1. Current & Future Perspectives in the Treatment of Heart Failure

2. Stewart et al. Eur J of Heart Failure 2001, 3(3):pp315-322. HF – More malignant than cancer?

3. HF admission rates per annum – 7 countries 1978-1993 McMurray & Stewart, Heart 2000;83:pp596-602.

4. Change in causal factors for HF Framingham 1950-1987 McMurray & Stewart, Heart 2000;83:pp596-602.

5. Prevalence of HF by age in Framingham Lakatta & Levy, Circulation 2003;107:pp139-146 Rate per 1000 Age

6. HF Epidemiology - Australia HF prevalence: 1% of patients aged 50-59yrs but >50% for those 85+ Likely to be 300,000 Australians affected by CHF 30,000 new cases annually Between 1996 and 1997 41,000 hospitalisations for HF as principal diagnosis CHF accounted for 0.8% of all hospitalisations (NHF guidelines, MJA 2001;174:pp.459-466)

7. Chronic Heart Failure in Australian General Practice Diuretics ACEI Digoxin BB CCB-DHP CCB-nonDHP Aspirin Warfarin Spironolactone Hydralaz ine AIIRA 70 60 50 40 30 20 10 0 % of patients prescribed each class of drug Adapted from Krum et al. The Cardiac Awareness Survey & Evaluation (CASE study), MJA 2001; 174:pp.439-444.

8. Causes of Chronic Heart Failure Systolic (impaired ventricular contraction) –Common Ischaemic heart disease Hypertension –Less common Non-ischaemic idiopathic dilated cardiomyopathy Diastolic (impaired ventricular relaxation) – Common Hypertension Ischaemic heart disease Diabetes – Less common Valvular disease, especially aortic stenosis (NHF guidelines, MJA 2001;174:pp.459-466)

9. Severe symptoms (NYHA Class IV) Pharmacological TreatmentNon-pharmacological treatment Salt/fluid restriction Exercise/conditioning program Add Beta Blocker Add Beta Blocker (irrespective of NYHA class*) Consider heart transplantation if age <65yrs + no major co-morbidity Diuretic + ACE inhibitor ImprovementNo improvement Add spironolactone +/- Digoxin No improvement not tolerated Improvement Palliative care if unsuitable for heart transplantation** Continue medical treatment **Palliative care options may include use of multiple diuretics, hydralazine, nitrates and/or short term use of inotropic agents to control intractable heart failure symptoms. Treatment of systolic HF – (LVEF<40%) Identify/treat acute precipitant e.g. acute ischaemia/infarction arrhythmia non-compliance *Patients with NYHA Class IV heart failure should be challenged with beta blockers provided they have been rendered euvolaemic and do not have any contra-indication to beta blockade. (NHF guidelines, MJA 2001;174:pp.459-466)

10. **With rare exception, patients with diastolic heart failure present with symptoms and signs of fluid overload, either pulmonary or systemic congestion, or both ***Choice of therapy will vary according to clinical circumstances. E.g. thiazide diuretic – elderly, systolic hypertension ACEI – LVH, diabetes, IHD Beta blocker - angina Management of diastolic heart failure (heart failure with preserved systolic function) Is there fluid overload**? DiureticTreat cause Is there an identifiable cause? Hypertension Ischaemic heart disease Cardiomyopathy Anti-Hypertensive therapy*** Investigate suitability for revascularisation Pharmacological treatment ACEI Beta blocker CCB Pharmacological treatment Beta blocker CCB Hypertrophic CM Investigate family hx Restrictive CM Endomyocardial biopsy for infiltrative diseases e.g. sarcoidosis amyloidosis If no specific cause found consider constrictive pericarditis Surgical pericardiectomy YesNo Management of diastolic HF (NHF guidelines, MJA 2001;174:pp.459-466)

11. Drug Use in Symptomatic Chronic Heart Failure First line agents ACEI Diuretics Beta Blockers for systolic heart failure despite appropriate doses of ACEI s and diuretics/or for advanced symptoms of CHF Spironolactone for severe HF despite appropriate doses of ACEI AIIRAs (currently) for patients intolerant of ACEI Second-line agents Digoxin Hydralazine and isosorbide dinitrate –Where no other option exists AIIRAs Are Not Approved for the Treatment of Heart Failure in Australia (NHF guidelines, MJA 2001;174:pp.459-466)

12. Inhibition of the RAAS in HF Because of the major importance of RAAS activation in the progression of CHF, blockade of this system has become the cornerstone of successful therapy for systolic ventricular dysfunction. ACE inhibitors have been shown to: –prolong survival (compared with placebo) in patients with New York Heart Association Class II, III and IV CHF; –improve patient symptom status, exercise tolerance and reduce hospitalisation for worsening CHF (in some but not all studies); and –increase ejection fraction compared with placebo in many studies. Krum et al. MJA 2001; 174: 459-466

13. Angiotensin II Chymase CAGE Angiotensinogen Angiotensin I Sodium and fluid retention Vaso- constriction Sympathetic activation Cell growth AT 1 -receptor Non-ACE pathways t-PA Cathepsin G Renin ACE ACE inhibitor Angiotensin II is produced both by ACE and non-ACE dependent pathways Peterson and Dunlap, CHF 2002, 8(5):pp.246-250. AIIRAs Are Not Approved for the Treatment of Heart Failure in Australia

14. AT 1 -Receptor Blockers (AIIRA) Clinical Outcome Studies HBP LIFE SCOPE VALUE 04? Vascular ONTARGET 06 TRANSCEND 06 HF ELITE II Val-Heft CHARM 03 HEAAL 05 I-PRESERVE Pre Diabetes NAVIGATOR 06 Diabetes Opht DIRECT 05 Diabetes Renal RENAAL IDNT MI OPTIMAAL VALIANT 03 Stroke ACCESS PRoFESS MOSES These trials may discuss the use of non approved doses or indications, refer to Australian PI before prescribing AIIRAs Are Not Approved for the Treatment of Heart Failure in Australia

15. Val-HeFT Subgroup without ACE-I therapy (n=366) 0.6 Time Since Randomization (Months) 44.0% Risk Reduction P = 0.002 Event Free Survival Probability 3691221181524 27 0 Valsartan (N = 185) Placebo (N = 181) Cohn et al. NEJM 2001; 345(23):pp.1667-1675 AIIRAs Are Not Approved for the Treatment of Heart Failure in Australia

16. 8. Recent Heart Failure Data CHARM Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity Presented 31 st August 2003 at the European Society of Cardiology (ESC) meeting in Vienna, Austria, Published in the Lancet Sep 7, 2003. Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

17. CHARM Program 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARM Preserved CHARM Added CHARM Alternative n=2028 LVEF 40% ACE inhibitor intolerant n=2548 LVEF 40% ACE inhibitor treated n=3025 LVEF >40% ACE inhibitor treated/not treated Primary outcome for Overall Programme: All-cause death Primary outcome for each trial: CV death or CHF hospitalisation McMurray et al. Eur J Heart Failure, 2003:pp.261-270 candesartan 4mg/8mg-32mg Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily.

18. CHARM – Baseline Medication % Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. McMurray et al. Eur J Heart Failure, 2003:pp.261-270

19. CHARM-Alternative: Primary outcome CV death or CHF hospitalisation Number at risk candesartan 1013929831434122 Placebo 1015887798427126 Placebo 0 123 years 0 10 20 30 40 50 Candesartan % HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 3.5 406 (40.0%) 334 (33.0%) Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Granger et al. Lancet, 2003;362:pp.772-776

20. CHARM-Alternative Permanent study drug discontinuations 0 5 10 15 20 25 Percent of patients Placebo Candesartan 19.3 0.9 2.7 0.3 0.4 21.5 3.7 6.1 1.9 0.2 Hypo- tension Increased creatinine Increased potassium CoughAE/ lab. abnorm. 0 0.1 p=0.23p<0.0001 p=0.0005p=0.69p=0.50 Angio- edema Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Granger et al. Lancet, 2003;362:pp.772-776

21. CHARM-Alternative Permanent study drug discontinuations 4.2 12.0 1.0 0.5 9.1 23.1 13.6 0.3 According to prior ACE-I intolerance Percent of patients 0 5 10 15 20 25 Hypo- tension Increased creatinine Cough Placebo Candesartan Increased potassium 0 2.6 (1/39) Angioedema Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Granger et al. Lancet, 2003;362:pp.772-776

22. CHARM-Alternative Conclusions Despite prior intolerance to another inhibitor of the renin-angiotensin-aldosterone system, candesartan was well tolerated In patients with symptomatic chronic heart failure and ACE-inhibitor intolerance, candesartan reduces cardiovascular mortality and morbidity Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Granger et al. Lancet, 2003;362:pp.772-776

23. CHARM-Added:Primary outcome CV death or CHF hospitalisation 0123years 0 10 20 30 40 50 Placebo Candesartan Number at risk Candesartan127611761063948457 Placebo127211361013906422 3.5 HR 0.85 (95% CI 0.75-0.96), p=0.011 Adjusted HR 0.85, p=0.010 483 (37.9%) 538 (42.3%) % Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. McMurray et al. Lancet, 2003;362:pp.767-771

24. CHARM-Added Conclusions Addition of candesartan to an ACE inhibitor (and beta-blocker) leads to a further and clinically important reduction in CV mortality and morbidity in patients with CHF This benefit is obtained with relatively few adverse effects, although there is an increased risk of hypotension, hyperkalaemia and renal dysfunction Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. McMurray et al. Lancet, 2003;362:pp.767-771

25. n=3025 LVEF >40% ACE inhibitor treated/not treated CHARM Added CHARM Preserved CHARM Program 3 component trials comparing candesartan to placebo CHARM Alternative n=2028 LVEF 40% ACE inhibitor intolerant n=2548 LVEF 40% ACE inhibitor treated Primary outcome: CV death or CHF hosp Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Yusuf et al. Lancet, 2003;362:pp.777-781

26. CHARM - Preserved: Primary outcome CV death or CHF hospitalisation 0123years Number at risk Candesartan 151414581377833182 Placebo 150914411359824195 3.5 0 10 20 30 Placebo Candesartan 5 15 25 HR 0.89 (95% CI 0.77-1.03), p=0.118 Adjusted HR 0.86, p=0.051 % 366 (24.3%) 333 (22.0%) Yusuf et al. Lancet, 2003;362:pp.777-781 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Yusuf et al. Lancet, 2003;362:pp.777-781

27. CHARM-Preserved Development of new diabetes 47770.600.005 (0.41-0.86) Number of casesHRp-value CandesartanPlacebo(CI) Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Yusuf et al. Lancet, 2003;362:pp.777-781

28. CHARM-Overall All-cause death 0123years Number at risk Candesartan 3803356332712215761 Placebo 3796346431702157743 3.5 0 10 20 30 Placebo Candesartan 5 15 25 35 % HR 0.91 (95% CI 0.83-1.00), p=0.055 Adjusted HR 0.90, p=0.032 945 (24.9%) 886 (23.3%) Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Pfeffer et al. Lancet, 2003;362:pp.759-766

29. CHARM-Overall CV death and non-CV death 0123years 5 10 15 20 25 30 % 0 CV death Non-CV death Placebo Candesartan Placebo Candesartan HR 0.88 (95% CI 0.79-0.97), p=0.012 Adjusted HR 0.87, p=0.006 p=0.45 3.5 Number at risk Candesartan 3803356332712215761 Placebo 3796346431702157743 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Pfeffer et al. Lancet, 2003;362:pp.759-766

30. CHARM-Overall CV death or CHF hosp. 0123years 0 10 20 30 40 50 % Placebo Candesartan HR 0.84 (95% CI 0.77-0.91), p<0.0001 Adjusted HR 0.82, p<0.0001 3.5 Number at risk Candesartan 3803356332712215761 Placebo 3796346431702157743 1310 (34.5%) 1150 (30.2%) Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Pfeffer et al. Lancet, 2003;362:pp.759-766

31. CHARM-Overall Permanent study drug discontinuations Placebo Candesartan 0 5 10 15 20 25 Percent of patients p<0.0001 Hypo- tension Increased creatinine Increased potassium AE/ lab. abnorm. 16.7 1.7 3.0 0.6 21.0 3.5 6.2 2.2 Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Pfeffer et al. Lancet, 2003;362:pp.759-766

32. CHARM-Overall Implications The addition of the ARB, candesartan, can be considered in all patients with chronic heart failure irrespective of ejection fraction, age and sex Benefits were achieved on top of other effective concomitant therapies including ACE inhibitors and beta-blockers The consistent effects of candesartan across the three CHARM trials suggest that: Atacand® (candesartan) is approved in Australia for the treatment of hypertension at a maximum approved dosage of 16mg once daily. Pfeffer et al. Lancet, 2003;362:pp.759-766

33. MERIT-HF33 MERIT-HF A Double-Blind, Placebo-Controlled Survival Study With Metoprolol CR/XL in Patients With Decreased Ejection Fraction ( 0.40) and Symptoms of Heart Failure (NYHA II–IV) Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure The MERIT-HF Study Group:Am J Cardiol 1997;80:54-58J Lancet 1999;353:2001-7 JAMA 2000;283:1295-302 MORTALITY AND MORBIDITY RESULTS

34. MERIT-HF34 Primary Objectives To determine whether metoprolol CR/XL reduces: Total mortality The combined end point of all-cause mortality and all-cause hospitalisation (time to first event) Am J Cardiol 1997;80:54-58J

35. MERIT-HF35 Months of follow-up % 036912151821 20 15 10 5 0 Placebo Metoprolol-XL P=0.0062 (adjusted) P=0.00009 (nominal) Risk reduction = 34% Total Mortality Lancet 1999;353:2001-7

36. MERIT-HF36 12 9 6 Metoprolol-XL P=0.0002 Sudden Death 036912151821 Months of follow-up % Placebo Risk reduction = 41% 3 0 Lancet 1999;353:2001-7

37. MERIT-HF37 5 4 3 1 Placebo Metoprolol-XL P=0.0023 2 Death From Worsening Heart Failure % 0 3 6 9 12 15 18 21 Months of follow-up 0 Risk reduction = 49% Lancet 1999;353:2001-7

38. 0 5 10 15 20 All-cause -10% 310/279 Adverse events -17% 234/196 Worsening HF -25% 85/64 Withdrawal of Study Medicine % No. of withdrawals Placebo Metoprolol-XL JAMA 2000;283:1295-302

39. Improvement in NYHA Functional Class and Quality of Life: Last Visit Change in NYHA ClassP=0.0028 (n=3952) Change in QOL (OTE)P=0.0089* (n=741) *Among the 185 patients in the metoprolol CR/XL group who reported an improvement, 72% judged this improvement as important, very important, or extremely important to carry out daily activities. JAMA 2000;283:1295-302

40. MERIT-HF40 Improves survival Reduces the need for hospital admission due to worsening heart failure Improves symptoms of heart failure Increases well-being Conclusions Treatment with metoprolol CR/XL once daily added to standard heart- failure therapy: Lancet 1999;353:2001-7 JAMA 2000;283:1295-302

41. Interpreting Outcomes of Recent Major Cardiovascular Trials KB Swedberg (Göteborg, Sweden)

42. 1803691215212427303633 Months Probability of Survival Placebo Spironolactone 0.30 0.50 0.70 0.80 0.90 0.40 0.601.0039 Risk Reduction 30% (- 18 - 40) P < 0.001 Pitt et al NEJM 1999 RALES : All-cause Mortality 1,663 Patients randomised to placebo/spironolactone 95% background ACEI 11% background blocker

43. 0369121518212427 Months 0 65 70 75 80 85 90 95 ValsartanPlacebo 100 RR = 13.3% P = 0.009 Event-free Survival (%) Cohn et al. NEJM 2002 Val-HeFT: All-Cause Mortality or Morbidity 5,010 patients in NYHA class II (61.7%), III (36.2%) or IV (3.1%) with mean EF 27% and age 63 years Background: ACEI 92.3%, blocker 35.5%

44. Conclusions Treatment of heart failure has resulted in major survival benefits during the last 10-15 years The challenge facing the medical community remains to ensure that ACE-inhibitors and blockers are used in all appropriate patients Inhibition of aldosterone seems to carry further benefits Addition of an ARB could be considered in all patients To optimise neurohormonal blockade, care delivery structures need to be revisited

45. HOPE study results – primary endpoints Combined cardiovascular endpoint Cardiovascular mortality, myocardial infarction, stroke Cardiovascular mortality Myocardial infarction Stroke -22% p<0.001 -26% p<0.001 -20% p<0.001 -32% p<0.001 Ramipril n=4645, Placebo n=4652 The HOPE Study Investigators, 2000

46. ArgentinaFinlandNetherlandsSpain AustraliaFranceNorwaySweden AustriaGermanyPhilippines Switzerland BelgiumGreecePoland Taiwan BrazilHungaryPortugalTurkey Canada IrelandRedcliffeSingapore UKChinaItalySlovakia United Arab EmiratesCzech Republic KoreaSouth AfricaUSA DenmarkMexico Participating countries

47. Impact of Heart Failure

48. A prevalent condition Prevalence of HF (per 1000 population) Age (years) 50-59 80-89 All ages Men 8 66 7.4 Women 8 79 7.7 Framingham Heart Study: Ho et al. 1993 J Am Coll Cardiol;22:6-13

49. A growing burden Vital Statistics of the United States, National Center for Health Statistics Deaths from HF 1979-1997 (USA)

50. An economic burden American Heart Association, 2000 Heart and Stroke Statistical Update Healthcare providers Indirect Costs Home health/Other medical durables Drugs 15.5 2.2 1.5 1.1 2.2 Annual cost of HF estimated to be $22.5 billion (USA) Costs in billions of dollars Hospital/Nursing home

51. Results: Neurohormones

52. Time Since Randomization (months) Per cent mortality 13.8 16.5 23.0 24.2 NE (pg / mL) < 274 274-394 395-572 > 572 < Q1 Q1 - < Q2 Q2 - < Q3 > = Q3 Survival Probability p value (log - rank): < 0.00001 1.000 0.962 0.924 0.887 0.849 0.811 0.773 0.736 0.698 0.660 0 4 8 12 16 20 24 28 32 26 Baseline norepinephrine (NE) levels correlate with total mortality Anand et al. AHA Scientific Sessions 2001

67. CarvedilOl ProspEctive RaNdomIzed CumUlative Survival Trial (COPERNICUS)

68. COPERNICUS Study Design 2289 patients with symptoms of heart failure at rest or minimal exertion with a LV ejection fraction < 25%, despite diuretics and an ACE inhibitor (+ digitalis). Diuretics were optimized to achieve euvolemia. No need for intensive care and no treatment with IV inotropic or IV vasodilator therapy within 4 days. Patients were randomized to placebo or carvedilol (1:1) [target dose 25 mg BID] to up to 29 months.

69. Months 100 80 60 40 20 390621181512 % Survival Carvedilol Placebo All-cause mortality COPERNICUS Risk reduction 35% P =0.00013

70. COPERNICUS In patients with severe chronic heart failure, carvedilol Improved the patients overall sense of well-being. Was well tolerated. Was associated with a lower risk of a serious adverse event, particularly one related to the progression of heart failure. Was associated with fewer patients requiring withdrawal of treatment for an adverse event or for another reason.