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SS-1 Candesartan Support Slides. SS-2 Baseline Beta-Blocker Charm Added β-blocker Of patients on β-blockers Mean daily dose of β-blocker CandesartanPlacebo.

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Presentation on theme: "SS-1 Candesartan Support Slides. SS-2 Baseline Beta-Blocker Charm Added β-blocker Of patients on β-blockers Mean daily dose of β-blocker CandesartanPlacebo."— Presentation transcript:

1 SS-1 Candesartan Support Slides

2 SS-2 Baseline Beta-Blocker Charm Added β-blocker Of patients on β-blockers Mean daily dose of β-blocker CandesartanPlacebo Metoprolol50%89 mg84 mg Carvedilol31%29 mg28 mg Atenolol8%44 mg47 mg Bisoprolol5%6 mg5 mg Other6%–– 65

3 SS-3 37 Patients, n (%) Val-HeFT n = 5010 CHARM Added n = 2548 All patients Deaths979 (19.5)789 (26.2) CV deaths846 (16.9)649 (25.5) Patients on ACEi and β-blockern = 1610n = 1413 Deaths226 (14.0)370 (26.2) CV deaths201 (12.5)307 (21.7) Death and CV Death in Patients on ACEi and β-blocker CHARM Added Compared to Val-HeFT CHARM FDA questions.ppt

4 SS-4 Discontinuation † by Baseline Estimated GFR CHARM Added AZ BD T 40 P 75 Placebo n = 464 Candesartan n = 465 eGFR, mL/min/1.73 m 2 < 6060 - < 90≥ 90< 6060 - < 90≥ 90 Patients in each stratified group, n 153203108153206106 Discontinuation in each stratified group, n (%) 46 (30.1)33 (16.3)13 (12.0)63 (41.2)60 (29.1)12 (11.3) † Calculated by Modification of Diet in Renal Disease formula. North American sites.

5 SS-5 Outcomes in Patients Discontinued for Renal Dysfunction CHARM Added 62 Outcome_data.ppt Patients, n/N (%) Alive at end of studyPlaceboCandesartan Renal dysfunction20/53 (38)58/105 (55)

6 SS-6 Estimated GFR † Over Study Time CHARM Added 0 20 40 60 80 100 120 140 BaselineWk 6Mo 14Mo 38LOCF 59 SAS pgm: box_wisher_gfr_006 0 20 40 60 80 100 120 140 BaselineWk 6Mo 14Mo 38LOCF PlaceboCandesartan n =464424365255447n =465412359234436 LOCF = Last observation carried forward. † Calculated by Modification of Diet and Renal Disease formula. North American sites. eGFR, ml/min/1.73 m 2 95% 75% 25% 5% Median

7 SS-7 CV Mortality or CHF Hospitalization Subgroup Analysis CHARM Added Patients, n/N PlaceboCandesartan Age< 65211/636192/632 ≥ 65 < 75193/391176/432 ≥ 75134/245115/212 GenderMale427/1000387/1006 Female111/27296/270 NYHAII104/30293/312 III / IV434/970390/964 LVEF< 25203/382186/388 ≥ 25335/890297/888 Medical history DiabetesNo334/890291/900 Yes204/382192/376 HypertensionNo261/653248/667 Yes277/619235/609 Previous MINo224/569188/562 Yes314/703295/714 Atrial fibrillationNo375/931335/929 Yes163/341148/346 DiureticNo27/12626/128 Yes511/1146457/1148 DigitalisNo185/519172/541 Yes353/753311/735 AspirinNo264/613240/624 Yes274/659243/652 Lipid loweringNo336/751294/748 Yes202/521189/528 USNo410/970355/981 Yes128/302128/295 All patients (N = 2548)538/1272483/1276 DV CSR SH-AHS-0006 T 101, 102 20 Placebo betterCandesartan better Hazard ratio (95% CI) 0.60.70.80.911.11.21.31.41.51.6 Interaction p value 0.115

8 CV Death or CHF Hospitalization by Country CHARM Added Patients, n Sweden64 Norway97 Denmark207 Finland14 Iceland21 Italy14 Spain17 Portugal19 The Netherlands128 France70 Czech Republic71 Poland79 Hungary69 Switzerland25 Belgium/Luxembourg82 Malaysia38 Singapore21 United Kingdom89 Germany346 Canada357 US597 Australia76 South Africa32 Russia15 All patients2548 Hazard ratio (95% CI) > > > > > 012345 46 US-8 Interaction p value 0.557

9 SS-9 Patients, n/N p value for interaction PlaceboCandesartan CHARM Added US128/302128/295 0.115 Non-US410/970355/981 All patients538/1272483/1276 CHARM Alternative US99/23882/232 0.675 Non-US307/777252/781 All patients406/1015334/1013 CHARM Preserved US105/36195/3730.733 Non-US261/1148238/1141 All patients366/1509333/1514 2 Low LVEF trials pooled US227/540210/527 0.138 Non-US717/1747607/1762 All patients944/2287817/2289 CHARM—3 trials pooled US332/901305/900 0.272 Non-US978/2895845/2903 All patients1310/37961150/3803 US vs Non-US Patients CV Death or CHF Hospitalization CHARM Program Candesartan better Placebo better SH-AHS-0006 T101, 102, 12.1.9.11.1, 2, 3; SH-AHS-0003 T106, 107, 12.1.9.11.1, 2, 3; SH-AHS-0003, 0006 - 12.1.9.4.126, 87, 12.1.9.11.4, 5, 6; SH-AHS-pooled T 12.1.9.4.1; 12.1.9.11.1, 12.1.9.11.2,12.19.94.40, DV Hazard ratio (95% CI) 0.60.81.01.21.4

10 SS-10 CV Death or CHF Hospitalization by US and Non-US Patients CHARM Program Patients, n/N p value for interaction PlaceboCandesartan CHARM Added US128/302128/295 0.115 Non-US410/970355/981 All patients538/1272483/1276 CHARM Alternative US99/23882/232 0.675 Non-US307/777252/781 All patients406/1015334/1013 2 Low LVEF trials pooled US227/540210/527 0.138 Non-US717/1747607/1762 All patients944/2287817/2289 CHARM Overall—3 trials pooled US332/901305/900 0.272 Non-US978/2895845/2903 All patients1310/37961150/3803 Candesartan better Placebo better Hazard ratio (95% CI) DV 0.60.81.01.21.4

11 SS-11 Baseline Medications CHARM Added Patients, % US n = 597 Non-US n = 1951 Baseline therapy, % ACE inhibitor100 Recommended dose59.148.1 β-blocker 56.655.1 Diuretic 91.189.7 Spironolactone15.217.7 Digitalis 75.053.3 Aspirin 51.851.4 Lipid-lowering 48.139.1 CSR SH-AHS-0006 T 20; 12.1.9.3.1 50

12 SS-12 Baseline Medical History CHARM Added US n = 597 Non-US n = 1951 Medical history, % Myocardial infarction51.356.9 Diabetes38.427.1 Hypertension67.042.4 Atrial fibrillation Coronary artery bypass graft PCI ICD Pacemaker 25.8 32.2 19.4 8.5 13.9 27.3 22.1 13.3 2.5 7.6 CSR SH-AHS-pooled T 81, S1; CSR SH-AHS-0007 T 80, S1; CSR SH-AHS-0003 T 85, S1; CSR SH-AHS-0006 T 80, S1

13 SS-13 Most Common † Adverse Events Leading to Treatment Discontinuation CHARM Added Patients, n (%) North AmericaRest of world Placebo n = 477 Candesartan n = 477 Placebo n = 795 Candesartan n = 799 Abnormal renal function ‡ 30 (6.3)46 (9.6)23 (2.9)59 (7.4) Cardiac failure32 (6.7)28 (5.9)49 (6.2)41 (5.1) Hypotension17 (3.6)28 (5.9)27 (3.4)41 (5.1) Hyperkalemia 8 (1.7)21 (4.4) 3 (0.4)28 (3.5) Acute renal failure 8 (1.7) 5 (1.0) 6 (0.8)10 (1.3) † Five leading reasons. ‡ Renal function abnormal/aggravated.

14 SS-14 Patients, n/N CHARMPlaceboCandesartan AlternativeNon-black387/970328/985 Black19/456/28 AddedNon-black509/1210459/1211 Black29/6224/65 PreservedNon-black355/1452317/1445 Black11/5716/69 3 PooledNon-black1251/36321104/3641 Black59/16446/162 All patients1310/37961150/3803 CV Death or CHF Hospitalization by Black and Non-Black Patients CHARM Overall Candesartan better Placebo better 0.40.60.811.21.41.60.2 Hazard ratio (95% CI)

15 SS-15 Time to First All-Cause Hospitalization 1 mo6 mo12 mo Candesartan69297458 Placebo80304485

16 SS-16 At risk, n Placebo12721017852736338 Candesartan12761074914793395 Primary Outcome CV Death or CHF Hospitalization CHARM Added 123 Time, yr 0 10 20 30 40 50 Placebo Candesartan % 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%) 15% risk reduction 0 NNT = 23

17 SS-17 Investigator-Reported HF Hospitalizations for the Individual CHARM Trials and Overall Program 608 836 566 2010 445 607 402 1454 0 500 1000 1500 2000 2500 AlternativeAddedPreserved3 pooled Total hospitalizations for CHF Placebo Candesartan p < 0.001 † p = 0.002 † p = 0.013 † p < 0.001 † † Wilcoxon Rank Sum Test based on number of hospitalizations/follow up time.

18 SS-18 Total Number of Hospitalizations CHARM Overall—3 Trials Pooled and CHARM Added 7178 2798 6690 2462 0 1500 3000 4500 6000 7500 CHARM OverallCHARM Added Total number of hospitalizations Placebo Candesartan

19 SS-19 Doses of Most Common ACE Inhibitors at Selected Study Visits CHARM Added Mean ACEi dose, mg/d Patients at baseline, % 1 Baseline 4 6 wk 5 6 mo 7 14 mo 10 26 mo 13 38 mo 19 Closing visit Enalapril26.7P C 17.2 16.8 17.3 16.3 17.6 16.6 17.2 15.7 16.9 16.4 16.4 17.2 16.5 15.8 Lisinopril19.1P C17.7 17.3 17.6 17.7 17.5 17.6 17.1 17.9 17.617.5 19.4 18.1 Captopril16.8P C 82.7 82.2 80.7 81.1 81.4 79.4 81.1 76.8 82.7 72.8 82.8 72.4 77.2 69.4 Ramipril11.0P C 7.3 6.8 7.5 6.7 7.8 6.7 8.7 6.7 7.9 6.8 7.9 7.2 Attachment A, 28 Jan Addendum to Jan Briefing Doc

20 SS-20 BD Table 48—Summary Table of Concomitant ACE Inhibitor Use (CHARM-Added)

21 SS-21 Patients, n CV death or CHF hospitalization Recommended dose of ACEiNo1012 Yes1535 Maximum dose of ACEiNo1788 Yes759 All-cause mortality or CHF hospitalization Recommended dose of ACEiNo1012 Yes1535 Maximum dose of ACEiNo1788 Yes759 CV death or CHF hospitalization or nonfatal MI Recommended dose of ACEiNo1012 Yes1535 Maximum dose of ACEiNo1788 Yes759 All-cause mortality Recommended dose of ACEiNo1012 Yes1535 Maximum dose of ACEiNo1788 Yes759 Endpoint Analyses Based on Recommended or Maximum † ACEi Doses During Study CHARM Added 36 Peter Johanson ACE analyses to US T 11 – T 20 Candesartan betterPlacebo better † FDA communication 12-17-04. 0.60.70.80.911.11.21.3 Hazard ratio (95% CI)

22 SS-22 Doses of Most Common ACEi at Selected Study Visits CHARM Added Enalapril (27%) Captopril (17%) Lisinopril (19%) Ramipril (11%) Baseline Closing Baseline Closing Baseline Closing Baseline Closing 6 wk6 mo14 mo26 mo38 mo6 wk6 mo14 mo26 mo38 mo

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