1. On behalf of the CHARM Programme Investigators and Committees Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity CHARM

2. 2 Background (1)  ACE inhibitors, beta-blockers and spironolactone have been demonstrated to be life-saving in patients with CHF  However, these patients still remain at high risk for cardiovascular death and recurrent hospital admissions for heart failure

3. 3 Burden of chronic heart failure (CHF)  CHF is an increasing burden to health care [1]  Pharmacological treatments improve survival and reduce hospitalisations in patients with low LVEF [2–5]  Despite these treatments, morbidity and mortality remain high  30–50% of CHF patients have preserved LVEF [6]  Not known what treatments benefit CHF patients with preserved LVEF 1.Cowie et al. Eur Heart J 1997; 18(2): 208–25 2.Garg et al. Lancet 1999; 353: 9–13 3.CIBIS-II Investigators and Committees. Lancet 1999; 353: 9–13 4.Hjalmarson et al. JAMA 2000; 283(10): 1295–302 5.Pitt et al. N Engl J Med 1999; 341(10): 709–17 6.Senni et al. Circulation 1998; 98: 2282–89

4. 4 Background (2)  Angiotensin II type 1 (AT 1 ) receptor blockers (ARBs) provide a pharmacologically distinct mechanism of inhibiting the renin-angiotensin- aldosterone system  ARBs offer the potential to produce further clinical improvements above and beyond ACE inhibitors as well as an alternative for those previously intolerant to an ACE inhibitor

5. 5 AT 1 -receptor blockers: mechanism of action  Angiotensin II type 1 (AT 1 ) receptor blockers – pharmacologically distinct mechanism of inhibiting RAAS  AT 1 -receptor inhibition – more complete blockade of angiotensin II action  Existence of alternative, non-ACE enzymatic pathways – angiotensin II can be generated from angiotensin I even in presence of ACE inhibitor [1]  Reflex increase in angiotensin I induced by ACE inhibition may overcome competitive blockade of ACE enabling angiotensin II (and aldosterone) ‘escape’  Blockade of AT 1 -receptor, rather than ACE, could be better at inhibiting adverse effects of RAAS 1. Wolny et al. Circ Res 1997; 80(2): 219–27

6. 6 AT 1 -receptor blockers: improving heart function  Reducing hypertension [1]  Reducing LV hypertrophy/improving LV relaxation  Antagonising adverse effects of elevated neurohormones  Reducing aldosterone levels  Maintaining renal function 1.Goodfriend et al. N Engl J Med 1996; 334: 1649–54 2.Swedberg et al. J Card Failure 1999; 5: 276–82

7. 7 AT 1 -receptor blockers reduce left ventricular hypertrophy: CATCH study 50 40 30 20 10 0 Patients with regression of ventricular mass (%) Enalapril Candesartan Week 24Week 48 30 25 36 30 Cuspidi et al. J Hypertens 2002; 20: 2293–300

8. 8 Trials with AT 1 -receptor blockers in CHF: ELITE II and Val-HeFT  ELITE-II  ELITE-II: losartan vs captopril [1] Losartan similar in efficacy compared to captopril in patients with CHF and an impaired left ventricular function, and losartan better tolerated  Val-HeFT  Val-HeFT: valsartan vs placebo in addition to standard heart failure therapy [2] Modest but significant reduction in one of the primary endpoints, but no effect on all-cause mortality 1.Pitt et al. Lancet 2000; 355: 1582–7 2.Cohn et al. N Engl J Med 2001; 345: 1667–75

9. 9 Candesartan: potent and long- acting AT 1 -receptor blocker  Highly potent [1]  Long-acting [1]  10,000 greater affinity for AT 1 -receptor than AT 2 - receptor [1]  ‘Insurmountable’ antagonist [1]  Antihypertensive agent [2]  Well tolerated [3–6]  Effect on morbidity and mortality? 1.Ojima et al. Eur J Pharmacol 1997; 319: 137–46. 2.Andersson et al. J Hum Hypertens 1997; 11(Supp2): S63–4. 3.McKelvie et al. Circulation 1999; 100: 1056–64. 4.Granger et al. Am Heart J 2000 139(4): 609–17. 5.Riegger et al. Circulation 1999; 100: 2224–30. 6.Mitrovic et al. Am Heart J 2003; 145: E14.

10. 10 Clinical experience with candesartan in CHF  RESOLVD pilot study  RESOLVD pilot study: candesartan combined with enalapril improved LV function more than either of agents alone, and suppressed aldosterone levels to a greater extent [1]  SPICE pilot study  SPICE pilot study: in patients with history of ACE inhibitor intolerance, similar percentage of patients completed 12-week treatment period on candesartan vs placebo [2]  STRETCH study  STRETCH study: maximal exercise capacity increased dose- dependently with candesartan compared to placebo [3]  Mitrovic et al. study  Mitrovic et al. study: candesartan demonstrated significant short- and long-term improvements in haemodynamic, neurohormonal and symptomatic status [4] 1.McKelvie et al. Circulation 1999; 100: 1056–64 2.Granger et al. Am Heart J 2000 139(4): 609–17 3.Riegger et al. Circulation 1999; 100: 2224–30 4.Mitrovic et al. Am Heart J 2003; 145: E14

11. 11 CHARM design rationale  An international, multicentre programme comprising of three double-blind studies  To provide definitive and quantitative clinical information on the role of candesartan in a broad spectrum of symptomatic heart failure  To allow uniform procedures across the three independent studies  To provide adequate power for study objectives Swedberg et al. J Card Failure 1999; 5(3): 276–82

12. 12 CHARM programme studies  CHARM-Alternative  CHARM-Alternative: patients with depressed LV systolic function (LVEF  40%) and not treated with an ACE inhibitor (due to intolerance)  CHARM-Added  CHARM-Added: patients with depressed LV systolic function (LVEF  40%) and treated with an ACE inhibitor  CHARM-Preserved  CHARM-Preserved: patients with preserved LV systolic function (LVEF > 40%) treated or not treated with an ACE inhibitor Swedberg et al. J Card Failure 1999; 5(3): 276–82

13. 13 Design of CHARM programme CHF: NYHA class II–IV EF  40% EF > 40% ACE-intoleranceACE-I treated Randomisation ‘Alternative’ Randomisation ‘Added’ Randomisation ‘Preserved’ Candesartan  4/8 32 mgPlacebo Titration period Visit every 4 months up to at least 24 months Mortality/morbidity endpoints Swedberg et al. J Card Failure 1999; 5(3): 276–82

14. 14 Aims: CHARM Programme Effects of Candesartan on  Each trial: Cardiovascular death or CHF hospitalisation  Overall programme: All-cause death Key secondary outcomes  Other major CV-outcomes  Mortality in patients with LVEF  40% Other prespecified outcomes  Development of diabetes mellitus  Investigator reported outcomes

15. 15 CHARM Added CHARM Preserved CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure 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

16. 16 CHARM secondary objectives for each study To determine if candesartan, compared with placebo, reduces the combined endpoint of:  cardiovascular mortality, hospitalisation for the management of CHF, or nonfatal myocardial infarction  cardiovascular mortality, or hospitalisation for the management of CHF, or nonfatal myocardial infarction, or coronary revascularisation procedures  all-cause mortality and all-cause hospitalisation Swedberg et al. J Card Failure 1999; 5(3): 276–82

17. 17 CHARM other objectives for each study To determine if candesartan, compared with placebo:  influences of assignment to candesartan on each of the individual components of the composite endpoints  effects the functional state and symptoms according to the NYHA classification, as well as the safety and tolerability  influences the use of candesartan on health care costs Swedberg et al. J Card Failure 1999; 5(3): 276–82

18. 18 Countries and national leaders CountryCo-ordinator Patients AustraliaP. Aylward227 Belg/LuxJ. Vanhaecke249 CanadaR. S. McKelvie J-L. Rouleau943 Czech RepM. J. Hradec194 DenmarkP. Thayssen487 FinlandM. Niemelä102 FranceA. Cohen Solal225 GermanyR. Dietz803 HungaryI. Edes204 IcelandA. Kristinson82 ItalyA. Maggioni151 MalaysiaC. C. Lang140 NetherlandsD.J. van Veldhuisen420 NorwayT. Gundersen217 PolandJ. Kuch215 PortugalR. Seabra Gomes93 RussiaA. Yurenev200 SingaporeD. Zee Pin 62 South AfricaA. J. Dalby120 SpainJ. Soler Soler125 SwedenH. Persson192 SwitzerlandO. Hess68 UK/IrelandA. J. S. Coats281 USAJ. Young 1.801 M. Dunlap Total number of patients 7,601 CountryCo-ordinator Patients

19. 19 Recruitment in the three component CHARM-trials 0 2000 4000 6000 8000 JanJuneDecJune 19992000 Number of patients First patient March 22 1999 Overall 7601 Preserved 3025 Added 2548 Alternative 2028 Dec 2001

20. 20 Inclusion and exclusion criteria Inclusion  Aged  18 years  Symptomatic CHF NYHA class II–IV  4 weeks pre-randomisation  LVEF documentation  6 months Exclusion  Heart transplant recipients  Hypertension, stroke, acute MI, recent open heart surgery  Life expectancy < 2 years due to noncardiac disease Swedberg et al. J Card Failure 1999; 5(3): 276–82

21. 21 Inclusion and exclusion criteria Key exclusion criteria  S-creatinine  265  mol/L (  3mg/dL)  S-potassium  5.5mmol/L  Bilateral renal artery stenosis  Symptomatic hypotension  ARB within two weeks Inclusion criteria  Age >18 years  Symptomatic heart failure for at least 4 weeks (New York Heart Association Class II-IV)

22. 22 Study design Dose-titration and visit schedule Time0 w2 w4 w6 w6 m Every 4 months until study end 31 March 2003 Visit12345 32 mg Candesartan/ matching placebo once daily 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg

23. 23 Statistical methods (1)  In each component trial, sample size was independently estimated for the composite outcome of cardiovascular death or hospitalisation for heart failure  All-cause mortality was evaluated in the Overall programme

24. 24 Statistical methods (2)  Main analysis for each trial: CV death and hospitalisation for CHF based on adjudicated events  Supportive analysis: Cox regression model with 33 prespecified baseline covariates to improve precision  Other analyses: investigor reported outcomes and prespecified subgroups

25. 25 Baseline data: number of patients randomised per country and study CountryCHARM- CHARM-CHARM-Total Alternative Added Preserved Alternative Added Preserved Australia547697227 Belgium6082106248 Canada208357378943 Czech Republic667157194 Denmark92207188487 Finland291459102 France5570100225 Germany154346303803 Hungary666969204 Iceland25213682 Italy201491151 Luxembourg0011 Malaysia533849140 The Netherlands173128118419 Norway479773217 Poland667970215 Portugal21195393 Russia5315132200 Singapore20212162 South Africa483240120 Spain501758125 Sweden536475192 Switzerland15252868 United Kingdom1048987280 USA4705977341801 Total2028254830237599 McMurray et al. Eur J Heart Fail; 5(3): 261–70

26. 26 Baseline data: characteristics of patients VariableCHARM-Alternative CHARM-Added CHARM-Preserved (n=2028)(n=2548)(n=3025) Mean age (years)676467 Males (%)687960 LVEF0.300.280.54 Diabetes mellitus (%)273028 Hypertension (%)504864 Atrial fibrillation (%)252629 Previous MI (%)625644 Angina pectoris (%)585360 Previous stroke (%)999 NYHA II (%)482461 NYHA III (%)497338 NYHA IV (%)432 Current smoker (%)141714 McMurray et al. Eur J Heart Fail; 5(3): 261–70

27. 27 Mean age (years) 67646766 Women (%)32214032 NYHA class (%) II48246045 III49733852 IV 3323 Mean LVEF30285439 Medical history (%) myocardial infarction6156 4453 diabetes27302828 hypertension50486455 atrial fibrillation25262927 Baseline characteristics (1) AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

28. 28 LVEF (%) - Mean 30285439 - Proportion <0.40 100100060 SBP/DBP (mmHg)130/77125/75136/78131/77 Heart rate (beats/min)74747173 Baseline characteristics (2) AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

29. 29 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics (3) AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

30. 30 Baseline data: background medication VariableCHARM- CHARM- CHARM- Alternative AddedPreserved Digoxin (%)465928 Diuretics (%)869075 Loop diuretics (%)788463 Spironolactone (%)241712 Beta blocker (%)555656 Calcium antagonist (%)161031 Long acting nitrates (%)373333 Amiodarone (%)12118 Lipid lowering agent (%)424242 Oral anticoagulant (%)313825 Aspirin (%)585258 McMurray et al. Eur J Heart Fail; 5(3): 261–70

31. 31 Baseline data: principal aetiology of heart failure McMurray et al. Eur J Heart Fail; 5(3): 261–70 0 20 40 60 80 % IschaemicIdiopathicHypertensiveAF CHARM alternative CHARM added CHARM preserved

32. 32 Baseline data: reason for ACE- intolerance for patients in CHARM- Alternative ACE-inhibitor intolerance due to:CHARM- Alternative AllMenWomen Angioedema, anaphylaxis (%)445 Cough (%)726977 Symptomatic hypotension (%)1314 10 Renal dysfunction (%)12138 Other adverse events (%)111110 McMurray et al. Eur J Heart Fail; 5(3): 261–70

33. 33 Baseline data: physical examination and ECG VariableCHARM-Alternative CHARM-Added CHARM-Preserved BMI (kg/m 2 )272829 Heart rate (bpm)747471 Mean DBP (mm Hg)777578 Mean SBP (mm Hg)130125136 Atrial fib/flutter (%)141616 Bundle branch block (%)303114 Pathological Q waves (%)302720 LVH (%)151715 BMI=body mass index; bpm=beats per minute; DBP=diastolic blood pressure; SBP=systolic blood pressure McMurray et al. Eur J Heart Fail; 5(3): 261–70

34. 34 Baseline data: ELITE-II vs CHARM- Alternative and Val-HeFT vs CHARM- Added ELITE-II CHARM-Val-HeFT CHARM- [1] Alternative [4] [2,3]Added [4] Number3152202850102548 Mean age (years)71676364 Men (%)70688079 LVEF (%)31302728 NYHA II (%)49486224 NYHA III (%)45493673 Digoxin (%)50466858 Beta blocker24553655 Spironolactone (%)—24217 ACEI=ACE inhibitors Variable Alternative to ACEI Addition to ACEI 1.Pitt et al. Lancet 2000; 355:1582–7 2.Cohn et al. N Engl J Med 2001; 345:1667–75 3.Cohn et al. Eur J Heart Failure 2000; 2: 439–46 4.McMurray et al. Eur J Heart Fail; 5(3): 261–70

35. 35 Conclusions from baseline characteristics  CHARM patient population represents broad spectrum of heart failure patients  Patients have a modern background pharmacological heart failure treatment  CHARM results will answer many questions unresolved by previous large trials on AT 1 -receptor blockers in CHF McMurray et al. Eur J Heart Fail; 5(3): 261–70

36. 36 CHARM Programme n=3025 LVEF >40% ACE inhibitor treated/not treated CHARM Added CHARM Preserved 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

37. 37 CHARM-Alternative Background At least 20% of patients with CHF are not receiving ACE inhibitors, about half (10%) due to ACE inhibitor intolerance. Aim  To evaluate effects of candesartan in patients with symptomatic CHF and intolerance to ACE-I

38. 38 CHARM-Alternative Patient disposition Median follow-up of 34 months Candesartan n=1013 Placebo n=1015 Completed Study n=1011 Completed Study n=1014 Lost to follow-up n=2 Lost to follow-up n=1 2028 patients randomised NYHA II-IV, LVEF  40% ACE inhibitor intolerant

39. 39 Mean age (years) 67646766 Women (%)32214032 NYHA class (%) II48246045 III49733852 IV 3323 Mean LVEF30285439 Medical history (%) myocardial infarction6156 4453 diabetes27302828 hypertension50486455 atrial fibrillation25262927 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

40. 40 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

41. 41 Reason for ACE-I intolerance (%) cough7074 hypotension1412 renal dysfunction1310 angioedema/anaphylaxis44 other1011 CHARM-Alternative Baseline characteristics CandesartanPlacebo n=1013n=1015

42. 42 CHARM-Alternative: Primary outcome CV death or CHF hospitalisation 0123years 0 10 20 30 40 50 Placebo Candesartan % HR 0.77 (95% CI 0.67-0.89), p=0.0004 Adjusted HR 0.70, p<0.0001 Number at risk Candesartan 1013929831434122 Placebo 1015887798427126 3.5 406 (40.0%) 334 (33.0%)

43. 43 CHARM-Alternative Secondary outcomes CV death219252 CHF hosp. 207286 CV death, CHF hosp,353420 MI CV death, CHF hosp,369432 MI, stroke CV death, CHF hosp,396456 MI, stroke, revasc Candesartan Placebo candesartan better Hazard ratio placebo better 0.60.81.01.21.4 p-value 0.072 <0.0001 0.0007 0.001 0.002 0.85 0.68 0.78 0.80 0.81

44. 44 CHARM-Alternative Investigator reported CHF hospitalisations Placebo Candesartan Proportion of patients (%) Patients hospitalised Hospitalisations p<0.0001 p=0.0001 Number of episodes

45. 45 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 p=0.23p<0.0001 p=0.0005p=0.69 Hypo- tension Increased creatinine Increased potassium CoughAE/ lab. abnorm. 0 0.1 p=0.50 Angio- edema Among all patients

46. 46 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

47. 47 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

48. 48 n=3025 LVEF >40% ACE inhibitor treated/not treated CHARM Added CHARM Preserved CHARM Programme 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

49. 49  Despite full conventional treatment, patients with CHF have a poor prognosis - new treatments are needed  Non-ACE pathways produce angiotensin II  ACE (kininase II) inhibition increases bradykinin CHARM-Added Background Aim  To evaluate the effects of adding candesartan to a ACE-inhibitor in patients with symptomatic CHF

50. 50 CHARM-Added Patient disposition Median follow-up of 41 months Candesartan n=1276 Placebo n=1272 Completed Study n=1273 Completed Study n=1271 Lost to follow-up n=3 Lost to follow-up n=1 2548 patients randomised NYHA II-IV, LVEF  40% ACE inhibitor treated

51. 51 Mean age (years) 67646766 Women (%)32214032 NYHA class (%) II48246045 III49733852 IV 3323 Mean LVEF30285439 Medical history (%) myocardial infarction6156 4453 diabetes27302828 hypertension50486455 atrial fibrillation25262927 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

52. 52 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

53. 53 CHARM-Added Baseline ACE inhibitor enalapril27% 1717 lisinopril19%1717 captopril17%8283 ramipril11% 7 7 Mean daily dose of ACE inhibitor (mg) Candesartan Placebo Proportion taking ACE inhibitor

54. 54 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%) %

55. 55 CHARM-Added Secondary outcomes CV death302347 CHF hosp.309 356 CV death, CHF hosp,495550 MI CV death,CHF hosp,512559 MI, stroke CV death,CHF hosp,548596 MI, stroke, revasc candesartan better Hazard ratio placebo better 0.60.81.01.21.4 p-value 0.029 0.014 0.010 0.020 0.015 Candesartan Placebo 0.84 0.83 0.85 0.87

56. 56 CHARM-Added Prespecified subgroups, CV death or CHF hosp. Beta- Yes223/702274/711 blockerNo260/574264/561 Recom.Yes232/643275/648 dose ofNo251/633263/624 ACE inhib. All patients483/1276538/1272 CandesartanPlacebo candesartan better Hazard ratio placebo better 0.60.81.01.21.4 p-value for treatment interaction 0.14 0.26

57. 57 CHARM-Added Investigator reported CHF hospitalisations Placebo Candesartan p=0.002 p=0.008 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes

58. 58 CHARM-Added Permanent study drug discontinuations Placebo Candesartan 0 5 10 15 20 25 Percent of patients p=0.0003p=0.079p=0.0001p<0.0001 Hypo- tension Increased creatinine Increased potassium AE/ lab. abnorm. 18.3 3.1 4.1 0.7 24.2 4.5 7.8 3.4

59. 59 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

60. 60 CHARM - Low EF trials  A prespecified and important analysis was performed of the two trials defined by EF  40% (CHARM Alternative and CHARM Added)  This was carefully considered because earlier studies with ACE inhibitors, beta-blockers, aldosterone antagonists, and ARBs in CHF were done specifically in this population Young et al, Circulation 2004

61. 61 CHARM - Low EF trials Patient disposition Median follow-up of 40 months 5 lost to follow-up 2 lost to follow-up 2284 completed study 2289 assigned to Candesartan 2285 completed study 2287 assigned to Placebo 4576 patients randomised Young et al, Circulation 2004

62. 62 Mean age (years) 6565 Women (%) 2626 NYHA class (%) II3534 III6262 IV 34 Mean LVEF (%) 2929 Medical history (%) myocardial infarction59 58 diabetes2929 hypertension4850 atrial fibrillation2626 CandesartanPlacebo n=2289n=2287 Young et al, Circulation 2004 CHARM - Low EF trials Baseline characteristics (1)

63. 63 Baseline therapy (%) ACE inhibitor5656 beta-blocker*5555 diuretic8888 spironolactone*2120 digitalis5253 ASA5455 lipid lowering4241 CHARM - Low EF trials Baseline characteristics (2) * At end of study usage of beta-blockade was 64% and 67% and of spironolactone 22% and 27%, for candesartan and placebo respectively Young et al, Circulation 2004 CandesartanPlacebo n=2289n=2287

64. 64 CHARM - Low EF trials All-cause death Number at risk Candesartan2289210518941382580 Placebo2287202318111333548 Placebo 708 (31.0%) Candesartan 642 (28.0%) yrs3.50123 0 10 20 30 All cause death (%) 5 35 25 15 40 Hazard ratio 0.88 (95% CI 0.79 – 0.98), p=0.018 One year HR 0.67 p<0.001 Two year HR 0.80 p=0.001 Young et al, Circulation 2004

65. 65 yrs3.50123 0 10 20 30 CV deaths and Non CV deaths (%) 5 25 15 CHARM - Low EF trials CV death and non-CV death Non CV death Placebo Candesartan Placebo Hazard ratio 0.84 (95% CI 0.75 – 0.95), p=0.005 p=0.60 CV death Number at risk Candesartan2289210518941382580 Placebo2287202318111333548 Young et al, Circulation 2004

66. 66 CHARM LVEF  40% (Alternative and Added) All-cause death0.880.79-0.980.018 CV death0.840.75-0.950.005 HRCIp-value

67. 67 CHARM - Low EF trials CV death or CHF hospitalisations Placebo 944 (41.3%) Candesartan 817 (35.7%) yrs3.50123 0 10 20 30 CV death or CHF hosp (%) 40 Hazard ratio 0.82 (95% CI 0.74 – 0.90), p<0.001 50 One year HR 0.70 p<0.001 Two year HR 0.77 p<0.001 Number at risk Candesartan2289210518941382580 Placebo2287202318111333548 Young et al, Circulation 2004

68. 68 CHARM - Low EF trials Investigator reported CHF hospitalisations 0 5 10 15 20 25 30 35 0 200 400 600 800 1000 1200 1400 HR 0.73 p<0.001 HR 0.80 p<0.001 Patients hospitalisedHospitalisations Proportion of patients (%) Number of episodes Young et al, Circulation 2004 Placebo Candesartan

69. 69 CHARM - Low EF trials Permanent study drug discontinuations 0 5 10 15 20 25 Percent of patients p<0.001 Hypo- tension Increased potassium AE/ lab. abnorm. 18.8 2.1 3.5 0.5 23.1 4.2 7.1 2.8 Young et al, Circulation 2004 Increased creatinine Placebo Candesartan

70. 70 CHARM-Low EF Implications  Candesartan significantly reduces cardiovascular death, hospital admission for heart failure, and all-cause mortality in patients with CHF and LVEF  40% when added to standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonist  This approach offers the clinician an opportunity to make additional improvements in the poor prognosis of CHF patients when left ventricular systolic dysfunction is present Young et al, Circulation 2004

71. 71 CHARM Programme n=3025 LVEF >40% ACE inhibitor treated/not treated CHARM Added CHARM Preserved 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

72. 72 CHARM-Preserved Background Although half of patients with CHF have preserved ejection fractions (>40%), few treatments have specifically been evaluated in such patients Aim  To evaluate effects of candesartan in patients with symptomatic CHF and LVEF >40%

73. 73 CHARM-Preserved Patient disposition Median follow-up of 37 months Candesartan n=1514 Placebo n=1509 Completed Study n=1512 Completed Study n=1508 Lost to follow-up n=2 Lost to follow-up n=1 3025 patients randomised NYHA II-IV LVEF > 40% 2 patients with no data

74. 74 Mean age (years) 67646766 Women (%)32214032 NYHA class (%) II48246045 III49733852 IV 3323 Mean LVEF30285439 Medical history (%) myocardial infarction6156 4453 diabetes27302828 hypertension50486455 atrial fibrillation25262927 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

75. 75 Baseline signs, symptoms and radiographic findings Preserved Added Alternative 35 30 25 20 15 10 5 0 % Oedema Orthop- noea PND Rest dyspnoea S3S3 CracklesJVP >6 cm Cardio- megaly

76. 76 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

77. 77 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%)

78. 78 CHARM-Preserved Primary and secondary outcomes CV death, CHF hosp.333 366 - CV death170170 - CHF hosp. 241276 CV death, CHF hosp,365399 MI CV death,CHF hosp,388429 MI, stroke CV death,CHF hosp,460497 MI, stroke, revasc candesartan better Hazard ratio placebo better 0.81.01.2 p-value 0.918 0.072 0.118 0.126 0.078 0.123 Covariate adjusted p-value 0.635 0.047 0.051 0.037 0.13 Candesartan Placebo 0.89 0.99 0.85 0.90 0.88 0.91

79. 79 CHARM-Preserved Investigator reported CHF hospitalisations Placebo Candesartan p=0.014 p=0.017 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes

80. 80 CHARM-Preserved Development of new diabetes 47770.600.005 (0.41-0.86) Number of casesHRp-value CandesartanPlacebo(CI)

81. 81 CHARM-Preserved Permanent study drug discontinuations Hypo- tension Increased creatinine Increased potassium Any adverse event 0 5 10 15 20 25 30 Placebo Candesartan Percent of patients p=0.001p=0.006p<0.001p=0.019 13.5 1.1 2.4 0.6 17.8 2.4 4.8 1.5

82. 82 CHARM-Preserved Conclusions The CHARM Preserved trial provides supportive evidence that the ARB, candesartan can prevent CHF hospitalisations and can prevent the development of diabetes mellitus.

83. 83 CHARM-Preserved  This trial provides information on the poorly studied, but large, group of CHF patients with LVEF >40%  Data on their own are suggestive of benefit  When taken in the context of the results of the two parallel CHARM trials in patients with low LVEF, physicians may consider candesartan in patients with CHF irrespective of EF

84. 84 CHARM Programme CHARM Added CHARM Preserved 3 component trials comparing candesartan to placebo 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: All-cause death

85. 85 CHARM-Overall Patient disposition Median follow-up of 38 months Candesartan n=3803 Placebo n=3796 Completed Study n=3796 Completed Study n=3793 Lost to follow-up n=7 Lost to follow-up n=3 7601 patients randomised NYHA II-IV 2 patients with no data

86. 86 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%)

87. 87 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

88. 88 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%)

89. 89 CHARM Programme Mortality and morbidity 0.70.80.91.01.11.20.60.70.80.91.01.11.2 All Cause Mortality CV Death or CHF Hospitalisation Hazard ratio p heterogeneity=0.43 Alternative Added Preserved Overall p heterogeneity=0.37 p=0.0004 p=0.055 p=0.011 p=0.118 p<0.0001 0.77 0.85 0.89 0.84 0.91

90. 90 CHARM-Overall Secondary composite outcomes CV death691769 CHF hosp.757918 CV death, CHF hosp.11501310 CV death, CHF hosp,12131369 MI CV death, CHF hosp,12691420 MI, stroke CV death, CHF hosp,14041549 MI, stroke, revasc candesartan better Hazard ratio placebo better 0.60.81.01.21.4 p-value <0.0001 0.012 0.88 0.79 0.84 0.85 0.86 0.84 Candesartan Placebo

91. 91 CV death or hospitalisation for CHF candesartan better Hazard ratio placebo better 0.60.81.01.21.4 Age 65 75 350/852421/884 LVEF 40333/1516366/1504 Gender Male813/2617917/2582 Female337/1186393/1214 NYHAII359/1730415/1686 III/IV791/2073895/2110 Overall1150/38031310/3796 Candesartan event/n Placebo event/n p=0.26 p=0.93 p=0.63 p=0.40 Test for interaction

92. 92 CV death or hospitalisation for CHF DiabetesNo680/2715815/2721 Yes470/1088495/1075 Hyper-No484/1710579/1703 tensionYes666/2093731/2093 ACE No586/2230688/2244 inhibitors Yes564/1573622/1552 Beta-No611/1701710/1695 blockerYes539/2102600/2101 Spirono-No880/31601041/3167 lactoneYes270/643269/629 Overall1150/38031310/3796 Test for interaction p=0.09 p=0.51 p=0.32 p=0.19 p=0.17 candesartan better Hazard ratio placebo better 0.60.81.01.21.4 Candesartan event/n Placebo event/n

93. 93 CHARM-Overall CHF hospitalisations Placebo Candesartan p<0.0001 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes p<0.0001

94. 94 CHARM-Overall Development of new diabetes 163 (6)202 (7)0.780.020 (0.64-0.96) Number of cases (%)HRp-value CandesartanPlacebo(CI) n=2715n=2721

95. 95 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

96. 96 CHARM-Overall Conclusions  9% reduction in all cause deaths (p=0.055, covariate adj. p=0.032)  12% reduction in CV mortality (p=0.012)  21% reduction in CHF hosp. (p<0.0001)  16% reduction in CV deaths or CHF hosp. (p<0.0001) Treatment of a broad spectrum of patients with symptomatic heart failure with candesartan resulted in a:

97. 97 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: