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C andesartan in H eart failure A ssessment of R eduction in M ortality and morbidity

CHARM. C andesartan in H eart failure A ssessment of R eduction in M ortality and morbidity. On behalf of the CHARM Programme Investigators and Committees. Background (1). ACE inhibitors, beta-blockers and spironolactone have been demonstrated to be life-saving in patients with CHF

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C andesartan in H eart failure A ssessment of R eduction in M ortality and morbidity

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  1. CHARM CandesartaninHeart failureAssessment ofReductioninMortalityand morbidity On behalf of the CHARM Programme Investigators and Committees

  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. Background (2) • Angiotensin II type 1 (AT1) 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. 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. CHARM Programme 3 component trials comparing candesartan to placebo in patients with symptomatic heart failure CHARMAlternative CHARM Added CHARMPreserved 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 each trial: CV death or CHF hospitalisation Primary outcome for Overall Programme: All-cause death

  6. Countries and national leaders Country Co-ordinator Patients Country Co-ordinator Patients Australia P. Aylward 227 Belg/Lux J. Vanhaecke 249 Canada R. S. McKelvie J-L. Rouleau 943 Czech Rep M. J. Hradec 194 Denmark P. Thayssen 487 Finland M. Niemelä 102 France A. Cohen Solal 225 Germany R. Dietz 803 Hungary I. Edes 204 Iceland A. Kristinson 82 Italy A. Maggioni 151 Malaysia C. C. Lang 140 Netherlands D.J. van Veldhuisen 420 Norway T. Gundersen 217 Poland J. Kuch 215 Portugal R. Seabra Gomes 93 Russia A. Yurenev 200 Singapore D. Zee Pin 62 South Africa A. J. Dalby 120 Spain J. Soler Soler 125 Sweden H. Persson 192 Switzerland O. Hess 68 UK/Ireland A. J. S. Coats 281 USA J. Young 1.801 M. Dunlap Total number of patients 7,601

  7. Recruitment in the three component CHARM-trials Number of patients 8000 Overall7601 6000 4000 First patient March 22 1999 Preserved 3025 Added 2548 2000 Alternative 2028 0 Jan June Dec June Dec 2001 1999 2000

  8. Inclusion and exclusion criteria Inclusion criteria • Age >18 years • Symptomatic heart failure for at least 4 weeks (New York Heart Association Class II-IV) 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

  9. Study designDose-titration and visit schedule Candesartan/matching placebo once daily 32 mg 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg Every 4 months until study end31 March 2003 Time 0 w 2 w 4 w 6 w 6 m Visit 1 2 3 4 5

  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. 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. Baseline characteristics (1) Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 Mean age (years) 67 64 67 66 Women (%) 32 21 40 32 NYHA class (%) II 48 24 60 45 III 49 73 38 52 IV 3 3 2 3Mean LVEF 30 28 54 39 Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27

  13. Baseline characteristics (2) Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 LVEF (%) - Mean 30 28 54 39 - Proportion <0.40 100 100 0 60 SBP/DBP (mmHg) 130/77 125/75 136/78 131/77 Heart rate (beats/min) 74 74 71 73

  14. Baseline characteristics (3) Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 Baseline therapy (%) ACE inhibitor 0 100 19 41 beta-blocker 55 56 56 55 diuretic 86 90 75 83 spironolactone 24 17 12 17 digitalis 46 58 28 43 aspirin 58 52 58 56 lipid lowering 41 41 42 42

  15. CHARM Programme 3 component trials comparing candesartan to placebo CHARMAlternative CHARM Added CHARMPreserved 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: CV death or CHF hosp

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

  18. Baseline characteristics Alternative Added PreservedOveralln=2028 n=2548 n=3023 n=7599 Mean age (years) 67 64 67 66 Women (%) 32 21 40 32 NYHA class (%) II 48 24 60 45 III 49 73 38 52 IV 3 3 2 3Mean LVEF 30 28 54 39 Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27

  19. Baseline characteristics Alternative Added PreservedOveralln=2028 n=2548 n=3023 n=7599 Baseline therapy (%) ACE inhibitor 0 100 19 41 beta-blocker 55 56 56 55 diuretic 86 90 75 83 spironolactone 24 17 12 17 digitalis 46 58 28 43 aspirin 58 52 58 56 lipid lowering 41 41 42 42

  20. CHARM-AlternativeBaseline characteristics Candesartan Placebo n=1013 n=1015 Reason for ACE-I intolerance (%)cough 70 74 hypotension 14 12 renal dysfunction 13 10 angioedema/anaphylaxis 4 4 other 10 11

  21. CHARM-Alternative: Primary outcome CV death or CHF hospitalisation % 50 406 (40.0%) Placebo 40 334 (33.0%) 30 Candesartan 20 10 HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001 0 0 1 2 3 3.5 years Number at risk Candesartan 1013 929 831 434 122 Placebo 1015 887 798 427 126

  22. CHARM-Alternative Secondary outcomes p-value Placebo Candesartan 0.85 CV death 219 252 CHF hosp. 207 286 CV death, CHF hosp, 353 420 MI CV death, CHF hosp, 369 432 MI, stroke CV death, CHF hosp, 396 456 MI, stroke, revasc 0.072 0.68 <0.0001 0.78 0.0007 0.80 0.001 0.81 0.002 0.6 0.8 1.0 1.2 1.4 candesartan better Hazard ratio placebo better

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

  24. CHARM-Alternative Permanent study drug discontinuations Among all patients Percent of patients Placebo 25 Candesartan 21.5 19.3 20 15 10 6.1 5 3.7 2.7 1.9 0.9 0.4 0.2 0.3 0.1 0 0 AE/lab. abnorm. Hypo-tension Increased creatinine Increasedpotassium Cough Angio-edema p=0.23 p<0.0001 p<0.0001 p=0.0005 p=0.69 p=0.50

  25. CHARM-Alternative Permanent study drug discontinuations According to prior ACE-I intolerance Percent of patients Placebo 25 23.1 Candesartan 20 15 13.6 12.0 9.1 10 (1/39) 4.2 5 2.6 1.0 0.5 0.3 0 0 Hypo-tension Increased creatinine Cough Angioedema Increasedpotassium

  26. CHARM-AlternativeConclusions • 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. CHARM Programme 3 component trials comparing Candesartan to placebo CHARMAlternative CHARM Added CHARMPreserved 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: CV death or CHF hosp

  28. CHARM-AddedBackground • 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 Aim • To evaluate the effects of adding candesartan to a ACE-inhibitor in patients with symptomatic CHF

  29. 2548 patients randomised NYHA II-IV, LVEF  40%ACE inhibitor treated Candesartan n=1276 Placebo n=1272 Lost to follow-up n=3 Lost to follow-up n=1 Completed Study n=1273 Completed Study n=1271 Median follow-up of 41 months CHARM-AddedPatient disposition

  30. Baseline characteristics Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 Mean age (years) 67 64 67 66 Women (%) 32 21 40 32 NYHA class (%) II 48 24 60 45 III 49 73 38 52 IV 3 3 2 3Mean LVEF 30 28 54 39 Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27

  31. Baseline characteristics Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 Baseline therapy (%) ACE inhibitor 0 100 19 41 beta-blocker 55 56 56 55 diuretic 86 90 75 83 spironolactone 24 17 12 17 digitalis 46 58 28 43 aspirin 58 52 58 56 lipid lowering 41 41 42 42

  32. CHARM-AddedBaseline ACE inhibitor ACE inhibitor Proportion taking Mean daily dose of ACE inhibitor (mg) Candesartan Placebo enalapril 27% 17 17 lisinopril 19% 17 17 captopril 17% 82 83 ramipril 11% 7 7

  33. CHARM-Added:Primary outcomeCV death or CHF hospitalisation % 50 538 (42.3%) Placebo 40 483 (37.9%) 30 Candesartan 20 10 HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted HR 0.85, p=0.010 0 0 1 2 3 3.5 years Number at risk Candesartan 1276 1176 1063 948 457 Placebo 1272 1136 1013 906 422

  34. CHARM-Added Secondary outcomes p-value Placebo Candesartan 0.84 CV death 302 347 CHF hosp. 309 356 CV death, CHF hosp, 495 550 MI CV death,CHF hosp, 512 559 MI, stroke CV death,CHF hosp, 548 596 MI, stroke, revasc 0.029 0.83 0.014 0.85 0.010 0.87 0.020 0.87 0.015 0.6 0.8 1.0 1.2 1.4 candesartan better Hazard ratio placebo better

  35. CHARM-AddedPrespecified subgroups, CV death or CHF hosp. p-value for treatment interaction Candesartan Placebo Beta- Yes 223/702 274/711blocker No 260/574 264/561 Recom. Yes 232/643 275/648dose of No 251/633 263/624ACE inhib. All patients 483/1276 538/1272 0.14 0.26 0.6 0.8 1.0 1.2 1.4 candesartan better Hazard ratio placebo better

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

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

  38. CHARM-AddedConclusions • 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. CHARM Programme 3 component trials comparing candesartan to placebo CHARMAlternative CHARM Added CHARMPreserved 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: CV death or CHF hosp

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

  42. Baseline characteristics Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 Mean age (years) 67 64 67 66 Women (%) 32 21 40 32 NYHA class (%) II 48 24 60 45 III 49 73 38 52 IV 3 3 2 3Mean LVEF 30 28 54 39 Medical history (%) myocardial infarction 61 56 44 53 diabetes 27 30 28 28 hypertension 50 48 64 55 atrial fibrillation 25 26 29 27

  43. Baseline signs, symptoms and radiographic findings % Alternative 35 Added Preserved 30 25 20 15 10 5 0 Oedema PND Restdyspnoea S3 Crackles JVP>6 cm Cardio-megaly Orthop-noea

  44. Baseline characteristics Alternative Added PreservedOverall n=2028 n=2548 n=3023 n=7599 Baseline therapy (%) ACE inhibitor 0 100 19 41 beta-blocker 55 56 56 55 diuretic 86 90 75 83 spironolactone 24 17 12 17 digitalis 46 58 28 43 aspirin 58 52 58 56 lipid lowering 41 41 42 42

  45. CHARM-Preserved: Primary outcome CV death or CHF hospitalisation % 30 366 (24.3%) Placebo 25 333 (22.0%) 20 Candesartan 15 10 HR 0.89 (95% CI 0.77-1.03), p=0.118Adjusted HR 0.86, p=0.051 5 0 0 1 2 3 3.5 years Number at risk Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195

  46. CHARM-Preserved Primary and secondary outcomes Covariate adjustedp-value p-value Placebo Candesartan 0.89 0.118 0.051 CV death, CHF hosp. 333 366 - CV death 170 170 - CHF hosp. 241 276 CV death, CHF hosp, 365 399 MI CV death,CHF hosp, 388 429 MI, stroke CV death,CHF hosp, 460 497 MI, stroke, revasc 0.99 0.918 0.635 0.85 0.072 0.047 0.90 0.126 0.051 0.88 0.078 0.037 0.91 0.123 0.13 0.8 1.0 1.2 candesartan better Hazard ratio placebo better

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

  48. CHARM-Preserved Development of new diabetes Number of cases HR p-value Candesartan Placebo (CI) 47 77 0.60 0.005 (0.41-0.86)

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

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

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