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 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

4. 4 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

5. 5 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

6. 6 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

7. 7 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

8. 8 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)

9. 9 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

10. 10 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

11. 11 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

12. 12 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

13. 13 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

14. 14 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics (3) AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

15. 15 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

16. 16 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

17. 17 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

18. 18 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

19. 19 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

20. 20 Reason for ACE-I intolerance (%) cough7074 hypotension1412 renal dysfunction1310 angioedema/anaphylaxis44 other1011 CHARM-Alternative Baseline characteristics CandesartanPlacebo n=1013n=1015

21. 21 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%)

22. 22 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

23. 23 CHARM-Alternative Investigator reported CHF hospitalisations Placebo Candesartan Proportion of patients (%) Patients hospitalised Hospitalisations p<0.0001 p=0.0001 Number of episodes

24. 24 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

25. 25 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

26. 26 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

27. 27 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

28. 28  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

29. 29 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

30. 30 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

31. 31 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

32. 32 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

33. 33 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%) %

34. 34 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

35. 35 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

36. 36 CHARM-Added Investigator reported CHF hospitalisations Placebo Candesartan p=0.002 p=0.008 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes

37. 37 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

38. 38 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

39. 39 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

40. 40 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%

41. 41 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

42. 42 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

43. 43 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

44. 44 Baseline therapy (%) ACE inhibitor01001941 beta-blocker55565655 diuretic86907583 spironolactone24171217 digitalis46582843 aspirin 58525856 lipid lowering41414242 Baseline characteristics AlternativeAddedPreservedOverall n=2028n=2548n=3023n=7599

45. 45 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%)

46. 46 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

47. 47 CHARM-Preserved Investigator reported CHF hospitalisations Placebo Candesartan p=0.014 p=0.017 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes

48. 48 CHARM-Preserved Development of new diabetes 47770.600.005 (0.41-0.86) Number of casesHRp-value CandesartanPlacebo(CI)

49. 49 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

50. 50 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.

51. 51 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

52. 52 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

53. 53 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

54. 54 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%)

55. 55 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

56. 56 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%)

57. 57 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

58. 58 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

59. 59 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

60. 60 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

61. 61 CHARM LVEF  40% (Alternative and Added) All-cause death0.880.79-0.980.018 CV death0.840.75-0.950.005 HRCIp-value

62. 62 CHARM-Overall CHF hospitalisations Placebo Candesartan p<0.0001 Patients hospitalised Hospitalisations Proportion of patients (%) Number of episodes p<0.0001

63. 63 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

64. 64 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

65. 65 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:

66. 66 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: