1. McMurray JJV, Young JB, Dunlap ME, Granger CB, Hainer J, Michelson EL et al on behalf of the CHARM investigators Relationship of dose of background angiotensin-converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Added trial CHARM

2. CHARM participants 618 centers in 26 countries

3. 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) Pfeffer et al. Lancet 2003

4. 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

5. 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%) McMurray et al. Lancet 2003 CHARM-Added Primary outcome, CV death or CHF hospitalisation

6. RecommendedYes232/643275/648 dose of ACE-INo251/633263/624 All patients483/1276538/1272 p-value for treatment interaction 0.26 0.60.81.01.21.4 CHARM-Added Prespecified subgroups, CV death or CHF hospitalisation Candesartan better Hazard ratio Placebo better Candesartan event/n Placebo event/n McMurray et al. Lancet 2003

7. McMurray et al. Am Heart J 2006 CHARM-Added Use of ACE inhibitors  Stable dose of ACE inhibitor for ≥30 days  Investigators were provided list of recommended doses of ACE inhibitor based on target doses in positive trials  Individualised optimum doses of ACE inhibitor at baseline  96% of patients were determined to be on an individualised optimum dose of ACE inhibitor at baseline

8. CHARM-Added Dose of enalapril achieved, compared to other trials using forced titration McMurray et al. Am Heart J 2006 CONSENSUS (1987)12720 bid18.4 SOLVD-T (1991) † 128410 bid16.6 V-HeFT II (1991)40310 bid15.0 OVERTURE (2002)288410 bid17.7 CARMEN (2004)190 E only10 bid 16.8 191 10 bid14.9 E+Carv CHARM Added680-17.0 TrialNTarget dose Mean daily dose mgmg † N.B. active run-in; 49% reached target dose

9. CHARM-Added Investigators did optimise enalapril dose  Daily dose of enalapril in CHARM-Added exceeded those in other outcome studies using add-on therapy – MERIT-HF, enalapril dose 14 mg – RALES, enalapril dose 15 mg – CHARM-Added, enalapril dose 17.0 mg  As well as those used in clinical practice – Weighted mean daily dose of enalapril from 13,764 patients was 13.8 mg – CHARM-Added, enalapril dose 17.0 mg McMurray et al. Am Heart J 2006

10. CHARM-Added Summary of ACE inhibitor dose used  CHARM Added patients received – Evidence-based ACE inhibitor (80% of patients) – ACE inhibitor doses comparable to those achieved with forced titration (eg, 17 mg of enalapril) – Higher doses of ACE inhibitor than in other recent “add-on” treatment trials – Much higher doses of ACE inhibitor than in ordinary clinical practice McMurray et al. Am Heart J 2006

11. Time0 w2 w4 w6 w6 m Visit12345 32 mg Candesartan/ placebo 16 mg 8 mg 32 mg 4 mg 16 mg 8 mg ACE inhibitor mean daily dose, mg Enalapril1717171717161717 Lisinopril18 18181718171818 Captopril83 82828180797878 Ramipril7 7777787 Trandolapril2.52.42.52.42.52.52.52.5 14 m 7 26 m 10 38 m 13 CHARM-Added Dosing and visit schedule McMurray et al. Am Heart J 2006

12. Proportion of patients on recommended or FDA defined maximum dose of ACE inhibitor at baseline McMurray et al. Am Heart J 2006  Recommended  Maximum  Maximum (CHARM pre-spec.)(FDA) † (FDA revised) ‡ n=1291n=721n=529 Enalapril27205220524010 Lisinopril19205240152052 Captopril1715021150213002 Ramipril11103910391039 Trandolapril6290427427 Perindopril6483161161 Quinapril52060807807 Fosinopril5205940204020 Benazepril32062805805 Other1 All100512821 ACE inhibitor% onDosePatientsDosePatientsDosePatients Rxmg/d %mg/d%mg/d% † FDA communication December 2004 ‡ FDA communication January 2005

13. CV death or CHF hospitalisation McMurray et al. Am Heart J 2006 Patients n CHARM Added CHARM Alternative 2 Pooled Low LVEF trials Maximum dose of ACEi (FDA) ‡ revised Maximum dose of ACEi (FDA) † Recommended dose of ACEi (CHARM) No Yes No Yes No Yes 2548 2028 4576 2019 529 1827 721 1257 1291 0.60.70.80.911.11.21.3 Hazard ratio (95% CI) 0.26 0.78 0.29 p-value for interaction Candesartan better Placebo better † FDA communication December 2004 ‡ FDA communication January 2005

14. Patients n p-value for Interaction Candesartan better Placebo better All-cause mortality CV death or HF hospitalization or non-fatal MI All-cause mortality or HF hospitalization CV death or HF hospitalisation Recommended dose of ACEiNo1257 Yes1291 Maximum dose of ACEi † No2019 Yes529 Recommended dose of ACEiNo1257 Yes1291 Maximum dose of ACEi † No2019 Yes529 Recommended dose of ACEiNo1257 Yes1291 Maximum dose of ACEi † No2019 Yes529 Recommended dose of ACEiNo1257 Yes1291 Maximum dose of ACEi † No2019 Yes529 All patients2548 0.26 0.29 0.30 0.34 0.58 0.60 0.85 0.48 Other outcome analyses McMurray et al. Am Heart J 2006 0.60.70.80.911.11.21.30.5 Hazard ratio (95% CI) † FDA communication January 2005

15. All-cause mortality CV death or HF hospitalization or non-fatal MI All-cause mortality or HF hospitalization CV death or HF hospitalization Recommended dose of ACEiNo1383 Yes1165 Maximum dose of ACEi † No2072 Yes476 Recommended dose of ACEiNo 1383 Yes 1165 Maximum dose of ACEi † No 2072 Yes 476 Recommended dose of ACEiNo 1380 Yes 1168 Maximum dose of ACEi † No 2072 Yes 476 Recommended dose of ACEiNo 1432 Yes 1116 Maximum dose of ACEi † No 2089 Yes 459 All patients2548 0.10 0.25 0.09 0.28 0.18 0.24 0.13 0.42 Other outcome analyses Patients maintained on ACE inhibitor doses over the trial McMurray et al. Am Heart J 2006 0.60.70.80.911.11.21.30.5 Hazard ratio (95% CI) † FDA communication January 2005 Patients n p-value for Interaction Candesartan better Placebo better

16. 0.60.70.80.911.11.21.3 Hazard ratio (95% CI) 0.5 All-cause mortality CV death or HF hospitalization or non-fatal MI All-cause mortality or HF hospitalization CV death or HF hospitalization Recommended dose of ACEiNo692 Yes721 Maximum dose of ACEi † No1100 Yes313 Recommended dose of ACEiNo 692 Yes 721 Maximum dose of ACEi † No 1100 Yes 313 Recommended dose of ACEiNo 692 Yes 721 Maximum dose of ACEi † No 1100 Yes 313 Recommended dose of ACEiNo 692 Yes 721 Maximum dose of ACEi † No 1100 Yes 313 Hazard ratio (95% CI) All patients1413 0.69 0.64 0.77 0.70 0.79 0.32 0.89 0.57 † FDA communication January 2005 Other outcome analyses Patients on beta-blocker combined with ACE inhibitor McMurray et al. Am Heart J 2006 Patients n p-value for Interaction Candesartan better Placebo better

17. In patients with symptomatic CHF and left ventricular systolic dysfunction, the addition of candesartan to an ACE inhibitor provides incremental benefit. There was no evidence of modification of the beneficial effect of candesartan on CV death or CHF hospitalisation based on ACE inhibitor dose or choice of ACE inhibitor McMurray et al. Am Heart J 2006 Summary CHARM Added