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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. 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. 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

  5. AT1-receptor blockers: mechanism of action • Angiotensin II type 1 (AT1) receptor blockers – pharmacologically distinct mechanism of inhibiting RAAS • AT1-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 AT1-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. AT1-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. Candesartan 50 Enalapril 40 36 30 30 30 25 Patients with regression of ventricular mass (%) 20 10 0 Week 24 Week 48 AT1-receptor blockers reduce left ventricular hypertrophy: CATCH study Cuspidi et al. J Hypertens 2002; 20: 2293–300

  8. Trials with AT1-receptor blockers in CHF: ELITE II and Val-HeFT • 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: 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. Candesartan: potent and long-acting AT1-receptor blocker • Highly potent [1] • Long-acting [1] • 10,000 greater affinity for AT1-receptor than AT2-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. Clinical experience with candesartan in CHF • 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: in patients with history of ACE inhibitor intolerance, similar percentage of patients completed 12-week treatment period on candesartan vs placebo [2] • STRETCH study: maximal exercise capacity increased dose-dependently with candesartan compared to placebo [3] • 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. 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. CHARM programme studies • CHARM-Alternative: patients with depressed LV systolic function (LVEF  40%) and not treated with an ACE inhibitor (due to intolerance) • CHARM-Added: patients with depressed LV systolic function (LVEF  40%) and treated with an ACE inhibitor • 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. CHF: NYHA class II–IV EF  40% EF > 40% ACE-intolerance ACE-I treated Randomisation ‘Alternative’ Randomisation ‘Added’ Randomisation ‘Preserved’ Candesartan  4/8 32 mg Placebo Titration period Visit every 4 months up to at least 24 months Mortality/morbidity endpoints Design of CHARM programme Swedberg et al. J Card Failure 1999; 5(3): 276–82

  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. 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

  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. 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. 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

  19. 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

  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. 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

  22. 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

  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. 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. Baseline data: number of patients randomised per country and study McMurray et al. Eur J Heart Fail; 5(3): 261–70 Country CHARM- CHARM- CHARM- Total Alternative Added Preserved Australia 54 76 97 227 Belgium 60 82 106 248 Canada 208 357 378 943 Czech Republic 66 71 57 194 Denmark 92 207 188 487 Finland 29 14 59 102 France 55 70 100 225 Germany 154 346 303 803 Hungary 66 69 69 204 Iceland 25 21 36 82 Italy 20 14 91 151 Luxembourg 0 0 1 1 Malaysia 53 38 49 140 The Netherlands 173 128 118 419 Norway 47 97 73 217 Poland 66 79 70 215 Portugal 21 19 53 93 Russia 53 15 132 200 Singapore 20 21 21 62 South Africa 48 32 40 120 Spain 50 17 58 125 Sweden 53 64 75 192 Switzerland 15 25 28 68 United Kingdom 104 89 87 280 USA 470 597 734 1801 Total 2028 2548 3023 7599

  26. Baseline data: characteristics of patients Variable CHARM-Alternative CHARM-Added CHARM-Preserved (n=2028) (n=2548) (n=3025) Mean age (years) 67 64 67 Males (%) 68 79 60 LVEF 0.30 0.28 0.54 Diabetes mellitus (%) 27 30 28 Hypertension (%) 50 48 64 Atrial fibrillation (%) 25 26 29 Previous MI (%) 62 56 44 Angina pectoris (%) 58 53 60 Previous stroke (%) 9 9 9 NYHA II (%) 48 24 61 NYHA III (%) 49 73 38 NYHA IV (%) 4 3 2 Current smoker (%) 14 17 14 McMurray et al. Eur J Heart Fail; 5(3): 261–70

  27. 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

  28. 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

  29. 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

  30. Baseline data: background medication Variable CHARM- CHARM- CHARM- Alternative Added Preserved Digoxin (%) 46 59 28 Diuretics (%) 86 90 75 Loop diuretics (%) 78 84 63 Spironolactone (%) 24 17 12 Beta blocker (%) 55 56 56 Calcium antagonist (%) 16 10 31 Long acting nitrates (%) 37 33 33 Amiodarone (%) 12 11 8 Lipid lowering agent (%) 42 42 42 Oral anticoagulant (%) 31 38 25 Aspirin (%) 58 52 58 McMurray et al. Eur J Heart Fail; 5(3): 261–70

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

  32. Baseline data: reason for ACE-intolerance for patients in CHARM-Alternative ACE-inhibitor intolerance due to: CHARM-Alternative All Men Women Angioedema, anaphylaxis (%) 4 4 5 Cough (%) 72 69 77 Symptomatic hypotension (%) 13 14 10 Renal dysfunction (%) 12 13 8 Other adverse events (%) 11 11 10 McMurray et al. Eur J Heart Fail; 5(3): 261–70

  33. Baseline data: physical examination and ECG Variable CHARM-Alternative CHARM-Added CHARM-Preserved BMI (kg/m2) 27 28 29 Heart rate (bpm) 74 74 71 Mean DBP (mm Hg) 77 75 78 Mean SBP (mm Hg) 130 125 136 Atrial fib/flutter (%) 14 16 16 Bundle branch block (%) 30 31 14 Pathological Q waves (%) 30 27 20 LVH (%) 15 17 15 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. Baseline data: ELITE-II vs CHARM-Alternative and Val-HeFT vs CHARM-Added Variable Alternative to ACEI Addition to ACEI ELITE-II CHARM- Val-HeFT CHARM- [1] Alternative [4] [2,3] Added [4] Number 3152 2028 5010 2548 Mean age (years) 71 67 63 64 Men (%) 70 68 80 79 LVEF (%) 31 30 27 28 NYHA II (%) 49 48 62 24 NYHA III (%) 45 49 36 73 Digoxin (%) 50 46 68 58 Beta blocker 24 55 36 55 Spironolactone (%) — 24 2 17 ACEI=ACE inhibitors 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. 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 AT1-receptor blockers in CHF McMurray et al. Eur J Heart Fail; 5(3): 261–70

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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

  50. 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

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