1. CS-1 Safety of Candesartan in CHF When Added to Evidence-based Doses of ACE Inhibitors James W. Hainer, MD, MPH AstraZeneca C

2. CS-2 CHARM Protocol—Monitoring Directives for Blood Pressure, Creatinine, and Potassium At baseline Within 2 wks of dose adjustment At end of dose titration Annually At any time in the judgment of the responsible clinician 59Client fax 2-7-05

3. CS-3 Hypotension CHARM Added C Patients, n (%) Placebo N = 1272 Candesartan N = 1276 Adverse event184 (14.5)296 (23.2) Discontinuation44 (3.5)69 (5.4) Hospitalization22 (1.7)55 (4.3) Serious fatal † 1 (0.1) 3 (0.2) † One of the reported causes of death. 2.7.4 Summ Clin safety T 22, 44; SH-AHS-pooled T 150

4. CS-4 Discontinuation Due to Hypotension in Important Baseline Subgroups CHARM Added 59 All patientsAge ≥ 75Baseline SBP < 100 β-blockerSpiro CSR SH-AHS-0006 App 12.1.9.5.22; SAS pgm: rr_hypo_disc_006 n =127212762452122152227117025477

5. CS-5 CSR SH-AHS-pooled; data from section 11.3.6.1, T 175; August 11 pmD2454 Briefing Document T22; T_disk_6mos_eos.doc T99 Renal Dysfunction CHARM Added C Patients, n (%) Placebo N = 1272 Candesartan N = 1276 Adverse event119 (9.4) 196 (15.4) Discontinuation 53 (4.2)105 (8.2) Hospitalization 38 (3.0) 58 (4.5) Dialysis 20 (1.6) Serious fatal †‡ 19 (1.5) 12 (0.9) † Renal function abnormal/aggravated, renal failure acute/aggravated, or renal failure NOS. ‡ One of the reported causes of death.

6. CS-6 Discontinuation Due to Renal Dysfunction in Important Baseline Subgroups CHARM Added 59 † North American sites. All patientsAge ≥ 75SCr ≥ 2.0 † Spiro SAS pgm: rr_renal_disc_006; Client analysis SBP < 100 n = Diabetes 3823761272127624521254772152222026

7. CS-7 Hyperkalemia CHARM Added C All patients, n (%) Placebo N = 1272 Candesartan N = 1276 Adverse event46 (3.6)123 (9.6) Discontinuation11 (0.9) 49 (3.8) Hospitalization 9 (0.7) 19 (1.2) Serious, fatal † 0 2 (0.2) Sudden death174 (13.7) 143 (11.2) Fatal ventricular fibrillation 16 (1.3) 9 (0.7) 2.7.4 Summ Clin Safety T22, 44; Clin Study Rpt T 150 † One of the reported causes of death.

8. CS-8 Discontinuation Due to Hyperkalemia in Important Baseline Subgroups CHARM Added CSR SH-AHS-Pooled T 66; T68; 12.1.9.5.22; AZ BD T 22 59 † North American sites. All patientsAge ≥ 75DiabetesSpiroSCr ≥ 2.0 † K+ ≥ 5.0 † n =1272127624521238237621522250642026

9. CS-9 Summary of Adverse Events CHARM Added Patients, n (%) Placebo N = 1272 Candesartan N = 1276 Any AE 992 (78.0)1026 (80.4) Serious AE 966 (75.9) 969 (75.9) Serious fatal 413 (32.5) 377 (29.5) Treatment discontinuation due to AE 224 (17.6) 310 (24.3) Dose reduction due to AE 123 (9.7) 220 (17.2) 2.7.4 Summ Clin safety T 21 C

10. CS-10 Common Serious Fatal Adverse Events CHARM Added Patients, n (%) Placebo N = 1272 Candesartan N = 1276 Sudden death 174 (13.7)143 (11.2) Cardiac failure112 (8.8)74 (5.8) Myocardial infarction 20 (1.6)21 (1.6) Pneumonia 19 (1.5)10 (0.8) Cerebrovascular disorder 11 (0.9)12 (0.9) Death 13 (1.0)19 (1.5) Cardiac arrest 13 (1.0) Sepsis 10 (0.8)11 (0.9) Ventricular fibrillation 16 (1.3)9 (0.7) Cardiomyopathy 8 (0.6) 10-6 2.7.4 Summ Clin safety T 33

11. CS-11 Outcomes by β-blocker and Spironolactone Use CHARM Added GroupN Events placebo Events candesartan CV mortality or CHF hospitalization ACEi + spironolactoneNo: 2112 Yes: 436 441/1058 97/214 378/1054 105/222 ACEi + β-B + spironolactoneNo: 2311 Yes: 237 487/1144 51/128 444/1167 39/109 All patients2548538/1272483/1276 Table 102, App 12.1.9.4.73,74,77,78 Candesartan better Placebo better Hazard ratio (95% CI) 0.511.5 All-cause hospitalization ACEi + spironolactoneNo: 2112 Yes:436 714/1058 144/214 696/1054 156/222 ACEi + β-B + spironolactoneNo: 2311 Yes: 237 775/1144 83/128 776/1167 76/109 All patients2548858/1272852/1276 All-cause mortality ACEi + spironolactoneNo: 2112 Yes: 436 324/1058 88/214 304/1054 73/222 ACEi + β-B + spironolactoneNo: 2311 Yes: 237 368/1144 44/128 350/1167 27/109 All patients2548412/1272377/1276

12. CS-12 Cumulative Number of Hospital Admissions for Any Cause CHARM Added 0 500 1000 1500 2000 2500 3000 050100150200 No. of admissions Week Candesartan Placebo

13. CS-13 Rates of Hospital Admission by Cause CHARM Added AllCVHFNon-CV Admissions/patient/yr 0.4 0.8 1.0 1.2 1.4 1.6 0.6 0 0.2 PlaceboCandesartan

14. CS-14 All-Cause Mortality CHARM Added Time, mo Cumulative risk, % 0 5 10 15 20 25 30 35 0612182430364248 Placebo Candesartan HR = 0.88 (95% CI: 0.77, 1.02)

15. CS-15 Safety Findings and Conclusions CHARM Added As expected, due to the greater RAAS inhibition, rates of hypotension, abnormal renal function, and hyperkalemia were greater with candesartan These predictable adverse events did not translate into any increases in all-cause hospitalization and/or mortality as well as sudden death, renal failure, or ventricular fibrillation Candesartan is safe and generally well-tolerated by patients with CHF receiving evidence-based doses of ACE inhibitors C

16. CS-16 Risk Minimization CHARM Added Warnings/precautions Hypotension, renal dysfunction, hyperkalemia Patients/populations at risk Recommendations for monitoring and reducing risk Interactions with major societies/treatment guideline committees Sales force/scientific liaison training Physician, pharmacists continuing medical education programs Risks displayed in promotional materials Patient information brochures and updated websites