart J 2012;33:1787–847; 12. Ramirez & Abelmann. N Engl J Med 1974;290:499–501 2000–Present day Launch of two new agents for acute heart failure, but they are not approved by regulatory authorities in all markets: B-type natriuretic peptide (nesiritide; 2001; US only 1 ); calcium sensitizer (levosimendan; 2000; Scandinavia, Russia, Latin America 2 ) A number of novel therapies fail to demonstrate outcome benefits in clinical trials in patients with acute heart failure: 3–6 Clinical trials with a vasopressin V2 receptor blocker, an endothelin receptor antagonist and an adenosine receptor fail to demonstrate improvements in long-term ouctomes 3–5 2011: Several years after launch, a pivotal study shows artificial B-type natriuretic peptide has no effect on outcomes in patients with acute heart failure 6 Hope on the horizon? The need to raise awareness of acute heart failure and improve patient care pathways is being increasingly recognized and many medical associations and have initiatives to address this. 7–9 Meanwhile, a number of potential novel therapies for acute heart failure are currently in clinical development 10 Did you know? The main therapies for acute heart failure recommended by the guidelines (loop diuretics, vasodilators and inotropes) are the same therapies that have been used for decades 11,12 There remains a significant need for improved disease management and new treatment options that reduce mortality in patients with acute heart failure

5. Incidence: 1 million/year Pre-hospital mortality: unknown In-hospital mortality: 3–4 % 60–90 day mortality: 10 % Lack of awareness: Acute coronary syndromes and acute heart failure: similar burden but different levels of understanding and progress ACS=acute coronary syndrome; AHF=acute heart failure; ESC=European Society of Cardiology; RCTs=randomized controlled trials Adapted from Weintraub et al. Circulation 2010; 122:1975–96; McMurray et al. Eur Heart J 2012;33:1787–847; Hamm et al. Eur Heart J 2011;32:2999–3054 AHF ACS Incidence: 1 million/year Targets of therapy: unclear Pre-hospital mortality: high In-hospital mortality: 3–4 % 60–90 day mortality: 2 % Targets of therapy: thrombosis Clinical trial results: minimal; no mortality benefits Clinical trial results: numerous; beneficial Diuretics and vasodilatorsAntiplatelets; anticoagulants Few, small RCTs ESC: level B–C Numerous, large RCTs ESC: level A Evidence level for current standard of therapy: Current standard of therapy: Clinical trial results: Targets of therapy: Mortality: Incidence:

6. Resource and economic burden: Heart failure imposes a significant economic burden on the healthcare system More than 2 % of the total healthcare budget in many countries is spent on the treatment of HF 2 $$$$$$$$$$ IN THE USA ALONE, THE ESTIMATED ECONOMIC BURDEN OF HF FOR 2013 IS US$ 32 billion ‡ 1 HF=heart failure; ‡ Estimate includes direct costs (total annual medical spending) and indirect costs (lost productivity due to morbidity and mortality) 1. Go et al. Circulation 2013;127:e6–e245; 2. Dickstein et al. Eur Heart J 2008;29:2388–442; 3. Hunt et al. J Am Coll Cardiol 2009;53:e1–90 70 % OF THE COST OF HF IS DUE TO HOSPITALIZATIONS 2 $$$$$$$$$$ ~ 10 % OF THE COST OF HF IS DUE TO PHARMACOLOGICAL TREATMENT 3 $$$$$$$$$$ ~120% by 2030 THE TOTAL COST OF HF IN THE USA ALONE IS EXPECTED TO INCREASE $$$$$ $ $$$$ $$$$$ $ $$$$ ‡1

7. An introduction to the burden of heart failure : Heart failure is a major and growing public health problem HF=heart failure; MI=myocardial infarction; ‡ Calculated using the incidence rate of HF in 1997 for 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 HF PREVALENCE Improved post-MI survival 5 Increasing prevalence of risk factors 5,6 An aging population 5 PREVALENCE 1 GROWTH 5 ~2 % ~15 m ~2 % of the population in Europe have HF 1 As many as 1 in 5 people aged 70–80 years have HF 1 INCIDENCE 2–4 (new cases per 100,000 per year) 219130 70 ‡ Item Code: 153050 Copyright © Novartis Pharma AG.