CLINICAL REVIEW

 

                Application Type    NDA 20-838

            Submission Number    S-022

                 Submission Code    SE 1           

 

                                           

 

                  Reviewer Name    Khin Maung U, MD

    Review Completion Date    16-Oct-2004

 

               Established Name    Candesartan Cilexetil

      (Proposed) Trade Name    Atacandâ

               Therapeutic Class    Selective AT1 subtype angiotensin

                                                II receptor antagonist

                            Applicant    AstraZeneca LP

 

            Priority Designation    P

 

                         Formulation    oral

                  Dosing Regimen    Initial dose 4 mg q.d., up-titrated

                                                to a target dose of 32 mg q.d.

                            Indication    Treatment of heart failure

(Labeling claim = Treatment with Atacandâ reduces relative risk of death from cardiovascular causes or hospitalization for heart failure, and improves symptoms)

            Intended Population    Patients with chronic heart failure

                                                (NYHA functional class II – IV)


Table of Contents

Table of Contents.. 2

List of Tables.. 5

List of Figures.. 17

1      Executive Summary.. 22

1.1        Recommendation on Regulatory Action.. 22

1.2        Recommendation on Postmarketing Actions. 23

1.2.1      Risk Management Activity. 23

1.2.2      Required Phase 4 Commitments. 23

1.2.3      Other Phase 4 Requests. 23

1.3        Summary of Clinical Findings. 24

1.3.1      Brief Overview of Clinical Program.. 24

1.3.2      Efficacy. 25

1.3.3      Safety. 26

1.3.4      Dosing Regimen and Administration. 26

1.3.5      Drug-Drug Interactions. 26

1.3.6      Special Populations. 26

2      Introduction and Background.. 27

2.1        Product Information.. 27

2.2        Currently Available Treatment for Indications. 27

2.3        Availability of Proposed Active Ingredient in the United States. 27

2.4        Important Issues with Pharmacologically Related Products. 27

2.5        Pre-submission Regulatory Activity.. 27

2.6        Other Relevant Background Information.. 27

3      Significant Findings from Other Review Disciplines.. 27

3.1        CMC (and Product Microbiology, if Applicable) 27

3.2        Animal Pharmacology/Toxicology.. 27

4      Data Sources, Review Strategy, and Data Integrity.. 28

4.1        Sources of Clinical Data.. 28

4.2        Tables of Clinical Studies. 30

4.3        Review Strategy.. 31

4.4        Data Quality and Integrity.. 35

4.5        Compliance with Good Clinical Practices. 35

4.6        Financial Disclosures. 35

5      Clinical Pharmacology.. 37

5.1        Pharmacokinetics. 38

5.2        Pharmacodynamics. 42

5.3        Exposure-Response Relationships. 51

5.3.1      Total exposure of candesartan. 51

5.3.2      Dose Selection. 52

6      Integrated Review of Efficacy.. 54

6.1        Indication.. 54

6.1.1      Methods. 54

6.1.2      General Discussion of Endpoints. 57

6.1.3      Study Design. 62

6.1.4      Efficacy Findings. 63

6.1.5      Is there a dose response of the dose of candesartan (plus heart failure dose or low dose of ACE-inhibitors) on the primary and secondary efficacy outcomes?. 72

6.1.6      Efficacy Conclusions. 77

7      Integrated Review of Safety.. 83

7.1        Methods and Findings. 83

7.1.1      Deaths. 83

7.1.2      Other Serious Adverse Events. 86

7.1.3      Discontinuations and Other Significant Adverse Events. 87

7.1.4      Common Adverse Events. 101

7.1.5      Laboratory Findings. 104

7.1.6      Vital Signs. 107

7.1.7      Overdose Experience. 112

7.1.8      Postmarketing Experience. 112

7.2        Adequacy of Patient Exposure and Safety Assessments. 113

7.2.1      Extent of exposure (dose/duration) 113

7.2.2      Literature. 117

7.2.3      Additional submissions, including safety update. 117

7.3        Summary of Selected Drug-Related Adverse Events, Important Limitations of Data, and Conclusions. 117

7.3.1      Hypotensive events. 117

7.3.2      Abnormal renal function. 122

7.3.3      Hyperkalemia. 126

7.3.4      Angioedema. 130

7.3.5      Myocardial ischemia. 131

7.3.6      Abnormal hepatic function. 132

7.3.7      Neoplasms. 132

7.3.8      Rare Adverse events in CHARM-Pooled (SH-AHS-0003, -0006, -0007) Studies: 133

7.4        Is there is relationship between the dose of candesartan and the important adverse events?  134

7.4.1      Relationship of dose of candesartan to permanent study drug discontinuation due to an adverse event or an abnormal laboratory. 134

7.4.2      Relationship of dose of candesartan to permanent study drug discontinuation due hypotension. 134

7.4.3      Relationship of dose of candesartan to permanent study drug discontinuation due to hyperkalemia. 135

7.4.4      Relationship of dose of candesartan to permanent study drug discontinuation due to increased serum creatinine  135

7.4.5      Relationship of dose of candesartan to dose reductions of study drug due to an adverse event or an abnormal laboratory  136

7.5        Summary of Safety.. 136

7.5.1      Summary of safety for CHARM-Added (SH-AHS-0006) Study: 136

7.5.2      Summary of safety for CHARM-Pooled (SH-AHS-0003, -0006, -0007) Studies: 137

7.5.3      Pooling Data Across Studies to Estimate and Compare Incidence. 139

8      Additional Clinical Issues.. 140

8.1        Dosing Regimen and Administration.. 140

8.1.1      Dose of Candesartan (or ARB) 140

8.1.2      ACE inhibitor dose. 144

8.2        Drug-Drug Interactions. 150

8.2.1      Is there an interaction of candesartan with b-blockers?. 151

8.2.2      Is there an interaction of candesartan with spironolactone or aldosterone blockers?. 160

8.2.3      Is there an interaction of candesartan with digoxin?. 165

8.3        Special Populations. 167

8.3.1      CHF patients with symptomatic hypotension. 167

8.3.2      CHF patients with impaired renal function (creatinine increase) 167

8.3.3      CHF patients with hyperkalemia. 168

8.3.4      Geriatric patients with CHF. 168

8.4        Pediatrics. 168

8.5        Literature Review... 169

8.5.1      Are angiotensin II-AT1-receptor blockers (ARBs) comparable to ACE-inhibitors or superior to ACE inhibitors?  170

8.5.2      Are the effects of ARBs additive on top of ACE-inhibitors?. 185

8.6        Issues related to the role of angiotensin receptor blockers in patients with heart failure and left ventricular dysfunction.. 191

8.7        Advisory Committee Meeting.. 193

8.8        Postmarketing Risk Management Plan.. 193

8.9        Other Relevant Materials. 193

9      Overall Assessment.. 195

9.1        Conclusions. 195

9.2        Recommendation on Regulatory Action.. 197

9.3        Recommendation on Postmarketing Actions. 198

9.3.1      Risk Management Activity. 198

9.3.2      Phase 4 Requests. 199

9.4        Labeling Review... 200

9.5        Comments to Applicant.. 203

10     Appendices.. 204

10.1       Review of Individual Study Reports. 204

10.1.1         Appendix PK1  Study EC602. 204

10.1.2         Appendix PK2  Study EC605-A (PK component) 206

10.1.3         Appendix PK3  Study EC608. 208

10.1.4         Appendix PK4  CPH 102. 210

10.1.5         Appendix PD1  Study EC602: 213

10.1.6         Appendix PD2  Study EC605-A (PD component) 215

10.1.7         Appendix PD3  Study EC604 (STRETCH Study) 219

10.1.8         Appendix PD4  Study EC610. 225

10.1.9         Appendix PD5  Study EC614. 228

10.1.10       Appendix PD6  SH-AHS-0001. 231

10.1.11       Appendix PD7  Study OCT105. 237

10.1.12       Appendix PD8  Study OCT106. 238

10.1.13       Appendix PD9  Study  CPH101. 239

10.1.14       Appendix PD10  Study CPH103. 240

10.1.15       Appendix PD11  Study CPH104. 241

10.1.16       Appendix PD12  Study SH-AHS-0004 (Ellis Study) 242

10.1.17       Appendix PD13  Study SH-AHS-0005 (Vaile study) 243

10.1.18       Appendix PD14  Study Hikosaka (Publication) 243

10.1.19       Apendix 15  CHARM-Added (SH-AHS-0006) Trial 244

10.1.20       Appendix 16 CHARM-Pooled studies. 314

10.2       Line-by-Line Labeling Review... 367

11     References.. 395


List of Tables

Table 1   Endpoints in the CHARM-Alternative study (SH-AHS-0003), CHARM-Added study (SH-AHS-0006) and the CHARM Program (Pooled studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007)............................................................................. 25

Table 2      List of Clinical Efficacy Trials.................................................................................................................................. 30

Table 3   Studies of CHF patients treated with ACE inhibitors AND Candesartan or placebo.......................................... 31

Table 4      List of Clinical pharmacology studies as submitted by the sponsor............................................................... 37

Table 5   Studies of patients with CHF treated with candesartan or placebo in which changes in hemodynamics, neurohormones changes and/or exercise tolerance were measured......................................................................................................................... 37

Table 6      Clinical studies of pharmacokinetics..................................................................................................................... 38

Table 7      Study EC608 – Summary statistics for candesartan and enalaprilat pharmacokinetic parameters separated by renal groups after repeat dose administration................................................................................................................................................. 40

Table 8        Study CPH102 – Pharmacokinetic parameters of M-I and M-II after administration of candesartan cilexetil in multiple doses of 4 mg/day in 5 patients with CHF.......................................................................................................................................... 41

Table 9    Study CPH102 – Urinary excretions of M-I and M-II.............................................................................................. 41

Table  10    Studies of patients with CHF treated with candesartan or placebo in which hemodynamics, neurohormonal changes and/or exercise tolerance were measured..................................................................................................................................... 42

Table 11   Studies of patients with CHF treated with candesartan showing the PD endpoints (statistically significant changes, except where mentioned as NS)................................................................................................................................................................. 43

Table 12   Study EC602:  PCWPmean –Mean AUC0-12 ±SD (difference to pre-dose [0h], Peak Change±SD (Efficacy (ITT) Population)           44

Table 13   Study EC602:  PAPmean –Mean AUC0-12 ±SD (difference to pre-dose [0h], Peak Change±SD (Efficacy (ITT) Population)              45

Table 14   Study EC605-A:  Pulmonary capillary wedge pressure – One-way ANCOVA................................................... 45

Table 15  Hemodynamic parameters in study CPH103 (Translated page 118 of Japanese report).................................... 46

Table 16  Ejection fraction and its % difference at “run-in” and “end-of-treatment”.......................................................... 46

Table 17   Study EC604 – Results of the non- parametric ANCOVA on the change in the cardiothoracic ratio between baseline (Visit 5) and last value – Intent-to-treat population ( n= 807)............................................................................................................. 47

Table 18   Study EC604 – Results of the non-parametric ANCOVA on the change in the cardiothoracic ratio between baseline (Visit 5) and last value............................................................................................................................................................................... 47

Table 19   Study EC605-A     Neurohormonal variables............................................................................................................ 49

Table 20   Studies of CHF patients treated with ACE inhibitors AND Candesartan or placebo........................................ 54

Table 21   The numbers of patients who received ACE inhibitors at heart failure dose and low dose, who were assigned to candesartan or placebo (Safety Population)............................................................................................................................................... 56

Table 22  Number of patients with events added (+) or subtracted (-) due to reclassification at the re- opening of the database.  59

Table 23 Interim results for CHARM-Pooled............................................................................................................................. 61

Table 24  Confirmed adjudicated CV death or hospitalization due to CHF.  Number of patients with at least one event by treatment group and events per 1000 years of follow-up.  Follow-up time is calculated to first event. ITT/Safety population ( SH-AHS-0006)     63

Table 25  Confirmed adjudicated CV death or hospitalization due to CHF. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006)............................................................................................................................ 63

Table 26  Confirmed adjudicated all-cause death or hospitalization due to CHF.  Number of patients with at least one event by treatment group and events per 1000 years of follow-up.  Follow-up time is calculated to first event.  ITT/Safety population (SH-AHS-0006)  64

Table 27  Confirmed adjudicated all-cause death or hospitalization due to CHF.  Comparison of candesartan versus placebo with Cox regression.  ITT/ Safety population (SH-AHS-0006)..................................................................................................... 64

Table 28 Confirmed adjudicated CV death or hospitalization due to CHF or nonfatal MI.  Number of patients with at least one event by treatment group and events per 1000 years of follow-up.  Follow-up time is calculated to first event.  ITT/Safety population (SH-AHS-0006)....................................................................................................................................................................................... 65

Table 29  Confirmed adjudicated CV death or hospitalization due to CHF or non-fatal MI. Comparison of candesartan vs. placebo with Cox regression. ITT/Safety population (SH-AHS-0006)....................................................................................................... 65

Table 30  Components of primary and secondary variables.  Number of patients with at least one event by treatment group and events per 1000 years of follow-up.  Follow-up time is calculated to first event.  ITT/Safety population (SH-AHS-0006).... 66

Table 31  Components of primary and secondary variables.  Comparison of candesartan versus placebo with Cox regression.  ITT/ Safety population (SH-AHS-0006)................................................................................................................................................ 66

Table 32  Number, proportion, and annualized incidence of deaths attributed to different causes in the 3 CHARM Trials and the overall CHARM Program8 (based on data from Circulation 2004; 110:2180-3)........................................................................ 67

Table 33  Endpoints in the CHARM-Added study (SH-AHS-0006)...................................................................................... 68

Table 34  Total number and total duration (days) of hospitalizations and percentage of time on each unit of care subdivided with respect to treatment and primary reason for hospitalization.  ITT/Safety population (SH-AHS-0006).................................... 69

Table 35  Number of patients and change from baseline to LVCF in NYHA class by treatment. ITT/ Safety population (SH- AHS- 0006)   69

Table 36  NYHA class shift table by treatment. ITT/Safety Population. ( SH-AHS-0006).................................................. 70

Table 37   The numbers of patients who received ACE inhibitors at heart failure dose and low dose, who were assigned to candesartan or placebo (Safety Population)............................................................................................................................................... 70

Table 38  Comparison of the primary efficacy endpoints for patients treated with candesartan versus those treated with candesartan plus an ACE inhibitor........................................................................................................................................................................ 72

Table 39  CV death or CHF hospitalization by subgroup: dose of study drug, (events per 1000 years of follow-up), Study SH-AHS-0006  73

Table 40  CV death or CHF hospitalization by subgroup: dose of study drug (Cox regression), Study SH-AHS-0006 73

Table 41  The numbers and event rates (primary efficacy endpoint of CV mortality or CHF hospitalization, confirmed, adjudicated) of patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose – CHARM-Added (SH-AHS-0006) Study..................................................................................................................................................................................... 74

Table 42  Comparison of the effect of high or low dose candesartan plus ACE inhibitor at heart failure dose or low dose on the primary endpoint of time to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study........................................................................................................................................................................... 75

Table 43  The numbers and event rates (secondary efficacy endpoint of all-cause mortality or CHF hospitalization, confirmed, adjudicated) of patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study........................................................................................................................................................................... 75

Table 44 Comparison of the effect of high or low dose candesartan plus ACE inhibitor at heart failure dose or low dose on the secondary efficacy endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study................................................................................................................................................................. 75

Table 45  The numbers and event rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI, confirmed, adjudicated) of patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study............................................................................................................................................ 76

Table 46 Comparison of the effect of high or low dose candesartan plus ACE inhibitor at heart failure dose or low dose on the secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................................................................ 76

Table 47   Endpoints in the CHARM-Alternative study (SH-AHS-0003), CHARM-Added study (SH-AHS-0006) and the CHARM Program (Pooled studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007)............................................................................. 77

Table 48  Number (%) of patients with the most commonly reporteda AEs leading to death, sorted by descending frequency in the total population during study. ITT/Safety population (SH-AHS-0006)............................................................................... 84

Table 49  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs leading to death, sorted by descending frequency in the total population during study. ITT/Safety population (SH-AHS-0003, -0006, -0007)................. 84

Table 50  Comparison of the leading causes of death in the CHARM studies.................................................................... 85

Table 51  Number (%) of patients with the most commonly reporteda SAEs other than death, sorted by descending frequency. ITT/Safety population (SH-AHS-0006)................................................................................................................................................ 86

Table 52    Number (%) of patients with symptomatic CHF with the most commonly reporteda SAEs other than death, sorted by descending frequency. ITT/Safety population (SH-AHS-0003, -0006, -0007)................................................................................. 87

Table 53  Number (%) of patients with the most commonly reporteda AEs leading to discontinuation of investigational product, sorted by descending frequency. ITT/Safety population (SH-AHS-0006).................................................................................. 88

Table 54  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs leading to discontinuation of the investigational product, sorted by descending frequency. ITT/Safety population (SH-AHS-0003, -0006, -0007) 89

Table 55   AEs in relation to withdrawal of study drug in ATLAS trial12 (Based on data from Circulation 1999; 100: 2312-8.)          89

Table 56  Permanent discontinuation and at least one discontinuation of investigational product due to any cause, an AE or an abnormal laboratory value. Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population (SH-AHS-0006).................................................................... 90

Table 57  Permanent discontinuation and at least one discontinuation of investigational product due to any cause, an AE or an abnormal laboratory value. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006)                90

Table 58  Permanent discontinuation, at least one discontinuation and decreased dose of investigational product due to any cause, an AE, an abnormal laboratory value, hypotension, hyperkalemia or increased creatinine. The difference in proportion (%) between treatments.  ITT/Safety population (SH-AHS-0006)............................................................................................................................ 91

Table 59  Exploratory safety variables for patients with symptomatic CHF.  Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population. (SH-AHS-0003, -0006, -0007)................................................................................................................................................................................................ 92

Table 60 Exploratory safety variables for patients with symptomatic CHF. Comparison of candesartan versus placebo with Logrank test. ITT/Safety population. (SH-AHS-0003, -0006, -0007).................................................................................................... 92

Table 61  Exploratory safety variables for patients with symptomatic CHF. The proportions of patients (%) with an event. ITT/Safety population. (SH-AHS-0003, -0006, -0007)......................................................................................................................... 93

Table 62  Exploratory safety variables for patients with symptomatic CHF. The difference in proportion (%) between treatments. Chi- square test. ITT/ Safety population. (SH-AHS-0003, -0006, -0007)........................................................................................... 94

Table 63  Exploratory safety variables. Comparison of candesartan cilexetil versus placebo with Cox regression test with 33 pre-specified baseline factors as covariates for the total population. ITT/Safety Population. (SH-AHS-0003, -0006, -0007).... 94

Table 64  Exploratory safety variables. Comparison of candesartan cilexetil versus placebo with Cox regression with 33 pre-specified baseline factors as covariates for the subpopulation. ITT/Safety Population. (SH-AHS-0003, -0006)................................. 94

Table 65  Discontinuation of investigational product due to hypertension, hyperkalemia and increased creatinine in patients with a history of diabetes for the total population. The proportions of patients (%) with an event. ITT/Safety Population. (SH-AHS-0003, -0006, -0007)................................................................................................................................................................................................ 95

Table 66  Permanent discontinuation of investigational product in patients with a history of diabetes for the total population. The difference in proportion (%) between treatments. Chi square test. ITT/Safety Population (SH-AHS-0003, -0006, -0007).... 95

Table 67 Adverse Events leading to dose reduction or discontinuation of study treatment in VALIANT trial25 (Based on data from N Engl J Med 2003; 349: 1893-1906.)................................................................................................................................................. 96

Table 68  Adverse events causing discontinuation in the OPTIMAAL trial22 (Based on data from Lancet 2002; 360: 752-60.)       96

Table 69  Number (%) of patients with the most commonly reporteda AEs leading to dose reduction of investigational product, sorted by descending frequency in the total population on treatment. ITT/Safety population (SH-AHS-0006)................... 98

Table 70  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs leading to dose reduction of the investigational product, sorted by descending frequency in the total population on treatment. ITT/Safety population (SH-AHS-0003, -0006, -0007)........................................................................................................................................................................... 99

Table 71  Number (%) of patients who had at least one adverse event in any category, and total numbers of adverse events. ITT/Safety population (SH-AHS-0006).............................................................................................................................................. 101

Table 72  Number (%) of patients with symptomatic CHF with at least one adverse event in any category, and total numbers of adverse events. ITT/Safety population (SH-AHS-0003, -0006, -0007)..................................................................................... 102

Table 73  Number (%) of patients who had at least one adverse event in any category, and total numbers of adverse events for the subpopulation ITT/Safety population (SH-AHS-0003, -0006).................................................................................... 102

Table 74  Number (%) of patients with the most commonly reporteda AEs, sorted by descending frequency in the total population during study.  ITT/Safety population (SH-AHS-0006)............................................................................................................. 103

Table 75  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs, sorted by descending frequency in the total population during study. ITT/ Safety population (SH-AHS-0003, -0006, -0007)............................................ 104

Table 76  Number (%) of patients with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population (North America) (SH-AHS-0003, -0006,-0007)..................................................................................................................................................... 106

Table 77  Number (%) of patients with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North America) (SH-AHS-0003, -0006,-0007)............................................................................................................................ 106

Table 78  Number (%) of patients with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population ( North America) (SH- AHS- 0003, -0006).............................................................................................................................................................. 106

Table 79  Number (%) of patients with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North America) (SH-AHS-0003, -0006)...................................................................................................................................... 106

Table 80 Estimated Means and 95% CI for the change from baseline to LVCF for BP variables with Region as an ANOVA factor for the total population. ITT/Safety Population. (SH-AHS-0003, -0006, -0007)............................................................................. 111

Table 81 Comparison for Change in BP variables with Region as an ANOVA factor for the total population. ITT/Safety Population. ( SH-AHS-0003, -0006, -0007).................................................................................................................................................... 111

Table 82 Number (%) of patients with decrease in SBP to £ 80 mm Hg or DBP to £40 mm Hg at any time after randomization for the total population. ITT/safety population. (SH-AHS-0003,-0006, -0007).............................................................................. 111

Table 83 Number (%) of patients with decrease in SBP to £ 80 mm Hg at any time after randomization for the subpopulation. ITT/safety population. (SH-AHS-0003, -0006).................................................................................................................................. 111

Table 84  Number (%) of patients with decrease in DBP to £ 40 mm Hg at any time after randomization for the subpopulation. ITT/safety population. (SH-AHS-0003, -0006).................................................................................................................................. 112

Table 85  Overview of exposure. ITT/Safety population (SH-AHS-0006)........................................................................... 114

Table 86  Overview of exposure in patients with symptomatic CHF.  ITT/Safety population (SH-AHS-0003, -0006, -0007)              115

Table 87  Exposure and number of patients with symptomatic CHF by time in the component studies. ITT/Safety population (SH-AHS-0003, -0006, -0007)......................................................................................................................................................................... 115

Table 88  Overview of exposure in the ITT/Safety population for the subpopulation. (SH-AHS-0003, -0006)............. 116

Table 89  Exposure and number of patients for the subpopulation by time in the study.  ITT/Safety population. (SH-AHS-0003, -0006)     116

Table 90  Number (%) of patients with any of the preferred terms hypotension, hypotension postural, dizziness/vertigo, syncope, circulatory failure or collapse not otherwise specified (NOS).  ITT/Safety population (SH-AHS-0006)................................. 118

Table 91 Number (%) of patients with any of the preferred terms hypotension, hypotension postural, dizziness/vertigo, syncope, circulatory failure or collapse not otherwise specified (NOS). ITT/Safety population (SH-AHS-0003, -0006, -0007)............ 119

Table 92  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs, sorted by descending frequency in the total population during study. ITT/Safety population (SH-AHS-0003, -0006, -0007)............................................. 120

Table 93  Number (%) of patients with fatal preferred terms hypotension, hypotension postural, dizziness/ vertigo, syncope, circulatory failure or collapse not otherwise specified (NOS). ITT/ Safety population (SH-AHS-0003, -0006, -0007)........... 120

Table 94  Number (%) of patients with any of the preferred terms renal function abnormal/ renal dysfunction aggravated, renal failure acute, renal failure not otherwise specified (NOS), uremia, non-protein nitrogen increased, renal failure aggravated, blood urea nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0006).............................................. 122

Table 95  Number (%) of patients with any of the preferred terms renal function abnormal/renal dysfunction aggravated, renal failure acute, renal failure NOS, uremia, non-protein nitrogen increased, renal failure aggravated, blood urea nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0003, -0006 and -0007)............................................................... 124

Table 96  Number (%) of patients with fatal renal function, abnormal/renal dysfunction, aggravated, renal failure acute, renal failure, NOS, uremia, non-protein nitrogen increased, renal failure aggravated, blood urea nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0003, -0006, -0007)................................................................................................... 124

Table 97  Permanent discontinuation due to pooled adverse events related to abnormal renal functiona or hypotensive eventsb or hyperkalemiac on treatment with candesartan cilexetil or placebo. Specified concomitant medication at the start of the event. ITT/safety population (SH-AHS-0003, -0006, -0007)d...................................................................................................................... 125

Table 98 Number (%) of patients with any of the preferred terms angina pectoris/angina pectoris aggravated, myocardial infarction or coronary artery disorder. ITT/Safety population (SH-AHS-0003, -0006, -0007)...................................................... 131

Table 99  Number (%) of patients with any of the preferred terms angina pectoris/angina pectoris aggravated, myocardial infarction or coronary artery disorder leading to death. ITT/Safety population (SH-AHS-0003, -0006, -0007)......................... 132

Table 100  The numbers and frequencies of permanent study drug discontinuation due to an adverse event or an abnormal laboratory valuea in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 134

Table 101  The numbers and frequencies of permanent study drug discontinuation due to hypotension in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study                135

Table 102  The numbers and frequencies of permanent study drug discontinuation due to hyperkalemia in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study                135

Table 103 The numbers and frequencies of permanent study drug discontinuation due to increased creatinine in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study    135

Table 104 The numbers and frequencies of dose reductions of study drug due to an adverse event or an abnormal laboratory valuea in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study......................................................................................................................................................................... 136

Table 105  Incidence of the primary composite endpoint and its components in RENAAL study24 (Based on data from N Engl J Med 2001; 345: 861-9.).......................................................................................................................................................................... 142

Table 106  Cardiovascular mortality and morbidity in VALIANT trial25 (Based on data from N Engl J Med 2003; 349: 1893-1906.) 143

Table 107   Target doses of ACE inhibitors for heart failure used in studies that demonstrate a reduction in mortality and morbidity          145

Table 108  CV death or hospitalization due to CHF (confirmed adjudicated) by use of ACE-inhibitors in study SH-AHS-0006.  Comparison of candesartan vs. placebo with Cox regression.  ITT/Safety population.................................................................... 146

Table 109  Comparison of the primary efficacy endpoints for patients treated with candesartan versus those treated with candesartan plus an ACE inhibitor...................................................................................................................................................................... 147

Table 110  Effect of high and low dose lisinopril on major clinical events (ATLAS Study)12 (Based on data from Circulation 1999; 100: 2312-8.).............................................................................................................................................................................................. 147

Table 111 Echocardiographic Characteristics of the CHF Patients Participating in the Low-Dose (5 mg/ day) Versus High-Dose (40 mg/ day) Enalapril Study13................................................................................................................................................................ 148

Table 112  Primary and secondary endpoints and exploratory analyses in CIBIS-II study35 (Based on data from Lancet 1999; 353: 9-13.)    151

Table 113 Comparative Effects of Two Different Treatment Strategies in Patients Receiving Low Doses of Angiotensin-Converting Enzyme (ACE) Inhibitors (Based on data from Am J Med 2001; 110: 81S-94S)44................................................................... 156

Table 114   CV death or hospitalization due to CHF (confirmed adjudicated) by use of b-blockers in study SH-AHS-0006.  Comparison of candesartan vs. placebo with Cox regression.  ITT/Safety population.................................................................... 157

Table 115  The numbers and event rates (primary efficacy endpoint of CV mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline – CHARM-Added (SH-AHS-0006) Study............... 158

Table 116 Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive b-blockers at baseline on the primary endpoint of time to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study....................................................................................................................................................... 158

Table 117  The numbers and event rates (secondary efficacy endpoint of all-cause mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline – CHARM-Added (SH-AHS-0006) Study.......... 159

Table 118 Comparison of the effect of high or low dose candesartan plus on CHF patients who did or did not receive b-blockers at baseline on the secondary efficacy endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 159

Table 119  The numbers and event rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline – CHARM-Added (SH-AHS-0006) Study           159

Table 120 Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive b-blockers at baseline on the secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 159

Table 121   CV death or hospitalization due to CHF (confirmed adjudicated) by use of spironolactone in study SH-AHS-0006.  Comparison of candesartan vs. placebo with Cox regression.  ITT/Safety population.................................................................... 162

Table 122 The numbers and event rates (primary efficacy endpoint of CV mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study...................... 163

Table 123  Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive spironolactone at baseline on the primary endpoint of time to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study.......................................................................................................................................... 163

Table 124  The numbers and event rates (secondary efficacy endpoint of all-cause mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study.. 163

Table 125  Comparison of the effect of high or low dose candesartan plus on CHF patients who did or did not receive spironolactone at baseline on the secondary efficacy endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................... 163

Table 126  The numbers and event rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI, confirmed, adjudicated) of patients who did or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study   164

Table 127  Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive spironolactone at baseline on the secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................... 164

Table 128  Deaths due to study group and cause in the DIG Study50 (Based on data from N Engl J Med 1997; 336: 525-33.)          165

Table 129  Patients hospitalized during the DIG study50, according to study group and reason for hospitalization.  (Based on data from N Engl J Med 1997; 336: 525-33.)......................................................................................................................................... 166

Table 130  CV death or hospitalization due to CHF (confirmed adjudicated) by use of spironolactone in study SH-AHS-0006.  Comparison of candesartan vs. placebo with Cox regression.  ITT/Safety population.................................................................... 167

Table 131 Incidence of the primary outcome and deaths from any cause in HOPE study51 (Based on data from N Engl J Med 2000; 342: 145-53)......................................................................................................................................................................................... 171

Table 132  Frequency of primary and selected secondary outcomes (EUROPA study)53 (Based on data from Lancet 2003; 362: 782-8)        171

Table 133  Primary endpoints and cause-specific first events in ANBP2 Study54 (Based on data from N Engl J Med 2003; 348: 583-92)       172

Table 134  Incidence of Severe Congestive Heart Failure or Death as the Combined Primary End Point of the SMILE Study60 (Based on data from N Engl J Med 1995; 332: 80-5)................................................................................................................................. 175

Table 135  Primary and secondary endpoints (CHARM-Alternative Study)63 (Based on data from Lancet 2003; 362: 772-6).          180

Table 136  Endpoints of LIFE23 study (Based on data from Lancet 2002; 359: 995-1003).................................................. 180

Table 137 Endpoint results in ELITE II trial20 (Based on data from Lancet 2000; 355: 1582-7)......................................... 181

Table 138 Crude rates and relative risks for pre-specified endpoints in OPTIMAAL Study22 (Based on data from Lancet 2002; 360: 752-60)............................................................................................................................................................................................... 182

Table 139  Cardiovascular Mortality and Morbidity* in VALIANT Study25 (Based on data from N Engl J Med 2003;  349; 1893-1906).        183

Table 140  Issues related to the role of angiotensin receptor blockers in patients with heart failure and left ventricular dysfunction            192

Table 141   PK parameters for candesartan.............................................................................................................................. 205

Table 142   Summary of pharmacokinetic data (geometric mean, min, max)......................................................................... 207

Table 143   PK parameters of candesartan and enalaprilat (by ANOVA)............................................................................ 209

Table 144  Summary statistics for candesartan and enalaprilat pharmacokinetic parameters separated by renal groups after repeat dose administration..................................................................................................................................................................... 210

Table 145   Pharmacokinetic parameters of M-I and M-II after administration of candesartan cilexetil in multiple doses of 4 mg/day in 5 patients with chronic congestive heart failure.............................................................................................................. 212

Table 146   Urinary excretions of M-I and M-II....................................................................................................................... 212

Table 147   PCWPmean –Mean AUC0-12 ±SD (difference to pre-dose [0h], Peak Change±SD (Efficacy (ITT) Population) 214

Table 148   PAPmean –Mean AUC0-12 ±SD (difference to pre-dose [0h], Peak Change±SD (Efficacy (ITT) Population) 214

Table 149   Neurohormones – Peak changes of concentration/activity [rennin], post-dose (Efficacy (ITT) Population) 215

Table 150   Pulmonary capillary wedge pressure – One-way ANCOVA............................................................................. 216

Table 151   Systemic vascular resistance – One-way ANCOVA.......................................................................................... 217

Table 152   Symptom score – One-way ANCOVA.................................................................................................................. 217

Table 153   Neurohormonal variables........................................................................................................................................ 218

Table 154   Total exercise time[s] (baseline (Visit 5) and last value)) – Intent- to- treat population (n= 807)................ 221

Table 155   Total exercise time[s] – Per- protocol population (n= 629)................................................................................ 221

Table 156   Results of the ANCOVA on change in total exercise time from baseline (Visit 5) to last value................... 221

Table 157   Results of the non- parametric ANCOVA on the change in the cardiothoracic ratio between baseline (Visit 5) and last value – Intent-to-treat population (n= 807)................................................................................................................................. 223

Table 158   Results of the non-parametric ANCOVA on the change in the cardiothoracic ratio between baseline (Visit 5) and last value    224

Table 159   Total exercise time (bicycle exercise test) [s] – ITT population (n=330).......................................................... 227

Table 160   Changes in Dyspnea Fatigue Index score – ITT population (n=330).............................................................. 228

Table 161   Total bicycle exercise time (sec) according to NYHA classification (ITT, n=440)......................................... 230

Table 162   NYHA functional classification - shift table (Safety population; n = 463)...................................................... 231

Table 163   Chronology of the CHARM Program highlights................................................................................................. 244

Table 164   Doses of ACE inhibitors used in studies that demonstrate a reduction in mortality and morbidity........... 246

Table 165   Summary of Protocol Amendments in the CHARM program............................................................................ 248

Table 166  Patients on expired drug........................................................................................................................................... 251

Table 167 Interim results for CHARM-Pooled......................................................................................................................... 261

Table 168  Number of patients with events added (+) or subtracted (-) due to reclassification at the re- opening of the database.                264

Table 169  Number of patients with protocol deviations....................................................................................................... 265

Table 170  Reasons for exclusion from PP population and number of patients excluded................................................. 266

Table 171  Confirmed adjudicated CV death or hospitalization due to CHF. Number of patients with at least one event by treatment group and events per 1000 years of follow- up. Follow- up time is calculated to first event.  ITT/Safety population ( H-AHS-0006)      268

Table 172  Confirmed adjudicated CV death or hospitalization due to CHF. Comparison of candesartan versus placebo with Cox regression.  ITT/Safety population (SH-AHS-0006).......................................................................................................................... 268

Table 173  Confirmed adjudicated all-cause death or hospitalization due to CHF. Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow- up time is calculated to first event. ITT/Safety population (SH-AHS-0006)   269

Table 174  Confirmed adjudicated all- cause death or hospitalization due to CHF. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006)..................................................................................................... 269

Table 175  Confirmed adjudicated CV death or hospitalization due to CHF or nonfatal MI. Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow- up time is calculated to first event. ITT/Safety population (SH-AHS-0006)..................................................................................................................................................................................... 270

Table 176  Confirmed adjudicated CV death or hospitalization due to CHF or nonfatal MI. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006).............................................................................................. 270

Table 177 CV death or CHF hospitalization by subgroup: dose of study drug, (events per 1000 years of follow-up), Study SH-AHS-0006 271

Table 178 CV death or CHF hospitalization by subgroup: dose of study drug (Cox regression), Study SH-AHS-0006 271

Table 179 The numbers and event rates (primary efficacy endpoint of CV mortality or CHF hospitalization, confirmed, adjudicated) of patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose – CHARM-Added (SH-AHS-0006) Study................................................................................................................................................................................... 272

Table 180 Comparison of the effect of high or low dose candesartan plus ACE inhibitor at heart failure dose or low dose on the primary endpoint of time to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................................................................... 273

Table 181 The numbers and event rates (secondary efficacy endpoint of all-cause mortality or CHF hospitalization, confirmed, adjudicated) of patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 273

Table 182 Comparison of the effect of high or low dose candesartan plus ACE inhibitor at heart failure dose or low dose on the secondary efficacy endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 274

Table 183  The numbers and event rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI, confirmed, adjudicated) of patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study.......................................................................................................................................... 275

Table 184  Comparison of the effect of high or low dose candesartan plus ACE inhibitor at heart failure dose or low dose on the secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study.......................................................................................................................................... 275

Table 185 Components of primary and secondary variables. Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population (SH-AHS-0006).... 276

Table 186  Components of primary and secondary variables. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006).............................................................................................................................................. 276

Table 187  Confirmed adjudicated all- cause hospitalization. Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population (SH-AHS-0006).... 277

Table 188  Confirmed adjudicated all-cause hospitalization. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population ( SH- AHS- 0006)........................................................................................................................................... 277

Table 189  The proportion of patients (%) with confirmed adjudicated fatal or nonfatal MI. ITT/Safety population (SH-AHS-0006)            277

Table 190  The difference in proportion (%) of patients with confirmed adjudicated fatal or non- fatal MI between treatments. Chi-square test.  ITT/Safety population (SH-AHS-0006).......................................................................................................................... 277

Table 191  Number of patients and change from baseline to LVCF in NYHA class by treatment. ITT/Safety population (SH-AHS-0006)    278

Table 192  NYHA class shift table by treatment. ITT/Safety Population. (SH-AHS-0006)............................................... 278

Table 193  Diagnosed onset of diabetes. Number of patients with an event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population (SH-AHS-0006)............................................... 278

Table 194  Diagnosed onset of diabetes. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006)..................................................................................................................................................................................... 279

Table 195  Development of atrial fibrillation. The proportions of patients (%) with an event. ITT/ Safety population (SH-AHS-0006)          279

Table 196  Development of atrial fibrillation. The difference in proportion (%) between treatments. Chi-square test. ITT/Safety population (SH-AHS-0006)................................................................................................................................................................... 279

Table 197  Number of deaths due to cancer by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/ Safety population (SH-AHS-0006)............................................................................................................. 279

Table 198  Deaths due to cancer. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006).............................................................................................................................................................................................. 280

Table 199  Total number of clinical events by variable and treatment. ITT/ Safety population (SH-AHS-0006).......... 280

Table 200  Difference between treatments by variable. Wilcoxon rank-sum test. ITT/Safety population (SH-AHS-0006)............... 280

Table 201  Total number and total duration (days) of hospitalizations and percentage of time on each unit of care subdivided with respect to treatment and primary reason for hospitalization.  ITT/Safety population (SH-AHS-0006).................................. 281

Table 202  The numbers and event rates (primary efficacy endpoint of CV mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline – CHARM-Added (SH-AHS-0006) Study............... 283

Table 203 Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive b-blockers at baseline on the primary endpoint of time to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study....................................................................................................................................................... 283

Table 204  The numbers and event rates (secondary efficacy endpoint of all-cause mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline – CHARM-Added (SH-AHS-0006) Study.......... 283

Table 205 Comparison of the effect of high or low dose candesartan plus on CHF patients who did or did not receive b-blockers at baseline on the secondary efficacy endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 284

Table 206  The numbers and event rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI, confirmed, adjudicated) of patients who did or did not receive b-blockers at baseline – CHARM-Added (SH-AHS-0006) Study           284

Table 207 Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive b-blockers at baseline on the secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study......................................................................................................................... 284

Table 208 The numbers and event rates (primary efficacy endpoint of CV mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study...................... 286

Table 209  Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive spironolactone at baseline on the primary endpoint of time to CV mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study.......................................................................................................................................... 286

Table 210  The numbers and event rates (secondary efficacy endpoint of all-cause mortality or CHF hospitalization, confirmed, adjudicated) of patients who did or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study.. 286

Table 211  Comparison of the effect of high or low dose candesartan plus on CHF patients who did or did not receive spironolactone at baseline on the secondary efficacy endpoint of all-cause mortality or CHF hospitalization (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................... 286

Table 212  The numbers and event rates (secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI, confirmed, adjudicated) of patients who did or did not receive spironolactone at baseline – CHARM-Added (SH-AHS-0006) Study   287

Table 213  Comparison of the effect of high or low dose candesartan on CHF patients who did or did not receive spironolactone at baseline on the secondary efficacy endpoint of CV mortality or CHF hospitalization or non-fatal MI (confirmed, adjudicated) using Cox Regressiona – CHARM-Added (SH-AHS-0006) Study............................................................................................... 287

Table 214  Overview of exposure. ITT/Safety population (SH-AHS-0006)......................................................................... 290

Table 215  Number (%) of patients who had at least one adverse event in any category, and total numbers of adverse events. ITT/Safety population (SH-AHS-0006).............................................................................................................................................. 291

Table 216  Number (%) of patients with the most commonly reporteda AEs, sorted by descending frequency in the total population during study.  ITT/Safety population (SH-AHS-0006)............................................................................................................. 291

Table 217  Number (%) of patients with the most commonly reporteda AEs leading to death, sorted by descending frequency in the total population during study. ITT/ Safety population (SH-AHS-0006)............................................................................ 293

Table 218  Number (%) of patients with the most commonly reporteda SAEs other than death, sorted by descending frequency in the total population during study. ITT/Safety population (SH-AHS-0006)............................................................................. 293

Table 219  Number (%) of patients with the most commonly reporteda AEs leading to discontinuation of investigational product, sorted by descending frequency in the total population on treatment. ITT/Safety population (SH-AHS-0006)................. 294

Table 220  Number (%) of patients with the most commonly reporteda AEs leading to dose reduction of investigational product, sorted by descending frequency in the total population on treatment. ITT/Safety population (SH-AHS-0006)................. 295

Table 221  Permanent discontinuation and at least one discontinuation of investigational product due to any cause, an AE or an abnormal laboratory value. Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population (SH-AHS-0006).................................................................. 296

Table 222  Permanent discontinuation and at least one discontinuation of investigational product due to any cause, an AE or an abnormal laboratory value. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0006)                296

Table 223  Permanent discontinuation, at least one discontinuation and decreased dose of investigational product due to any cause, an AE, an abnormal laboratory value, hypotension, hyperkalemia or increased creatinine. The proportions of patients (%) with an event. ITT/Safety population (SH-AHS-0006).......................................................................................................................... 297

Table 224  Permanent discontinuation, at least one discontinuation and decreased dose of investigational product due to any cause, an AE, an abnormal laboratory value, hypotension, hyperkalemia or increased creatinine. The difference in proportion (%) between treatments. Chi-square test. ITT/Safety population (SH-AHS-0006)............................................................................................. 298

Table 225  Number (%) of patients with any of the preferred terms hypotension, hypotension postural, dizziness/vertigo, syncope, circulatory failure or collapse not otherwise specified (NOS).  ITT/Safety population (SH-AHS-0006)............. 299

Table 226  Number (%) of patients with any of the preferred terms renal function abnormal/ renal dysfunction aggravated, renal failure acute, renal failure not otherwise specified (NOS), uremia, non-protein nitrogen increased, renal failure aggravated, blood urea nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0006).............................................. 301

Table 227  The numbers and frequencies of permanent study drug discontinuation due to an adverse event or an abnormal laboratory valuea in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study............................................................................................................................................................... 309

Table 228  The numbers and frequencies of permanent study drug discontinuation due to hypotensiona in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study                309

Table 229  The numbers and frequencies of permanent study drug discontinuation due to hyperkalemiaa in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study                310

Table 230 The numbers and frequencies of permanent study drug discontinuation due to increased serum creatininea in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study.............................................................................................................................................................................................. 310

Table 231 The numbers and frequencies of dose reductionsa of study drug due to an adverse event or an abnormal laboratory valuea in patients who received high or low dose candesartan plus ACE inhibitors at heart failure dose or low dose– CHARM-Added (SH-AHS-0006) Study......................................................................................................................................................................... 310

Table 232  Total-pooled patient population and disposition................................................................................................ 320

Table 233  Number of sites and randomized patients by country for patients with symptomatic CHF. ITT/Safety population (SH-AHS-0003, -0006, -0007)......................................................................................................................................................................... 321

Table 234  Number of patients with protocol deviations in CHARM-Pooled patient population................................... 322

Table 235  Confirmed adjudicated all-cause death in patients with symptomatic CHF. Number of patients with an event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to event. ITT/Safety population (SH-AHS-0003, -0006, -0007) 324

Table 236  Confirmed adjudicated all-cause death in patients with symptomatic CHF. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0003, -0006, -0007)............................................................................... 324

Table 237 Confirmed adjudicated all-cause death in patients with depressed LV systolic function. Number of patients with an event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to event. ITT/Safety population (SH-AHS-0003, -0006)..................................................................................................................................................................................... 325

Table 238 Confirmed adjudicated all-cause death in patients with depressed LV systolic function. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0003,-0006)........................................................................... 325

Table 239 Confirmed adjudicated components of the primary variable. Number of patients with event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to event. ITT/ Safety population (SH-AHS-0003, -0006, -0007) 326

Table 240 Confirmed adjudicated components of primary variable. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0003, -0006, -0007)................................................................................................... 326

Table 241 Confirmed adjudicated components of the primary variable. Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population (SH-AHS-0003, -0006)            327

Table 242  Confirmed adjudicated components of primary variable. Comparison of candesartan versus placebo with Cox regression. ITT/Safety population (SH-AHS-0003, -0006)............................................................................................................... 327

Table 243 Number of patients and change from baseline to LVEF in NYHA class by treatment in patients with symptomatic CHF. ITT/Safety Population. (SH-AHS-0003, -0006, -0007)....................................................................................................................... 327

Table 244 Number of patients and change from baseline to LVEF in NYHA class by treatment in patients with depressed LV systolic function. ITT/Safety Population. (SH-AHS-0003, -0006)............................................................................................. 328

Table 245 Frequency of patients by the outcome of the OTE questionnaire at last visit. ITT/Safety population....... 330

Table 246 OTE for patients with symptomatic CHF as assessed by a stratified Wilcoxon-Mann-Whitney test for comparison of the change for the two treatment groups. The data are stratified according to study. ITT/Safety population (SH-AHS-0003, -0006, -0007)           330

Table 247   Endpoints in the CHARM-Alternative study (SH-AHS-0003), CHARM-Added study (SH-AHS-0006) and the CHARM Program (Pooled studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007)........................................................................... 332

Table 248  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs leading to death, sorted by descending frequency in the total population during study. ITT/Safety population (SH-AHS-0003, -0006, -0007)............... 335

Table 249    Number (%) of patients with symptomatic CHF with the most commonly reporteda SAEs other than death, sorted by descending frequency in the total population during study. ITT/Safety population (SH-AHS-0003, -0006, -0007)............... 336

Table 250  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs leading to discontinuation of the investigational product, sorted by descending frequency in the total population on treatment. ITT/Safety population (SH-AHS-0003, -0006, -0007)......................................................................................................................................................................... 337

Table 251  Exploratory safety variables for patients with symptomatic CHF.  Number of patients with at least one event by treatment group and events per 1000 years of follow-up. Follow-up time is calculated to first event. ITT/Safety population. (SH-AHS-0003, -0006, -0007).............................................................................................................................................................................................. 338

Table 252 Exploratory safety variables for patients with symptomatic CHF. Comparison of candesartan versus placebo with Logrank test. ITT/Safety population. (SH-AHS-0003, -0006, -0007).................................................................................................. 338

Table 253  Exploratory safety variables for patients with symptomatic CHF. The proportions of patients (%) with an event. ITT/Safety population. (SH-AHS-0003, -0006, -0007)....................................................................................................................... 339

Table 254  Exploratory safety variables for patients with symptomatic CHF. The difference in proportion (%) between treatments. Chi-square test. ITT/ Safety population. (SH-AHS-0003, -0006, -0007)......................................................................................... 340

Table 255  Exploratory safety variables. Comparison of candesartan cilexetil versus placebo with Cox regression test with 33 pre-specified baseline factors as covariates for the total population. ITT/Safety Population. (SH-AHS-0003, -0006, -0007).. 340

Table 256  Exploratory safety variables. Comparison of candesartan cilexetil versus placebo with Cox regression with 33 pre-specified baseline factors as covariates for the subpopulation. ITT/Safety Population. (SH-AHS-0003, -0006)................ 340

Table 257  Discontinuation of investigational product due to hypertension, hyperkalemia and increased creatinine in patients with a history of diabetes for the total population. The proportions of patients (%) with an event. ITT/Safety Population. (SH-AHS-0003, -0006, -0007).............................................................................................................................................................................................. 341

Table 258  Permanent discontinuation of investigational product in patients with a history of diabetes for the total population. The difference in proportion (%) between treatments. Chi square test. ITT/Safety Population (SH-AHS-0003, -0006, -0007).. 341

Table 259  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs leading to dose reduction of the investigational product, sorted by descending frequency in the total population on treatment. ITT/Safety population (SH-AHS-0003, -0006, -0007)......................................................................................................................................................................... 342

Table 260  Number (%) of patients with symptomatic CHF with at least one adverse event in any category, and total numbers of adverse events. ITT/Safety population (SH-AHS-0003, -0006, -0007)..................................................................................... 344

Table 261  Number (%) of patients who had at least one adverse event in any category, and total numbers of adverse events for the subpopulation ITT/Safety population (SH-AHS-0003, -0006).................................................................................... 344

Table 262  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs, sorted by descending frequency. ITT/ Safety population (SH-AHS-0003, -0006, -0007)........................................................................................................... 345

Table 263  Number (%) of patients with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population (North America) (SH-AHS-0003, -0006,-0007)..................................................................................................................................................... 346

Table 264  Number (%) of patients with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North America) (SH-AHS-0003, -0006,-0007)............................................................................................................................ 346

Table 265  Number (%) of patients with increase in serum creatinine ³ 2 x from baseline value. ITT/Safety population ( North America) (SH- AHS- 0003, -0006).............................................................................................................................................................. 346

Table 266  Number (%) of patients with serum potassium to ³ 6 mmol/L at any time after randomization. ITT/Safety population (North America) (SH-AHS-0003, -0006)...................................................................................................................................... 346

Table 267 Estimated Means and 95% CI for the change from baseline to LVCF for BP variables with Region as an ANOVA factor for the total population. ITT/Safety Population. (SH-AHS-0003, -0006, -0007)............................................................................. 350

Table 268 Comparison for Change in BP variables with Region as an ANOVA factor for the total population. ITT/Safety Population. ( SH-AHS-0003, -0006, -0007).................................................................................................................................................... 350

Table 269 Number (%) of patients with decrease in SBP to £ 80 mm Hg or DBP to £40 mm Hg at any time after randomization for the total population. ITT/safety population. (SH-AHS-0003,-0006, -0007).............................................................................. 350

Table 270 Number (%) of patients with decrease in SBP to £ 80 mm Hg at any time after randomization for the subpopulation. ITT/safety population. (SH-AHS-0003, -0006).................................................................................................................................. 351

Table 271  Number (%) of patients with decrease in DBP to £ 40 mm Hg at any time after randomization for the subpopulation. ITT/safety population. (SH-AHS-0003, -0006).................................................................................................................................. 351

Table 272  Overview of exposure in patients with symptomatic CHF.  ITT/Safety population (SH-AHS-0003, -0006, -0007)            353

Table 273  Exposure and number of patients with symptomatic CHF by time in the component studies. ITT/Safety population (SH-AHS-0003, -0006, -0007)........................................................................................................................................................................ 354

Table 274  Overview of exposure in the ITT/Safety population for the subpopulation. (SH-AHS-0003, -0006)........... 354

Table 275  Exposure and number of patients for the subpopulation by time in the study.  ITT/Safety population. (SH-AHS-0003, -0006)   355

Table 276 Number (%) of patients with any of the preferred terms hypotension, hypotension postural, dizziness/vertigo, syncope, circulatory failure or collapse not otherwise specified (NOS). ITT/Safety population (SH-AHS-0003, -0006, -0007)............ 356

Table 277  Number (%) of patients with symptomatic CHF with the most commonly reporteda AEs, sorted by descending frequency in the total population during study. ITT/Safety population (SH-AHS-0003, -0006, -0007)............................................. 357

Table 278  Number (%) of patients with fatal preferred terms hypotension, hypotension postural, dizziness/ vertigo, syncope, circulatory failure or collapse not otherwise specified (NOS). ITT/ Safety population (SH-AHS-0003, -0006, -0007)........... 357

Table 279  Number (%) of patients with any of the preferred terms renal function abnormal/renal dysfunction aggravated, renal failure acute, renal failure NOS, uremia, non-protein nitrogen increased, renal failure aggravated, blood urea nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0003, -0006 and -0007)............................................................... 359

Table 280  Number (%) of patients with fatal renal function, abnormal/renal dysfunction, aggravated, renal failure acute, renal failure, NOS, uremia, non-protein nitrogen increased, renal failure aggravated, blood urea nitrogen increased, acute pre-renal failure or anuria. ITT/Safety population (SH-AHS-0003, -0006, -0007)................................................................................................... 359

Table 281  Permanent discontinuation due to pooled adverse events related to abnormal renal functiona or hypotensive eventsb or hyperkalemiac on treatment with candesartan cilexetil or placebo. Specified concomitant medication at the start of the event. ITT/safety population (SH-AHS-0003, -0006, -0007)d...................................................................................................................... 360

Table 282 Number (%) of patients with any of the preferred terms angina pectoris/angina pectoris aggravated, myocardial infarction or coronary artery disorder. ITT/Safety population (SH-AHS-0003, -0006, -0007)...................................................... 363

Table 283  Number (%) of patients with any of the preferred terms angina pectoris/angina pectoris aggravated, myocardial infarction or coronary artery disorder leading to death. ITT/Safety population (SH-AHS-0003, -0006, -0007)......................... 363



List of Figures

Figure 1     Mean Serum Concentration of CV-11974 (Safety population) – Study EC602. 38

Figure 2          AUC0-24 vs. administered dose (Efficacy (ITT) population) – Study EC602. 39

Figure 3     Cmax vs. administered dose (Efficacy (ITT) population) – Study EC602. 39

Figure 4     AUC0-24 versus dose on visits 2 (left) and 6 (right) – EC605-A.. 39

Figure 5     Cmax versus dose on visits 2 (left) and 6 (right) – EC605-A.. 39

Figure 6     AUC0-24h (following single doses of candesartan) vs. dose of candesartan cilexetil in patients with CHF (studies EC602 and EC605-A) 40

Figure 7        Study CPH102 – Plasma digoxin concentrations. 41

Figure 8   Study SH-AHS-0001 (RESOLVD) – Change in End Diastolic Volume (ml) by different treatments after 17 & 43 weeks. 46

Figure 9   Study SH-AHS-0001 (RESOLVD) – Change in End Systolic Volume (ml) by different treatments after 17 & 43 weeks. 46

Figure 10   Study SH-AHS-0001 (RESOLVD) – Change in angiotensin II levels after 17 and 43 weeks of treatment with candesartan, candesartan plus enalapril or enalapril 48

Figure 11   Study SH-AHS-0001 (RESOLVD) – Change in aldosterone levels after 17 and 43 weeks of treatment with candesartan, candesartan plus enalapril or enalapril 49

Figure 12   Study SH-AHS-0001 (RESOLVD) – Change in brain natriuretic peptide (BNP) levels after 17 and 43 weeks of treatment with candesartan, candesartan plus enalapril or enalapril 50

Figure 13   Study design. 62

Figure 14   Cumulative incidence (%) of confirmed adjudicated CV death. 63

Figure 15  Cumulative incidence (%) of confirmed adjudicated all-cause death or hospitalization due to CHF over time (ITT/Safety population) 65

Figure 16  Cumulative incidence (%) of confirmed adjudicated CV death or hospitalization due to CHF or non-fatal MI over time (ITT/Safety population) 66

Figure 17 Cumulative incidence (%) of confirmed adjudicated all-cause death in patients with symptomatic CHF over time.  ITT/Safety population. 79

Figure 18  Cumulative incidence (%) of confirmed adjudicated all-cause death in patients with LV systolic dysfunction over time.  ITT/Safety population. 79

Figure 19 Overall effect of candesartan on all-cause death in subgroups of conventional CHF treatment.  Point estimates of hazard ratios given with 95% confidence interval, and P values.  ITT/Safety population (SH-AHS-0003, SH-AHS-0006, SH-AHS-0007) 80

Figure 20  Overall effect of candesartan on CV death or hospitalization in subgroups of conventional CHF treatment.  Point estimates of hazard ratios given with 95% confidence interval, and P values.  ITT/Safety population (SH-AHS-0003, SH-AHS-0006, SH-AHS-0007). 81

Figure 21  Cumulative incidence (%) of permanent discontinuation of investigational product due to an AE or an abnormal laboratory value. ITT/Safety population. 90

Figure 22  Cumulative incidence (%) of permanent discontinuation of the investigational product due to an AE or an abnormal laboratory value. ITT/Safety population. 93

Figure 23  Kaplan–Meier Analysis of the time to permanent withdrawal of the study medication because of adverse reactions or for reasons other than death in placebo and Carvedilol groups in COPERNICUS trial37.  The risk of withdrawal was 23% lower in the carvedilol group (95% CI: 4% – 38%; P= 0.02).  (Based on data from Engl J Med 2001; 344: 1651-8.) 97

Figure 24  Adverse events resulting in discontinuation of study drug in LIFE study23 (Based on data from Lancet 2002; 359: 995-1003.) 98

Figure 25  Cumulative incidence (%) of first occurrence of dose decrease of investigational product due to an AE or an abnormal laboratory value. ITT/Safety population. 100

Figure 26  Cumulative incidence (%) of dose reduction of the investigational product due to an AE or an abnormal laboratory value. ITT/Safety population (SH-AHS-0003, -0006, -0007) 100

Figure 27  Mean DBP ± SEM (mmHg) by visit for the total population. ITT/Safety population. 108

Figure 28  Mean SBP ± SEM (mmHg) by visit for the total population. ITT/Safety population. 109

Figure 29  Mean Pulse Pressure ± SEM (mmHg) by visit for the total population. ITT/Safety population. 109

Figure 30  Mean heart rate ± SEM (bpm) by visit for the total population. ITT/Safety population. 109

Figure 31  Mean DBP ± SEM (mmHg) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  110

Figure 32  Mean SBP ± SEM (mmHg) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  110

Figure 33  Mean Pulse Pressure ± SEM (mmHg) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  110

Figure 34  Mean heart rate ± SEM (bpm) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  111

Figure 35  Cumulative incidence (%) of permanent discontinuation of investigational product due to hypotension (Ref. - Table 56).  ITT/Safety population. 119

Figure 36  Cumulative incidence (%) of permanent discontinuation of the investigational product due to hypotension. ITT/Safety population  121

Figure 37  Cumulative incidence (%) of permanent discontinuation of investigational product due to increased creatinine (Ref. - Table 56). ITT/Safety population. 123

Figure 38  Cumulative incidence (%) of permanent discontinuation of the investigational product due to increased creatinine. ITT/Safety population. 125

Figure 39  Cumulative incidence (%) of permanent discontinuation of investigational product due to hyperkalemia. ITT/Safety population (Ref. - Table 56). 127

Figure 40  Cumulative incidence (%) of permanent discontinuation of the investigational product due to hyperkalemia. ITT/ Safety population. 129

Figure 41  Blockade of the pressor response to intravenous infusions of angiotensin II (Ang II) in normal volunteers after oral administration of placebo (¢), losartan 50 mg (), or losartan 150 mg (˜). * P < 0.02, ** P < 0.0001 compared with placebo. (Based on data from J Cardiovasc Pharmacol 2001; 37: 692-6)21. 140

Figure 42  Dose of study drug Losartan was administered once daily and captopril three times daily. (OPTIMAAL Study)22 (Based on data from Lancet 2002; 360: 752-60.) 141

Figure 43  Kaplan Meier curves for primary composite endpoint (LIFE study)23 (Based on data from Lancet 2002; 359: 995-1003.) 141

Figure 44  Effect of candesartan compared with placebo on primary outcome in all patients, and patients taking or not taking recommended dose of ACE inhibitors at baseline. 146

Figure 45 Cumulative mortality in Groups 1 and 2 of High Enalapril Dose Study14. (Based on data from (J Am Coll Cardiol 2000; 36: 2090-5.) 148

Figure 46  Cumulative incidence of composite end point of mortality and hospital admission in the two treatment groups in High Enalapril Dose Study 14. (Based on data from (J Am Coll Cardiol 2000; 36: 2090-5.) 149

Figure 47  Relative risk (95% CI) for total mortality, cardiovascular mortality, sudden death, and death from worsening heart failure (MERIT-HF study)36 (Based on data from Lancet 1999; 353: 2001-7.) 152

Figure 48  Blood concentrations of angiotensin II and angiotensin I, and angiotensin II/ angiotensin I ratio29 (Based on data from Lancet 2001; 358: 1609-10.) 152

Figure 49  Changes in LVEF and LV volumes in response to metoprolol (˜) versus placebo () in stage II of the RESOLVD study40. Data are mean±SEM.  (Based on data from Circulation 2000; 101: 378-84.) 153

Figure 50  Kaplan-Meier Analysis of Time to Death in Placebo and Carvedilol Groups37 (Based on data from N Engl J Med 2001; 344: 1651-8.) The 35% lower risk in the carvedilol group was significant: P=0.00013 (unadjusted) and P=0.0014 (adjusted). 154

Figure 51  Kaplan-Meier Analysis of Time to Death or First Hospitalization for Any Reason in Placebo and Carvedilol Groups37. (Based on data from N Engl J Med 2001; 344: 1651-8.) 154

Figure 52  Mortality by subgroup (ELITE II20) (Based on data from Lancet 2000; 355: 1582-7.) 155

Figure 53  Relative Risks and 95 Percent Confidence Intervals for the Combined End Point (Death from Any Cause, Cardiac Arrest with Resuscitation, Hospitalization for Worsening Heart Failure, or Therapy with Intravenous Inotropes or Vasodilators), According to the Background Therapy at Base Line, in Val-HeFT study16. (Based on data from N Engl J Med 2001; 345: 1667-75.) 155

Figure 54  Effect of candesartan compared with placebo on primary outcome in all patients, and patients taking or not taking b-blockers, and/or recommended dose of ACE inhibitors at baseline. 157

Figure 55  Relative risk of all-cause mortality according to use of and ACE inhibitor (or ARB), a b-blocker or both in EPHESUS study46 (Based on data from N Engl J Med 2003; 348: 1309-21.) 161

Figure 56  Relative risk of CV death or hospitalization for CV events according to use of an ACE inhibitor (or ARB), a b-blocker or both in EPHESUS study46 (Based on data from N Engl J Med 2003; 348: 1309-21.) 161

Figure 57 Mortality Due to Worsening Heart Failure in the Digoxin and Placebo Groups50. (Based on data from N Engl J Med 1997; 336: 525-33.)  The number of patients at risk at each four-month interval is shown below the figure. 166

Figure 58  Stages of heart failure and treatment options for systolic heart failure (Based on data from Circulation 2001; 104: 2996-3007)27 169

Figure 59  Primary endpoints among all subjects, male subjects and female subjects (ANBP2 Study)54 (Based on data from N Engl J Med 2003; 348: 583-92).  ACE denotes angiotensin-converting enzyme, and CI confidence interval. 173

Figure 60  Cumulative mortality from all causes in the study groups in SAVE trial58  (Based on data from N Engl J Med 1992; 327: 669-77). The number of patients at risk at the beginning of each year is shown at the bottom.. 174

Figure 61  Life tables for cumulative fatal and non-fatal cardiovascular events in SAVE trial58 (Based on data from N Engl J Med 1992; 327: 669-77). CV denotes cardiovascular, CHF congestive heart failure, MI myocardial infarction.  The bottom right panel shows the following events: death from cardiovascular causes, sever heart failure requiring ACE inhibitors or hospitalization, or recurrent myocardial infarction.  For all combined analyses, only the time to the first event was used. 174

Figure 62  Mortality curves illustrating the primary endpoint of all-cause mortality analyzed by intention-to-treat in AIRE trial59 (Based on data from Lancet 1993; 342: 821-8). Most patients were followed for <18 months, and the curves have been terminated at 30 months because of the small numbers of patients with prolonged follow-up. 175

Figure 63  Incidence of Death or Severe Congestive Heart Failure during Six Weeks of Treatment with Zofenopril or Placebo in Patients with Acute Myocardial Infarction (SMILE Study)60 (Based on data from N Engl J Med 1995; 332: 80-5). 176

Figure 64 Cumulative Mortality during One Year of Follow- up among Patients with Acute Myocardial Infarction Treated for Six Weeks with Zofenopril or Placebo (SMILE Study)60 (Based on data from N Engl J Med 1995; 332: 80-5). 176

Figure 65  Cumulative Mortality from All Causes among Patients Receiving Trandolapril or Placebo (TRACE Study)61 (Based on data from N Engl J Med 1955; 333: 1670-6). 177

Figure 66  Event Rates for the Secondary End Points of Death from Cardiovascular Causes, Sudden Death, Reinfarction, and Severe or Resistant Heart Failure among Patients Receiving Trandolapril or Placebo (TRACE Study)61 (Based on data from N Engl J Med 1955; 333: 1670-6). 177

Figure 67  Kaplan-Meier Curves of the Percentage of Patients with a First Hospitalization for Heart Failure in the Losartan and Placebo Groups (RENAAL Study)24 (Based on data from N Engl J Med 2001;345: 861-9). 179

Figure 68  Kaplan-Meier cumulative event curves for primary endpoint (CHARM-Alternative Study)63 (Based on data from Lancet 2003; 362: 772-6). 179

Figure 69  Kaplan-Meier survival curves among patients with CHF in losartan and captopril groups.  Patients in losartan group had a 46% lower risk of death than patients in captopril group (p= 0·035).  Patients were followed up for 48 weeks (ELITE trial)19 (Based on data from Lancet 1997; 349: 747-52). 181

Figure 70  Kaplan- Meier curve for primary endpoint of all-cause mortality. (OPTIMAAL Study)22 (Based on data from Lancet 2002; 360: 752-60). 182

Figure 71  Kaplan-Meier Estimates of the Rate of Death from Any Cause (Panel A) and the Rate of Death from Cardiovascular Causes, Reinfarction, or Hospitalization for Heart Failure (Panel B), According to Treatment Group (VALIANT Study)25 (Based on data from N Engl J Med 2003; 349; 1893-1906). 183

Figure 72  Effect of enalapril or losartan on pulmonary diffusion capacity in heart failure patients64 (Based on data from J Am Coll Cardiol 2001; 37: 398-406).  The bars represent mean±SEM in patients during the control period, after 14 days treatment with enalapril, and after 14 days treatment with losartan. * P < 0.01 compared with control period. 184

Figure 73  Comparison of angiotensin receptor blockers versus controls on all-cause mortality. (Based on data from J Am Coll Cardiol 2002; 39: 463-70)69 Controls were either placebo or angiotensin-converting enzyme inhibitor (ACEI). Odds ratios (OR) and the 95% confidence intervals (CI) are shown on a logarithmic scale, with box size proportional to the sample size. The diamond represents the pooled effect. 186

Figure 74  Stratified comparisons of angiotensin receptor blockers (ARB) on all-cause mortality: (Based on data from J Am Coll Cardiol 2002; 39: 463-70)69.  ARB vs. placebo. Odds ratios (OR) and the 95% confidence intervals (CI) are shown on a logarithmic scale, with box size proportional to the sample size.  The diamond represents the pooled effect. 187

Figure 75  Stratified comparisons of angiotensin receptor blockers (ARB) on all-cause mortality: (Based on data from J Am Coll Cardiol 2002; 39: 463-70)69.  ARB versus angiotensin-converting enzyme inhibitors (ACEI). Odds ratios (OR) and the 95% confidence intervals (CI) are shown on a logarithmic scale, with box size proportional to the sample size.  The diamond represents the pooled effect. 187

Figure 76  Stratified comparisons of angiotensin receptor blockers (ARB) on all-cause mortality: (Based on data from J Am Coll Cardiol 2002; 39: 463-70)69.  ARB plus angiotensin-converting enzyme inhibitors (ACEI) combination versus ACEI. Odds ratios (OR) and the 95% confidence intervals (CI) are shown on a logarithmic scale, with box size proportional to the sample size.  The diamond represents the pooled effect. 188

Figure 77 CHF hospitalisation70 in CHARM-added, VALIANT (added) and Val-HeFT (Based on data from International Journal of Cardiology 2004 (In press; personal communication with Prof A. A. Voors). 188

Figure 78  All-cause mortality70 in CHARM-added, VALIANT (added) and Val-HeFT (Based on data from International Journal of Cardiology 2004 (In press; personal communication with Prof A. A. Voors). 189

Figure 79   Mean Serum Concentration of CV-11974 (Safety population) 205

Figure 80  AUC0-24 vs. administered dose (Efficacy (ITT) population) 205

Figure 81   Cmax vs. administered dose (Efficacy (ITT) population) 206

Figure 82   AUC0-24 versus dose on visits 2 (left) and 6 (right) 207

Figure 83   Cmax versus dose on visits 2 (left) and 6 (right) 207

Figure 84   AUC0-24h  (following single doses of candesartan) vs. dose of candesartan cilexetil in patients with CHF (studies 602 and 605-A) 208

Figure 85   Plasma concentrations of M-I and M-II after administration of candesartan in multiple doses of 4 mg/day in patients with CHF  211

Figure 86   Plasma digoxin concentrations. 212

Figure 87   Dose-response relationship for the change in total exercise time[s] between baseline (Visit 5) and last value – Intent-to-treat population (n=807) 222

Figure 88   Change in angiotensin II levels after 17 and 43 weeks of treatment with candesartan, candesartan plus enalapril or enalapril 234

Figure 89   Change in angiotensin II levels after 17 and 43 weeks of treatment with candesartan, candesartan plus enalapril or enalapril 234

Figure 90   Change in brain natriuretic peptide (BNP) levels after 17 and 43 weeks of treatment with candesartan, candesartan plus enalapril or enalapril 235

Figure 91   Increase in Ejection Fraction by different treatments after 17 and 43 weeks. 235

Figure 92   Change in End Diastolic Volume (ml) by different treatments after 17 & 43 weeks. 236

Figure 93   Change in End Systolic Volume (ml) by different treatments after 17 & 43 weeks. 236

Figure 94   Study design. 246

Figure 95  Patient disposition (completion or discontinuation) 265

Figure 96  Study populations. 266

Figure 97  Cumulative incidence (%) of confirmed adjudicated CV death or hospitalization due to CHF over time.  ITT/Safety population  268

Figure 98  Cumulative incidence (%) of confirmed adjudicated all- cause death or hospitalization due to CHF over time. ITT/Safety population  269

Figure 99  Cumulative incidence (%) of confirmed adjudicated CV death or hospitalization due to CHF or non- fatal MI over time.  ITT/Safety population. 270

Figure 100  Effect of candesartan compared with placebo on primary outcome in all patients and patients taking or not taking b-blocker and taking or not taking recommended dose of ACE inhibitors at baseline. 282

Figure 101  Cumulative incidence (%) of permanent discontinuation of investigational product due to an AE or an abnormal laboratory value. ITT/Safety population. 296

Figure 102  Cumulative incidence (%) of first occurrence of dose decrease of investigational product due to an AE or an abnormal laboratory value. ITT/Safety population. 298

Figure 103  Cumulative incidence (%) of permanent discontinuation of investigational product due to hypotension (Ref. - Table 221).  ITT/Safety population. 300

Figure 104  Cumulative incidence (%) of permanent discontinuation of investigational product due to increased creatinine (Ref. - Table 221). ITT/Safety population. 302

Figure 105  Cumulative incidence (%) of permanent discontinuation of investigational product due to hyperkalemia. ITT/Safety population (Ref. - Table 221). 304

Figure 106  Disposition of patients with symptomatic CHF (completion or discontinuation) (SH-AHS-0003, -0006 and -0007) 322

Figure 107  Cumulative incidence (%) of confirmed adjudicated all-cause death in patients with symptomatic CHF over time. ITT/Safety population. 324

Figure 108 Cumulative incidence (%) of confirmed adjudicated all-cause death in patients with depressed LV systolic function over time.  ITT/Safety population. 325

Figure 109 Cumulative incidence (%) of confirmed adjudicated cardiovascular death and non-cardiovascular death patients with symptomatic CHF over time. ITT/Safety population. 326

Figure 110 Overall effect of candesartan on cardiovascular death or first admission for CHF in pre-specified subgroups. Point estimates of hazard ratios given with 95 % confidence interval. P-values are for heterogeneity. ITT/ Safety population (SH-AHS-0003, -0006, -0007) 329

Figure 111 Overall effect of candesartan on all-cause death in pre-specified subgroups. Point estimates of hazard ratios given with 95% confidence interval. P-values are for heterogeneity. ITT/Safety population (SH- AHS-0003, -0006, -0007) 329

Figure 112  Cumulative incidence (%) of confirmed adjudicated all-cause death in patients with symptomatic CHF over time.  ITT/Safety population. 331

Figure 113  Cumulative incidence (%) of confirmed adjudicated all-cause death in patients with LV systolic dysfunction over time.  ITT/Safety population. 332

Figure 114  Cumulative incidence (%) of permanent discontinuation of the investigational product due to an AE or an abnormal laboratory value. ITT/Safety population. 339

Figure 115  Cumulative incidence (%) of dose reduction of the investigational product due to an AE or an abnormal laboratory value. ITT/Safety population (SH-AHS-0003, -0006, -0007) 343

Figure 116  Mean DBP ± SEM (mmHg) by visit for the total population. ITT/Safety population. 347

Figure 117  Mean SBP ± SEM (mmHg) by visit for the total population. ITT/Safety population. 348

Figure 118  Mean Pulse Pressure ± SEM (mmHg) by visit for the total population. ITT/Safety population. 348

Figure 119  Mean heart rate ± SEM (bpm) by visit for the total population. ITT/Safety population. 348

Figure 120  Mean DBP ± SEM (mmHg) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  349

Figure 121  Mean SBP ± SEM (mmHg) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  349

Figure 122  Mean Pulse Pressure ± SEM (mmHg) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  349

Figure 123  Mean heart rate ± SEM (bpm) by visit for the depressed LV systolic function subpopulation. ITT/Safety population  350

Figure 124  Cumulative incidence (%) of permanent discontinu