U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research

Office of Pharmacoepidemiology and Statistical Science

Office of Biostatistics

 

 

Statistical Review and Evaluation

Clinical Studies

NDA/Serial Number:          20-838/N022, 024, 025

Drug Name:                        Candesartan Cilexetil (ATACAND) Tablets

Indication(s):                       Treatment of Heart Failure

Applicant:                            Astra Zeneca

Review Priority:                  Standard

Biometrics Division:           DBI

Statistical Reviewer:          Chenxiong (Charles) Le, Ph.D. HFD-710

Concurring Reviewers:       James Hung, Ph.D. HFD-710

Medical Division:               Division of Cardio-Renal drug products (HFD-110)

Clinical Team:                     Khin M U, M.D.  & Mehul Desai, M.D. (HFD-110)

Project Manager:                Cheryl Ann Borden (HFD-110)

                                            

                                            

Keywords:                           Log rank test, Cox regression, subgroup analysis, survival analysis.


Table of Contents

 

1     EXECUTIVE SUMMARY.. 4

1.1     Conclusions and Recommendations. 4

1.2     Brief Overview of Clinical Studies. 4

1.3     Statistical Issues and Findings. 5

2     INTRODUCTION.. 6

2.1     Overview... 6

2.1.1     History of Drug Development 7

2.1.2     Specific Studies Reviewed. 7

2.1.3     Major Statistical Issues. 7

2.2     Data Sources. 8

3     STATISTICAL EVALUATION.. 8

3.1     Evaluation of Efficacy.. 8

3.1.1     Study Design and Endpoint 8

3.1.2     Patient Disposition, Demographic and Baseline Characteristics. 9

3.1.3     Statistical Methodologies. 12

3.1.4     Results and Conclusion. 13

3.2     Evaluation of Safety.. 19

4     FINDINGS IN SPECIAL/SUBGROUP POPULATIONS. 23

4.1     Age, Gender and Ethnic group. 23

4.2     Other Subgroup Populations. 29

5     SUMMARY AND CONCLUSIONS. 29

5.1     Statistical Issues and Collective Evidence. 29

5.2     Conclusions and Recommendations. 30

 


 

List of Tables

 

 

Table 1. Patient Participation, Demographic and Baseline Characteristics (SH-AHS-0003) 9

Table 2. Patient Participation, Demographic and Baseline Characteristics (SH-AHS-0006) 10

Table 3. Patient Participation, Demographic and Baseline Characteristics (SH-AHS-0007) 11

Table 4. Patient Participation, Demographic and Baseline Characteristics (Pooled) 11

Table 5. Analysis of the Primary and Secondary Endpoints (SH-AHS-0003) 14

Table 6. Analysis of the Priamry and Secondary Endpoints (SH-AHS-0006) 14

Table 7. Analysis of the Priamry and Secondary Endpoints (SH-AHS-0007) 15

Table 8. Analysis of the Priamry and Secondary Endpoints (Pooled) 15

Table 9. Most Commonly Reported AEs (SH-AHS-0003) 19

Table 10. Most Commonly Reported AEs (SH-AHS-0006) 20

Table 11. Most Commonly Reported AEs (SH-AHS-0007) 21

Table 12. Most Commonly Reported AEs (Three Studies Pooled) 21

Table 13. Most Commonly Reported AEs (Studies SH-AHS-0003 and SH-AHS-0006 Combined) 22

Table 14. Subgroup Analysis of Time to CV Death or CHF Hospitalization (SH-AHS-0003) 23

Table 15. Subgroup Analysis of Time to CV Death or CHF Hospitalization (SH-AHS-0006) 24

Table 16. Subgroup Analysis of Time to CV Death or CHF Hospitalization (SH-AHS-0007) 25

Table 17. Subgroup Analysis of Time to CV Death or CHF Hospitalization (Pooled) 25

Table 18. Subgroup Analysis of All-Cause Mortality (Three Studies Pooled) 26

Table 19. Subgroup Analysis of All-Cause Mortality (SH-AHS-0003 and -0006 Pooled) 27

 

 

List of Figures

 

 

Figure 1. Survival Estimate of Time to 1st CV Death or CHF Hospitalization (SH-AHS-0003) 16

Figure 2. Survival Estimate of Time to 1st CV Death or CHF Hospitalization (SH-AHS-0006) 16

Figure 3. Survival Estimate of Time to 1st CV Death or CHF Hospitalization (SH-AHS-0007) 17

Figure 4. Survival Estimate of Time to All Cause Death (Three Studies Combined) 17

Figure 5. Survival Estimate of Time to All Cause Death (Studies 0003 and 0006 Combined) 18

Figure 6. Survival Estimate of Time to CV Death (Studies 0003 and 0006 Combined) 18

Figure 7. Survival Estimate of Time to Non-CV Death (Studies 0003 and 0006 Combined) 19

Figure 8. Time to CV Death or CHF Hospitalization by Ethnicity (Study SH-AHS-0007) 28

Figure 9. Time to CV Death or CHF Hospitalization by Region (Study SH-AHS-0006) 28


1       EXECUTIVE SUMMARY

1.1      Conclusions and Recommendations

Candesartan cilexetil (Candesartan) significantly reduced cardiovascular (CV) death or Chronic Heart Failure (CHF) hospitalization in patients with depressed left ventricular (LV) systolic function and ejection fraction (EF) <= 40% treated with or without an angiotensin converting enzyme (ACE) inhibitor.  In the confirmatory analysis, Candesartan also significantly reduced the risk of all-cause death or CHF hospitalization, and the risk of CV death or CHF hospitalization or non-fatal MI.

 

In patients with preserved LV systolic function and EF > 40%, Candesartan failed to show that it significantly reduce the risk of CV death or CHF hospitalization.  It did not show that Candesartan significantly reduced the risk of all-cause death or CHF hospitalization, and the risk of CV death or CHF hospitalization or non-fatal MI.

 

It was not clear whether Candesartan reduced the risk of CV death or CHF hospitalization in patients with depressed or preserved LV systolic function in the oriental subgroup.

 

Candesartan probably significantly reduced the risk of CV death in patients with depressed LV systolic function and EF <= 40% treated with or without an ACE inhibitor.  It failed to show that it significantly reduced the risk of CV death in patients with preserved LV systolic function and EF > 40%.

1.2      Brief Overview of Clinical Studies

The CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and mobility) program consists of 3 pivotal studies (SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007) with the same primary endpoint and different patient populations.  The common primary endpoint was time to the first CV death or CHF hospitalization.  Study SH-AHS-0003 treated patients with heart failure who were ACE inhibitor intolerant and had depressed LV function and EF <= 40%, Study SH-AHS-0006 studied patients with heart failure who were treated with ACE inhibitors and had depressed LV systolic function and EF <= 40%, and Study SH-AHS-0007 had patients with heart failure and preserved LV systolic function and EF > 40%.  The Sponsor is seeking indication that Candesartan reduces the risk of CV death or CHF hospitalization in the three patient populations based on each of the three studies.  The Sponsor is also seeking the indication that Candesartan reduces the risk of all-cause mortality based on the data combining all three studies and the data combining the two studies (SH-AHS-0003 and SH-AHS-0006).

 

The indication for the patients treated with an ACE inhibitor (SH-AHS-0006) was granted with priority review status and the review was completed in another review.  This review considers all the other indications.

 

Study SH-AHS-0003 (Alternative) was a randomized, double-blind, placebo controlled, parallel group, multicenter study to evaluate the influence of Candesartan cilexetil with a target dose of 32 mg once daily on mortality and morbidity in patients with depressed LV systolic function and EF <= 40% and an intolerance to ACE inhibitors.  Male or female patients, over or equal to 18 years old, with symptomatic CHF corresponding to NYHA class II-IV were enrolled in the study.  A total of 2028 patients were randomized in a 1:1 ratio into Candesartan group (n = 1013) and placebo group (n = 1015).  The median follow-up time was 34 months, and individual follow-up time could last from 25 to 48 months.  The design for Studies SH-AHS-0006 (Added) and SH-AHS-0007 (Preserved) was similar to Study SH-AHS-0003 except the patient population.  Study SH-AHS-0006 enrolled patients with EF <= 40% and treated with an ACE inhibitor.  In this study, a total of 2548 patients were randomized in a 1:1 ratio into Candesartan group (n = 1276) and placebo group (n = 1272).  Patient follow-up time ranged from 41 to 48 months, with the median follow-up time of 41 months.  Study SH-AHS-0007 had patients with EF > 40% treated with or without ACE inhibitors.  The number of randomized patients was 3023, with 1514 patients in the Candesartan group and 1509 patients in the placebo group.  The patients were followed from 32 to 48 months, with a median follow-up time of 37 months.  All patients remained in the study until the last randomized patient had been in the CHARM program for two years.

 

1.3      Statistical Issues and Findings

 

In Study SH-AHS-0003 (Alternative), the primary endpoint, time to the first CV death or CHF hospitalization, achieved statistical significance (P < 0.001) with a relative risk reduction of 23% over placebo.  The two secondary endpoints, time to the all-cause mortality or CHF hospitalization and time to CV death or CHF hospitalization or non-fatal MI, also achieved statistical significance with 20% (P = 0.001) and 22% (P < 0.001) relative risk reductions, respectively.

 

In Study SH-AHS-0006 (Added), the primary endpoint achieved statistical significance with a relative risk reduction of 15% (P = 0.011).  The two secondary endpoints also achieved statistical significance. A separate review was completed earlier for Study SH-AHS-0006 since it was granted with priority review status.

 

In Study SH-AHS-0007 (Preserved), the primary endpoint did not achieve statistical significance, with a p-value = 0.12 and a relative risk reduction of 11%.  The two secondary endpoints did not achieve statistical significance either, with both p-values larger than 0.12.  

 

For the combined studies, the primary endpoint was the time to all-cause mortality for the three studies combined, and the secondary endpoint was time to all-cause mortality for the two studies combined (SH-AHS-0003 and SH-AHS-0006).  The primary endpoint did not, but was close to, achieve statistical significance with a p-value = 0.055 and a 9% relative risk reduction.  This p-value should be compared with 0.049 to account for the alpha adjustment due to the six interim analyses.  The secondary endpoint had a 12% relative risk reduction with a nominal p-value = 0.018.  The results for the primary and secondary endpoint were primarily driven by the CV deaths in Studies SH-AHS-0003 and SH-AHS-0006.  Strictly speaking, it can’t be declared that the secondary endpoint achieved statistical significance based on the pre-specified hierarchical test sequence.  However, Candesartan probably significantly reduced the risk of CV mortality in the patient populations in Studies SH-AHS-0003 and SH-AHS-0006 based on the following reasons.  Candesartan had no effect in the risk reduction of CV deaths or non-CV deaths in the patient population of Study SH-AHS-0007, but it had relative risk reductions of 15% (P = 0.072) and 16% (P = 0.029) in CV deaths in Studies SH-AHS-0003 and SH-AHS-0006, respectively, and no effect on non-CV deaths in either studies.  For CV mortality, the relative risk reductions were quite consistent in the two studies, and the nominal p-value was less than 0.05 in Study SH-AHS-0006.  The nominal p-value was bigger than 0.05 in Study SH-AHS-003 for CV deaths, the reason might be that the number of events was much smaller in this study.  When the two studies were combined, the relative risk reduction in CV mortality was 16% with a nominal p-value = 0.005. 

 

Six interim analyses were conducted on all-cause mortality and it is not clear how these analyses would affect the Type I error rate for the primary endpoint of each individual study (time to CV death or CHF hospitalization).  However, since the allocated Type I error rates were very small for the interim analyses, the effect should be small if any.

 

In the subgroup analysis of time to CV death or CHF hospitalization, the hazard ratio was 3.73 with a nominal p-value = 0.026 in the oriental subgroup of Study SH-AHS-0007, and the hazard ratios were bigger than 1 in the other two studies in the oriental subgroup.  The hazard ratio was 2.14 with a nominal p-value = 0.012 in the oriental subgroup when the three studies were combined (Table 17).  Since the sample size was small (n = 133 for three studies combined), further study would be needed for efficacy in this subgroup.

 

2       INTRODUCTION

2.1      Overview

 

Candesartan is indicated for the treatment of hypertension and it is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of Candesartan cilexetil.  In this efficacy supplement application, the Sponsor is seeking indications that Candesartan reduces the combined endpoint of CV mortality or hospitalization for the management of chronic heart failure.  Results from the CHARM program are submitted in this application.  CHARM was an international (26 countries including the US) program comprised of 3 independent concurrent double-blind, placebo-controlled trials (SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007) in which a total of 7601 patients (7599 with data) with NYHA class II-IV heart failure.  The patients in Study SH-AHS-0003 (CHARM-Alternative) were ACE inhibitor intolerant with depressed LV systolic function and EF <= 40%.  Study SH-AHS-0006 (CHARM-Added) studied the patients with depressed LV systolic function and EF <= 40% treated with an ACE inhibitor.  Study SH-AHS-0007 (CHARM-Preserved) enrolled patients with heart failure and preserved LV systolic function and EF > 40%.    

2.1.1    History of Drug Development

 

The Sponsor was seeking priority review for all 3 pivotal studies.  After negotiation with the Sponsor, the Division granted the priority review status for the review of Study SH-AHS-0006.  The other two studies are under standard review.  The priority review is completed.   

 

2.1.2    Specific Studies Reviewed

 

Studies SH-AHS-0003 and SH-AHS-0007 were fully reviewed.  Study SH-AHS-0003 enrolled patients with depressed LV systolic function (EF <= 40%) and intolerance to ACE inhibitors.  It is also called CHARM-alternative trial.  Study SH-AHS-0007 enrolled patients with preserved LV systolic function (EF > 40%) treated or not treated with an ACE inhibitor.  It is called CHARM-preserved trial.

2.1.3    Major Statistical Issues

 

The primary endpoint for each of the three studies is the composite of CV mortality and CV hospitalization for the management of CHF, and each study is intended for the indication that Candesartan reduces the risk of the composite endpoint when compared with placebo for its patient population.  The data from the two studies, together with Study SH-AHS-0006 in the CHARM program, are also used for the indication that Candesartan reduces the risk of all-cause mortality for the pooled patient population.  Six interim analyses were conducted on all-cause mortality at intervals of approximately 6 months over a total of recruitment and follow-up period of around 48 months.  In order to stop for efficacy, one required a p-value < 0.0001 for any interim analysis within 18 months, or a p-value < 0.001 for any subsequent interim analysis.

 

The hypothesis for the primary endpoint is tested at alpha = 0.05 in each study, and the analysis for all-cause mortality is also performed at alpha = 0.05 level based on the pooled data.  This is a typical situation for a clinical program consisting of several independent studies, each study has a primary endpoint for an indication and the primary endpoint is tested at alpha = 0.05.  There is another primary endpoint for the data combining all the studies, and this primary endpoint is different from the primary endpoint in each study, and it is tested at alpha = 0.05 as well.  Strictly speaking, the total alpha is not controlled for the whole program.  The data from each study are used twice for the primary analysis, once for the analysis of the primary endpoint in each individual study and once for the analysis of the primary endpoint of the studies combined.  It is a complicated issue how to control the total alpha for the whole program.

 

Since six interim analyses were conducted, some adjustment of the p-value should be made for the all-cause mortality for the pooled data of the 3 studies.  After adjusting for the interim analyses, the Type I error rate for the final analysis of all-cause mortality is 0.0492.  It is not clear how the interim analyses would affect the alpha level for the analysis of the primary endpoint for each individual study, since the interim analyses were conducted on all-cause mortality which was not the primary endpoint for each individual study.  However, the effect should be small since the alpha error rates allocated for the interim analyses were very small.

 

2.2      Data Sources

 

This application was submitted electronically.  All the materials are located at \\Cdsesub1\n20838\S_022\2004-06-30.  The final reports for the three studies and the summary of clinical efficacy for all the 3 studies were fully reviewed.  They are located at \\Cdsesub1\n20838\S_022\2004-06-30\clinstat\indication\controlled.  The main analyses were independently performed by this reviewer.  SAS data sets are located at \\Cdsesub1\n20838\S_022\2004-06-30\crt\datasets .  

 

3       STATISTICAL EVALUATION

3.1      Evaluation of Efficacy

3.1.1    Study Design and Endpoint

 

The three studies (SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007) were randomized, double-blind, placebo controlled, parallel group, multicenter studies to evaluate the influence of Candesartan with a target dose of 32 mg once daily on mortality and morbidity in patients with symptomatic CHF corresponding to NYHA class II-IV.  The patient population was male and female patients, over or equal to 18 years of age.  Study SH-AHS-0003 enrolled patients with depressed LV systolic function and EF <= 40% and an intolerance to ACE inhibitors, Study SH-AHS-0006 enrolled patients with depressed LV systolic function and EF <= 40% and treated with ACE inhibitors, and Study SH-AHS-007 had patients with preserved LV systolic function and EF > 40%.  The patients were randomized in a 1-1 ratio into one of the two treatment groups in each study.  In Study SH-AHS-0003, a total of 2028 patients were randomized with n = 1013 in the Candesartan group and n = 1015 in the placebo group.  Study SH-AHS-006 randomized 2548 patients with n = 1276 in the Candesartan group and n = 1272 in the placebo group.  Study SH-AHS-0007 had 3023 patients with n = 1514 in the Candesartan group and n = 1509 in the placebo group.  All patients remained in the study until the last randomized patient had been in the CHARM program for two years.  For Study SH-AHS-0003, the patients were followed from 25 to 48 months, with a median follow-up time of 34 months.  The study was conducted in 25 countries at a total of 484 sites, including 131 sites in the United States.  For Study SH-AHS-0006, the patients were followed from 41 to 48 months, with a median follow-up time of 41 months.  The study was conducted in 25 countries at a total of 473 sites, including 123 sites in the United States.  In Study SH-AHS-0007, the patients were followed from 32 to 48 months, with a median follow-up time of 37 months.  The study was conducted in 26 countries at a total of 514 sites, including 143 sites in the United States.  The first patient was randomized on March 22, 1999 and the last patient was completed on March 31, 2003 for each of the three studies.

 

For each study, the primary endpoint was time to the first CV death or hospitalization due to symptomatic chronic heart failure.  Secondary endpoints were time to the first all-cause mortality or hospitalization due to chronic heart failure, time to the first CV death or hospitalization due to chronic heart failure or nonfatal MI. 

 

For the combined studies, the primary endpoint was time to all-cause mortality for the three studies combined.  The secondary endpoint was the time to all-cause mortality for the combined studies of SH-AHS-0003 and SH-AHS-0006.

 

3.1.2    Patient Disposition, Demographic and Baseline Characteristics

 

Tables 1, 2, 3 and 4 are the summaries of the patient participation, demographic and baseline characteristics for Studies of SH-AHS-0003, SH-AHS-0006, SH-AHS-0007 and three studies combined, respectively.  Almost everybody completed the study in each group of the studies.  The demographic and baseline characteristics seem to be comparable between the two treatment groups for the variables listed in the tables in each of the three studies.

 

Table 1. Patient Participation, Demographic and Baseline Characteristics (SH-AHS-0003)

 

Placebo

N = 1015

Cand. Cil.

N = 1013

Total

N = 2028

Disposition N (%)

 

 

 

Completed

1014 (99.9)

1011 (99.8)

2025 (99.9)

Lost to Follow-up

      1 (0.1)

      2 (0.2)

      3 (0.1)

Demographic Characteristics

 

 

 

Sex  N (%)

 

 

 

        Male

 691 (68.1)

691 (68.2)

1382 (68.1)

        Female

 324 (31.9)

322 (31.8)

  646 (31.9)

Age  Mean (SD) Years

66.8 (10.5)

66.3 (11.0)

 66.6 (10.7)

Ethnicity  N (%)

 

 

 

        European Origin

 901 (88.8)

895 (88.4)

1796 (88.6)

        Black

   45 (4.4)

  28 (2.8)

    73 (3.6)

        South Asia

   15 (1.5)

  22 (2.2)

    37 (1.8)

        Arab/Middle East

     6 (0.6)

    9 (0.9)

    15 (0.7)

        Oriental

   27 (2.7)

  29 (2.9)

    56 (2.8)

        Malay

   10 (1.0)

  14 (1.4)

    24 (1.2)

        Other

   11 (1.1)

  16 (1.6)

    27 (1.3)

Baseline Characteristics

 

 

 

Ejection Fraction, Mean (SD)

0.30 (0.07)

0.30 (0.08)

0.30 (0.07)

Diabetes Mellitus, N (%)

 270 (26.6)

 278 (27.4)

 548 (27.0)

Hypertension, N (%)

 515 (50.7)

 500 (49.4)

1015 (50.0)

Atrial Fibrillation, N (%)

 261 (25.7)

 254 (25.1)

 515 (25.4)

Previous MI, N (%)

 618 (60.9)

 629 (62.1)

1247 (61.5)

Angina Pectoris, N (%)

 592 (58.3)

 593 (58.5)

1185 (58.4)

Stroke, N (%)

   90 (8.9)

   85 (8.4)

 175 (8.6)

NYHA II, N (%)

 479 (47.2)

 487 (48.1)

 966 (47.6)

NYHA III, N (%)

 499 (49.2)

 490 (48.4)

 989 (48.8)

NYHA IV, N (%)

   37 (3.6)

   36 (3.6)

   73 (3.6)

Current Smoker, N (%)

 127 (12.5)

 149 (14.7)

 276 (13.8)

Source: Table S1 of the clinical study report of Study SH-AHS-0003 by AstraZeneca.

 

 

Table 2. Patient Participation, Demographic and Baseline Characteristics (SH-AHS-0006)

 

Placebo

N = 1272

Cand. Cil.

N = 1276

Total

N = 2548

Disposition N (%)

 

 

 

Completed

1271 (99.9)

1273 (99.8)

2544 (99.8)

Lost to Follow-up

      1 (0.1)

      3 (0.2)

      4 (0.2)

Demographic Characteristics

 

 

 

Sex  N (%)

 

 

 

        Male

1000 (78.6)

1006 (78.8)

2006 (78.7)

        Female

  272 (21.4)

  270 (21.2)

  542 (21.3)

Age  Mean (SD) Years

 64.1 (11.3)

 64.0 (10.7)

 64.1 (11.0)

Ethnicity  N (%)

 

 

 

        European Origin

1164 (91.5)

1143 (89.6)

2307 (90.5)

        Black

    62 (4.9)

    65 (5.1)

  127 (5.0)

        South Asia

      8 (0.6)

    19 (1.5)

    27 (1.1)

        Arab/Middle East

      4 (0.3)

      8 (0.6)

    12 (0.5)

        Oriental

    13 (1.0)

    22 (1.7)

    35 (1.4)

        Malay

      7 (0.6)

    11 (0.9)

    18 (0.7)

        Other

    14 (1.1)

      8 (0.6)

    22 (0.9)

Baseline Characteristics

 

 

 

Ejection Fraction, Mean (SD)

0.28 (0.07)

0.28 (0.08)

0.28 (0.07)

Diabetes Mellitus, N (%)

 382 (30.0)

 376 (29.5)

 758 (29.7)

Hypertension, N (%)

 619 (48.7)

 609 (47.7)

1228 (48.2)

Atrial Fibrillation, N (%)

 341 (26.8)

 346 (27.1)

 687 (27.0)

Previous MI, N (%)

 703 (55.3)

 714 (56.0)

1417 (55.6)

Angina Pectoris, N (%)

 684 (53.8)

 666 (52.2)

1350 (53.0)

Stroke, N (%)

 112 (8.8)

 108 (8.5)

 220 (8.6)

NYHA II, N (%)

 302 (23.7)

 312 (24.5)

 614 (24.1)

NYHA III, N (%)

 925 (72.7)

 931 (73.0)

1856 (72.8)

NYHA IV, N (%)

   45 (3.5)

   33 (2.6)

   78 (3.1)

Current Smoker, N (%)

 235 (18.5)

 194 (15.2)

  429 (16.8)

Source: Table S1 of the clinical study report of Study SH-AHS-0006 by AstraZeneca.

 

 

 

 

Table 3. Patient Participation, Demographic and Baseline Characteristics (SH-AHS-0007)

 

Placebo

N = 1509

Cand. Cil.

N = 1514

Total

N = 3023

Disposition N (%)

 

 

 

Completed

1508 (99.9)

1512 (99.9)

3020 (99.9)

Lost to Follow-up

      1 (0.01)

      2 (0.01)

      3 (0.01)

Demographic Characteristics

 

 

 

Sex  N (%)

 

 

 

        Male

 891 (59.0)

 920 (60.8)

1811 (59.9)

        Female

 618 (41.0)

 594 (39.2)

1212 (40.1)

Age  Mean (SD) Years

 67.1 (11.1)

 67.2 (11.1)

 67.2 (11.1)

Ethnicity  N (%)

 

 

 

        European Origin

1393 (92.3)

1374 (90.8)

2767 (91.5)

        Black

    57 (3.8)

    69 (4.7)

  126 (4.2)

        South Asia

    11 (0.7)

    18 (1.2)

    29 (1.0)

        Arab/Middle East

      5 (0.3)

      5 (0.3)

    10 (0.3)

        Oriental

    22 (1.5)

    20 (1.3)

    42 (1.4)

        Malay

      8 (0.5)

    14 (0.9)

    22 (0.7)

        Other

    13 (0.9)

    14 (0.9)

    27 (0.9)

Baseline Characteristics

 

 

 

Ejection Fraction, Mean (SD)

0.54 (0.09)

0.54 (0.09)

0.54 (0.09)

Diabetes Mellitus, N (%)

 423 (28.0)

 434 (28.7)

 857 (28.4)

Hypertension, N (%)

 959 (63.6)

 984 (65.0)

1943 (64.3)

Atrial Fibrillation, N (%)

 442 (29.3)

 439 (29.0)

 881 (29.1)

Previous MI, N (%)

 659 (43.7)

 681 (45.0)

1340 (44.3)

Angina Pectoris, N (%)

 902 (59.8)

 915 (60.4)

1817 (60.1)

Stroke, N (%)

 128 (8.5)

 140 (9.2)

  268 (8.9)

NYHA II, N (%)

 905 (60.0)

 931 (61.5)

1836 (60.7)

NYHA III, N (%)

 584 (38.7)

 556 (36.7)

1140 (37.7)

NYHA IV, N (%)

   20 (1.3)

   27 (1.8)

    47 (1.6)

Current Smoker, N (%)

 187 (12.4)

 222 (14.7)

  409 (13.5)

Source: Table S1 of the clinical study report of Study SH-AHS-0007 by AstraZeneca.

 

Table 4. Patient Participation, Demographic and Baseline Characteristics (Pooled)

 

Placebo

N = 3796

Cand. Cil.

N = 3803

Total

N = 7599

Disposition N (%)

 

 

 

Completed

3793 (99.9)

3796 (99.8)

7589 (99.8)

Lost to Follow-up

      3 (0.01)

      7 (0.02)

    10 (0.02)

Demographic Characteristics

 

 

 

Sex  N (%)

 

 

 

        Male

 2582 (68.0)

2617 (68.8)

5199 (68.4)

        Female

 1214 (32.0)

1186 (31.2)

2400 (31.6)

Age  Mean (SD) Years

 66.0 (11.1)

 65.9 (11.0)

 66.0 (11.0)

Ethnicity  N (%)

 

 

 

        European Origin

3458 (91.1)

3412 (89.7)

6870 (90.4)

        Black

  164 (4.3)

   162 (4.3)

  326 (4.3)

        South Asia

    34 (0.9)

    59 (1.6)

    93 (1.2)

        Arab/Middle East

    15 (0.4)

    22 (0.6)

    37 (0.5)

        Oriental

    62 (1.6)

    71 (1.9)

  133 (1.8)

        Malay

    25 (0.7)

    39 (1.0)

    64 (0.8)

        Other

    38 (1.0)

    38 (1.0)

    76 (1.0)

Baseline Characteristics

 

 

 

Ejection Fraction, Mean (SD)

0.39 (0.15)

0.39 (0.15)

0.39 (0.15)

Diabetes Mellitus, N (%)

1075 (28.3)

1088 (28.6)

2163 (28.5)

Hypertension, N (%)

2093 (55.1)

2093 (55.0)

4186 (55.1)

Atrial Fibrillation, N (%)

1044 (27.5)

1039 (27.3)

2083 (27.4)

Previous MI, N (%)

1980 (52.2)

2024 (53.2)

4004 (52.7)

Angina Pectoris, N (%)

2178 (57.4)

2174 (57.2)

4352 (57.3)

Stroke, N (%)

  330 (8.7)

  333 (8.8)

  663 (8.7)

NYHA II, N (%)

1686 (44.4)

1730 (45.5)

3416 (45.0)

NYHA III, N (%)

2008 (52.9)

1977 (52.0)

3985 (52.4)

NYHA IV, N (%)

  102 (2.7)

   96 (2.5)

  198 (2.6)

Current Smoker, N (%)

 549 (14.5)

 565 (14.9)

1114 (14.7)

Source: Table S1 of the clinical study report of pooled clinical study report by AstraZeneca.

 

3.1.3    Statistical Methodologies

 

For each individual study, the primary endpoint, time to the first CV death or hospitalization due to symptomatic chronic heart failure, was compared between the two treatment groups using the log-rank test.  The hazard ratio and its 95% CI were obtained by a Cox proportional hazards model.  The survival distribution by treatment group was plotted using the Kaplan-Meier product limit estimator.  The analyses were conducted on the ITT population, which included all the randomized patients.  The two secondary endpoints were analyzed similarly as the primary endpoint.  The primary and two secondary endpoints were analyzed based on the principle of closed tests.  The analyses were conducted in a hierarchical sequence.  The primary endpoint was tested first and the two secondary endpoints were tested sequentially, conditional on a significant result of the preceding test.  Changes in the NYHA classification were tested using a Wilcoxon rank-sum test.   For continuous variables, the mean change from baseline to last observed value was tested in an ANCOVA model.

 

The analysis of the combined studies is similar to the analysis of each of the three studies.  The primary endpoint was tested first and the secondary endpoint was tested conditional on the significant result of the primary test for the combined studies. 

 

Six interim analyses were conducted on all-cause mortality at intervals of approximately 6 months over a total of recruitment and follow-up period of around 48 months for each individual study and the combined data of the three studies.  In order to stop for efficacy, one required a p-value < 0.0001 for any interim analysis within 18 months, or a p-value < 0.001 for any subsequent interim analysis.  The hypothesis for the test of the primary endpoint is tested at alpha = 0.05 in each study, and the analysis for all-cause mortality is also performed at alpha = 0.05 level based on the pooled data of the three studies.  After adjusting for the interim analyses, the Type I error rate for the final analysis of all-cause mortality is 0.0492.  No adjustment was made for the final analysis of the primary endpoint in each individual study.

 

3.1.4    Results and Conclusion

 

Tables 5, 6 and 7 present the results for the analysis of the primary endpoint and two secondary endpoints in each individual study, including the analysis of the components of the composite endpoints.  The primary endpoint and two secondary endpoints achieved statistical significance in Studies SH-AHS-0003 and SH-AHS-0006 based on the pre-specified hierarchical test sequence.  For the primary endpoint, time to the first CV death or CHF hospitalization, Candesartan had relative risk reductions of 23% and 15% over placebo, with p-values < 0.001 and 0.011 for Studies SH-AHS-0003 and SH-AHS-0006, respectively.  In these two studies, Candesartan also significantly reduced the risk of the two secondary endpoints.  In Study SH-AHS-0003, the relative risk reduction was 20% (P = 0.001) for all-cause death or CHF hospitalization and 22% (P < 0.001) for CV death or CHF hospitalization or nonfatal MI.  In Study SH-AHS-0006, the relative risk reduction was 13% (P = 0.021) for all-cause death or CHF hospitalization and 15% (P = 0.010) for CV death or CHF hospitalization or nonfatal MI.  The primary endpoint and the two secondary endpoints did not achieve statistical significance in Study SH-AHS-0007.  In this study, the relative risk reduction was 11% for the time to the first CV death or CHF hospitalization, with a p-value = 0.12.  The nominal p-values were more than 0.12 for both secondary endpoints as well.

 

Table 8 presents the results for the analysis of the primary endpoint and secondary endpoint of the combined studies.  The primary endpoint for the combined studies, the time to all-cause mortality combining the data from the three studies, did not achieve statistical significance with a p-value = 0.055 and 9% relative risk reduction.  This p-value should be compared with 0.0492 after adjusting for the interim analyses.  The secondary endpoint, the time to all-cause mortality combining the data from Studies SH-AHS-0003 and SH-AHS-0006, had a relative risk reduction of 12% with a nominal p-value = 0.018.  Based on the pre-specified hierarchical test sequence, statistical significance can not be declared for the secondary endpoint since the primary endpoint did not achieve statistical significance.  However, it can still be argued that Candesartan significantly reduced the risk of CV mortality in Studies SH-AHS-0003 and SH-AHS-0006.  In each of the two studies (SH-AHS-0003 and SH-AHS-0006), it had a clear trend in favor of Candesartan with relative risk reductions of 15% (P = 0.072) and 16% (P = 0.029) in CV mortality, respectively.  The relative risk reductions were very consistent in the two studies, and the nominal p-value was 0.029 in Study SH-AHS-006.  The nominal p-value was bigger than 0.05 in Study SH-AHS-003, the reason might be that there was not enough power to detect the difference since there was smaller number of events in that study.  No effects were observed for non-CV deaths in the two studies, with relative risks of 1.01 (P = 0.95) and 1.11 (P = 0.53) for Studies SH-AHS-0003 and SH-AHS-0006, respectively.  When the two studies (Study SH-AHS-0003 and Study SH-AHS-0006) were combined, the relative risk reduction for CV mortality was 16% with a nominal p-value = 0.005.  In Study SH-AHS-0007, it seemed that the drug had no effect on either CV deaths or non-CV deaths, with relative risks of 0.99 (P = 0.92) and 1.10 (P = 0.59) for CV deaths and non-CV deaths, respectively.  Therefore, in my view, Candesartan may have a benefit of reducing the risk of CV mortality in the patient populations of Studies SH-AHS-0003 and SH-AHS-0006, but not in the patient population of Study SH-AHS-0007.        

 

 

Table 5. Analysis of the Primary and Secondary Endpoints (SH-AHS-0003)

 

 

Endpoint

Patients with event

 

Hazard Ratio (95%CI)

 

P-value

Candesartan

N = 1013

Placebo

N = 1015

Primary

  CV death or CHF hospitalization

 

334

 

406

 

0.77 (0.67–0.89)

 

<0.001

Secondary

  All-cause death or CHF hospitalization

 

371

 

433

 

0.80 (0.70-0.92)

 

0.001

  CV death or CHF hospitalization or non-fatal MI

353

420

0.78 (0.68-0.90)

<0.001

Components of the composite endpoints

  CV death

 

219

 

252

 

0.85 (0.71-1.02)

 

0.072

  CHF hospitalization

207

286

0.68 (0.57-0.81)

<0.001

  All-cause mortality

265

296

0.87 (0.74-1.03)

0.104

  Nonfatal MI

41

36

1.11 (0.71-1.73)

0.66

Source: Table 8 of the Sponsor’s summary of clinical efficacy.  The results were confirmed independently by this reviewer, with minor difference for nonfatal MI.  Nominal P-values were from log-rank test and hazard ratios were from Cox regression model with treatment as the only independent variable.

 

 

 

 

Table 6. Analysis of the Primary and Secondary Endpoints (SH-AHS-0006)

 

 

Endpoint

Patients with event

 

Hazard Ratio (95%CI)

 

P-value

Candesartan

N = 1276

Placebo

N = 1272

Primary

  CV death or CHF hospitalization

 

483

 

538

 

0.85 (0.75–0.96)

 

0.011

Secondary

  All-cause death or CHF hospitalization

 

539

 

587

 

0.87 (0.78-0.98)

 

0.021

  CV death or CHF hospitalization or non-fatal MI

495

550

0.85 (0.76-0.96)

0.010

Components of the composite endpoints

  CV death

 

302

 

347

 

0.84 (0.72-0.98)

 

0.029

  CHF hospitalization

309

356

0.83 (0.71-0.96)

0.013

  All-cause mortality

377

412

0.89 (0.77-1.02)

0.086

  Nonfatal MI

26

49

0.51 (0.32-0.82)

0.005

Source: Table 8 of the Sponsor’s summary of clinical efficacy.  The results were confirmed independently by this reviewer, with minor difference for nonfatal MI.  Nominal P-values were from log-rank test and hazard ratios were from Cox regression model with treatment as the only independent variable.

 

 

Table 7. Analysis of the Primary and Secondary Endpoints (SH-AHS-0007)

 

 

Endpoint

Patients with event

 

Hazard Ratio (95%CI)

 

P-value

Candesartan

N = 1514

Placebo

N = 1509

Primary

  CV death or CHF hospitalization

 

333

 

366

 

0.89 (0.77–1.03)

 

0.12

Secondary

  All-cause death or CHF hospitalization

 

386

 

411

 

0.92 (0.80-1.05)

 

0.22

  CV death or CHF hospitalization or non-fatal MI

365

399

0.90 (0.78-1.03)

0.13

Components of the composite endpoints

  CV death

 

170

 

170

 

0.99 (0.80-1.22)

 

0.92

  CHF hospitalization

241

276

0.85 (0.72-1.01)

0.07

  All-cause mortality

244

237

1.02 (0.85-1.22)

0.84

  Nonfatal MI

49

63

0.77 (0.53-1.12)

0.17

Source: Table 8 of the Sponsor’s summary of clinical efficacy.  The results were confirmed independently by this reviewer, with minor difference for nonfatal MI.  Nominal P-values were from log-rank test and hazard ratios were from Cox regression model with treatment as the only independent variable.

 

Table 8. Analysis of the Primary and Secondary Endpoints (Pooled)

 

 

Endpoint

Number of Patients

 

Hazard Ratio (95%CI)

 

P-value

Candesartan

n (N)

Placebo

n (N)

Primary

  All-cause death (SH-AHS-0003, -0006, -0007)

 

886 (3803)

 

945 (3796)

 

0.91 (0.83-1.00)

 

0.055

Secondary

  All-cause death (SH-AHS-0003, -0006)

 

642 (2289)

 

708 (2287)

 

0.88 (0.79-0.98)

 

0.018

Components

 

 

 

 

  CV death (SH-AHS-0003, -0006, -0007)

  Non-CV death (SH-AHS-0003, -0006, -0007)

691 (3803)

195 (3803)

769 (3796)

176 (3796)

0.88 (0.79-0.97)

1.08 (0.88-1.33)

0.012*

0.452*

  CV death (SH-AHS-0003, -0006)

  Non-CV death (SH-AHS-0003, -0006)

521 (2289)

121 (2289)

599 (2287)

109 (2287)

0.84 (0.75-0.95)

1.07 (0.83-1.39)

0.005*

0.595*

  CV death (SH-AHS-0003)

  Non-CV death (SH-AHS-0003)

219 (1013)

  46 (1013)

252 (1015)

  44 (1015)

0.85 (0.71-1.02)

1.01 (0.67-1.53)

0.072*

0.948*

  CV death (SH-AHS-0006)

  Non-CV death (SH-AHS-0006)

302 (1276)

  75 (1276)

347 (1272)

  65 (1272)

0.84 (0.72-0.98)

1.11 (0.80-1.55)

0.029*

0.529*

  CV death (SH-AHS-0007)

  Non-CV death (SH-AHS-0007)

170 (1514)

  74 (1514)

170 (1509)

  67 (1509)

0.99 (0.80-1.22)

1.10 (0.79-1.52)

0.918*

0.589

Source: Tables S2, 28, 30 of the Sponsor’s pooled clinical study report, Table 55 of the Sponsor’s clinical study report of SH-AHS-0003, Table 54 of the Sponsor’s clinical study report of SH-AHS-0006, and Table 88 of the Sponsor’s clinical study report of SH-AHS-0007.  The results were confirmed independently by this reviewer.  Nominal P-values were from log-rank test and hazard ratios were from Cox regression model with treatment as the only independent variable.  * Nominal P-values were from Cox regression model with treatment as the only independent variable.

 

Figures 1, 2 and 3 are the Kaplan-Meier estimates for time to the first CV death or CHF hospitalization for Studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007, respectively.  Figures 4 and 5 are the Kaplan-Meier estimates for time to all-cause mortality for three studies combined and two studies combined (SH-AHS-0003 and SH-AHS-0006), respectively.   Figures 6 and 7 are the Kaplan-Meier estimates for CV and non-CV mortality when the two studies are combined (SH-AHS-0003 and SH-AHS-0006), respectively.

 

Figure 1. Survival Estimate of Time to 1st CV Death or CHF Hospitalization (SH-AHS-0003)

 Source: Reviewer’s analysis.

 

Figure 2. Survival Estimate of Time to 1st CV Death or CHF Hospitalization (SH-AHS-0006)

Source: Reviewer’s analysis.

 

 

Figure 3. Survival Estimate of Time to 1st CV Death or CHF Hospitalization (SH-AHS-0007)

Source: Reviewer’s Analysis.

 

 

Figure 4. Survival Estimate of Time to All Cause Death (Three Studies Combined)

Source: Reviewer’s Analysis.

 

Figure 5. Survival Estimate of Time to All Cause Death (Studies 0003 and 0006 Combined)

Source: Reviewer’s Analysis.

 

Figure 6. Survival Estimate of Time to CV Death (Studies 0003 and 0006 Combined)

Source: Reviewer’s Analysis.

 

Figure 7. Survival Estimate of Time to Non-CV Death (Studies 0003 and 0006 Combined)

Source: Reviewer’s Analysis.

 

3.2      Evaluation of Safety

 

The most commonly reported adverse events (AE) are in Tables 9, 10, 11, 12 and 13 for Studies SH-AHS-0003, SH-AHS-0006, SH-AHS-0007, three studies combined and two studies combined (SH-AHS-0003 and SH-AHS-0006), respectively.  The tables use a cut-off of 3% AEs in the total population during the study.  It seemed that most of reported AEs are comparable among the two treatment groups.  Among the AEs that occurred more in the Candesartan group during the study, Hypotension, Renal function abnormal/renal dysfunction aggravated occurred more in Candesartan group than Placebo group in each of the three studies, and Hyperkalaemia occurred more in Candesartan group than Placebo group in Studies SH-AHS-0003 and SH-AHS-0006.  

 

Table 9. Most Commonly Reported AEs (SH-AHS-0003)

 

 

Preferred Term

Placebo

on treatment

(N = 1015)

  n     %

Candesartan on treatment

(N = 1013)

  n     %

Placebo

during study

(N = 1015)

  n     %

Candesartan during study

(N = 1013)

n       %

Cardiac failure/cardiac failure aggravated

317 (31.2)

234 (23.1)

359 (35.4)

280 (27.6)

Hypotension

  76 (7.5)

190 (18.8)

  90 (8.9)

193 (19.1)

Angina pectoris/angina pectoris aggravated

110 (10.8)

105 (10.4)

120 (11.8)

127 (12.5)

Renal function abnormal/renal dysfunction aggravated

  49 (4.8)

136 (13.4)

  50 (4.9)

141 (13.9)

Sudden death

  85 (8.4)

65 (6.4)

106 (10.4)

80 (7.9)

Pneumonia

  64 (6.3)

65 (6.4)

  75 (7.4)

83 (8.2)

Myocardial infarction

  58 (5.7)

71 (7.0)

  68 (6.7)

85 (8.4)

Arrhythmia ventricular

  64 (6.3)

58 (5.7)

  79 (7.8)

73 (7.2)

Cerebrovascular disorder

  55 (5.4)

41 (4.0)

  61 (6.0)

52 (5.1)

Arrhythmia atrial

  41 (4.0)

44 (4.3)

  44 (4.3)

56 (5.5)

Fibrillation atrial

 46 (4.5)

34 (3.4)

 57 (5.6)

43 (4.2)

Chest pain

 42 (4.1)

37 (3.7)

 50 (4.9)

47 (4.6)

Coronary artery disorder

39 (3.8)

38 (3.8)

48 (4.7)

49 (4.8)

Tachycardia ventricular/arrhythmia

31 (3.1)

28 (2.8)

44 (4.3)

39 (3.8)

Cardiomyopathy

29 (2.9)

25 (2.5)

40 (3.9)

37 (3.7)

Tachycardia supraventricular

30 (3.0)

27 (2.7)

39 (3.8)

34 (3.4)

Hyperkalaemia

16 (1.6)

54 (5.3)

18 (1.8)

54 (5.3)

Dizziness/vertigo

21 (2.1)

43 (4.2)

23 (2.3)

45 (4.4)

Dyspnoea/dyspnoea (aggravated)

39 (3.8)

17 (1.7)

43 (4.2)

22 (2.2)

Syncope

28 (2.8)

26 (2.6)

35 (3.4)

30 (3.0)

Source: Table S4 of the Sponsor’s clinical study report of study SH-AHS-0003.

On treatment = on treatment with investigational product; During study = total study period, irrespective of treatment with investigational product or not.

 

Table 10. Most Commonly Reported AEs (SH-AHS-0006)

 

 

Preferred Term

Placebo

on treatment

(N = 1272)

  n     %

Candesartan on treatment

(N = 1276)

  n     %

Placebo

during study

(N = 1272)

  n     %

Candesartan during study

(N = 1276)

n       %

Cardiac failure/cardiac failure aggravated

435 (34.2)

350 (27.4)

472 (37.1)

421 (33.0)

Hypotension

176 (13.8)

288 (22.6)

184 (14.5)

296 (23.2)

Angina pectoris/angina pectoris aggravated

153 (12.0)

127 (10.0)

169 (13.3)

150 (11.8)

Sudden death

140 (11.0)

114 (8.9)

174 (13.7)

143 (11.2)

Renal function abnormal/renal dysfunction aggravated

115 (9.0)

192 (15.0)

119 (9.4)

196 (15.4)

Arrhythmia ventricular

107 (8.4)

78 (6.1)

121 (9.5)

88 (6.9)

Pneumonia

88 (6.9)

57 (4.5)

108 (8.5)

76 (6.0)

Hyperkalaemia

44 (3.5)

121 (9.5)

46 (3.6)

123 (9.6)

Myocardial infarction

73 (5.7)

60 (4.7)

88 (6.9)

70 (5.5)

Atrial fibrillation

69 (5.4)

52 (4.1)

73 (5.7)

66 (5.2)

Arrhythmia atrial

61 (4.8)

59 (4.6)

71 (5.6)

67 (5.3)

Tachycardia ventricular/arrhythmia/ arrhythmia aggravated

63 (5.0)

52 (4.1)

68 (5.3)

65 (5.1)

Cerebrovascular disorder

48 (3.8)

55 (4.3)

58 (4.6)

69 (5.4)

Chest pain

64 (5.0)

45 (3.5)

71 (5.6)

54 (4.2)

Coronary artery disorder

42 (3.3)

58 (4.5)

50 (3.9)

73 (5.7)

Syncope

45 (3.5)

49 (3.8)

49 (3.9)

59 (4.6)

Tachycardia supraventricular

46 (3.6)

47 (3.7)

50 (3.9)

54 (4.2)

Cardiomyopathy

38 (3.0)

33 (2.6)

48 (3.8)

51 (4.0)

Dizziness/vertigo

35 (2.8)

49 (3.8)

40 (3.1)

57 (4.5)

Pulmonary oedema

41 (3.2)

39 (3.1)

47 (3.7)

48 (3.8)

Renal failure acute

29 (2.3)

45 (3.5)

38 (3.0)

54 (4.2)

Anaemia

36 (2.8)

35 (2.7)

43 (3.4)

46 (3.6)

 

Accident and/or injury

32 (2.5)

34 (2.7)

43 (3.4)

44 (3.4)

Diabetes mellitus/diabetes mellitus aggravated

41 (3.2)

30 (2.4)

42 (3.3)

37 (2.9)

Dehydration

18 (1.4)

40 (3.1)

22 (1.7)

55 (4.3)

Source: Table S4 of the Sponsor’s clinical study report of study SH-AHS-0006.

On treatment = on treatment with investigational product; During study = total study period, irrespective of treatment with investigational product or not.

 

Table 11. Most Commonly Reported AEs (SH-AHS-0007)

 

 

Preferred Term

Placebo

on treatment

(N = 1509)

  n     %

Candesartan on treatment

(N = 1514)

  n     %

Placebo

during study

(N = 1509)

  n     %

Candesartan during study

(N = 1514)

n       %

Cardiac failure/cardiac failure aggravated

321 (21.3)

247 (16.3)

356 (23.6)

300 (19.8)

Angina pectoris/angina pectoris aggravated

198 (13.1)

182 (12.0)

217 (14.4)

213 (14.1)

Hypotension

120 (8.0)

236 (15.6)

125 (8.3)

247 (16.3)

Renal function abnormal/renal dysfunction aggravated

  74 (4.9)

146 (9.6)

  79 (5.2)

150 (9.9)

Pneumonia

  91 (6.0)

  78 (5.2)

116 (7.7)

102 (6.7)

Atrial fibrillation

103 (6.8)

  79 (5.2)

119 (7.9)

  93 (6.1)

Myocardial infarction

  85 (5.6)

  74 (4.9)

101 (6.7)

  87 (5.7)

Coronary artery disorder

  89 (5.9)

  73 (4.8)

102 (6.8)

  83 (5.5)

Cerebrovascular disorder

  86 (5.7)

  68 (4.5)

  97 (6.4)

  82 (5.4)

Chest pain

  71 (4.7)

  72 (4.8)

  81 (5.4)

  82 (5.4)

Tachycardia supraventricular

  76 (5.0)

  55 (3.6)

  88 (5.8)

  60 (4.0)

Arrhythmia atrial

  73 (4.8)

  53 (3.5)

  82 (5.4)

  64 (4.2)

Sudden death

  57 (3.8)

  55 (3.6)

  68 (4.5)

  68 (4.5)

Accident and/or injury

  49 (3.2)

  46 (3.0)

  63 (4.2)

  59 (3.9)

Dizziness/vertigo

  51 (3.4)

  62 (4.1)

  52 (3.4)

  66 (4.4)

Anaemia

  35 (2.3)

  46 (3.0)

  47 (3.1)

  63 (4.2)

Dyspnoea/dyspnoea (aggravated)

  48 (3.2)

  39 (2.6)

  51 (3.4)

  46 (3.0)

Source: Table S4 of the Sponsor’s clinical study report of study SH-AHS-0007.

On treatment = on treatment with investigational product; During study = total study period, irrespective of treatment with investigational product or not.

 

Table 12. Most Commonly Reported AEs (Three Studies Pooled)

 

 

Preferred Term

Placebo

on treatment

(N = 3796)

  n     %

Candesartan on treatment

(N = 3803)

  n     %

Placebo

during study

(N = 3796)

  n     %

Candesartan during study

(N = 3803)

n       %

Cardiac failure/cardiac failure aggravated

1073 (28.3)

831 (21.9)

1187 (31.3)

1001 (26.3)

Hypotension

  372 (9.8)

714 (18.8)

  399 (10.5)

  736 (19.4)

Angina pectoris/angina pectoris aggravated

  461 (12.1)

414 (10.9)

  506 (13.3)

  490 (12.9)

Renal function abnormal/renal dysfunction aggravated

  238 (6.3)

474 (12.5)

  248 (6.5)

  487 (12.8)

Sudden death

  282 (7.4)

234 (6.2)

  348 (9.2)

  291 (7.7)

Pneumonia

  243 (6.4)

200 (5.3)

  299 (7.9)

  261 (6.9)

Myocardial infarction

  216 (5.7)

205 (5.4)

  257 (6.8)

  242 (6.4)

Atrial fibrillation

  218 (5.7)

165 (4.3)

  249 (6.6)

  202 (5.3)

Arrhythmia ventricular

  207 (5.5)

159 (4.2)

  239 (6.3)

  193 (5.1)

Cerebrovascular disorder

  189 (5.0)

164 (4.3)

  216 (5.7)

  203 (5.3)

Coronary artery disorder

  170 (4.5)

169 (4.4)

  200 (5.3)

  205 (5.4)

Chest pain

  177 (4.7)

  154 (4.0)

  202 (5.3)

183 (4.8)

Arrhythmia atrial

  175 (4.6)

  156 (4.1)

  197 (5.2)

187 (4.9)

Hyperkalaemia

    78 (2.1)

  238 (6.3)

    84 (2.2)

242 (6.4)

Tachycardia supraventricular

  152 (4.0)

  129 (3.4)

  177 (4.7)

148 (3.9)

Dizziness/vertigo

  107 (2.8)

  154 (4.0)

  115 (3.0)

168 (4.4)

Accident and/or injury

  112 (3.0)

    99 (2.6)

  143 (3.8)

125 (3.3)

Tachycardia ventricular/arrhythmia/ arrhythmia aggravated

  110 (2.9)

  100 (2.6)

  132 (3.5)

128 (3.4)

Syncope

  105 (2.8)

  121 (3.2)

  119 (3.1)

139 (3.7)

Anaemia

    87 (2.3)

  110 (2.9)

  110 (2.9)

145 (3.8)

Source: Table S4 of the Sponsor’s clinical study report of pooled data.

On treatment = on treatment with investigational product; During study = total study period, irrespective of treatment with investigational product or not.

 

Table 13. Most Commonly Reported AEs (Studies SH-AHS-0003 and SH-AHS-0006 Combined)

 

 

Preferred Term

Placebo

on treatment

(N = 2287)

  n     %

Candesartan on treatment

(N = 2289)

  n     %

Placebo

during study

(N = 2287)

  n     %

Candesartan during study

(N = 2289)

n       %

Cardiac failure/cardiac failure aggravated

752 (32.9)

584 (25.5)

831 (36.3)

701 (30.6)

Hypotension

252 (11.0)

478 (20.9)

274 (12.0)

489 (21.4)

Angina pectoris/angina pectoris aggravated

263 (11.5)

232 (10.1)

289 (12.6)

277 (12.1)

Renal function abnormal/renal dysfunction aggravated

164 (7.2)

328 (14.3)

169 (13.7)

143 (11.2)

Sudden death

225 (9.8)

179 (7.8)

280 (12.2)

223 (9.7)

Arrhythmia ventricular

171 (7.5)

136 (5.9)

200 (8.7)

161 (7.0)

Pneumonia

152 (6.6)

122 (5.3)

183 (8.0)

159 (6.9)

Myocardial infarction

131 (5.7)

131 (5.7)

156 (6.8)

155 (6.8)

Hyperkalaemia

  60 (2.6)

175 (7.6)

  64 (2.8)

177 (7.7)

Cerebrovascular disorder

103 (4.5)

  96 (4.2)

119 (5.2)

121 (5.3)

Fibrillation atrial

115 (5.0)

  86 (3.8)

130 (5.7)

109 (4.8)

Arrhythmia atrial

102 (4.5)

103 (4.5)

115 (5.0)

123 (5.4)

Chest pain

106 (4.6)

  82 (3.6)

121 (5.3)

101 (4.4)

Coronary artery disorder

  81 (3.5)

  96 (4.2)

  98 (4.3)

122 (5.3)

Tachycardia ventricular/arrhythmia/ arrhythmia aggravated

  94 (4.1)

  80 (3.5)

112 (4.9)

104 (4.5)

Tachycardia supraventricular

  76 (3.3)

  74 (3.2)

  89 (3.9)

  88 (3.8)

Cardiomyopathy

  67 (2.9)

  58 (2.5)

  88 (3.8)

  88 (3.8)

Syncope

  73 (3.2)

  75 (3.3)

  84 (3.7)

  89 (3.9)

Dizziness/vertigo

  56 (2.4)

  92 (4.0)

  63 (2.8)

102 (4.5)

Pulmonary oedema

  67 (2.9)

  59 (2.6)

  77 (3.4)

  75 (3.3)

Accident and/or injury

  63 (2.8)

  53 (2.3)

  80 (3.5)

  66 (2.9)

Anaemia

  52 (2.3)

  64 (2.8)

  63 (2.8)

  82 (3.6)

Renal failure acute

  41 (1.8)

  69 (3.0)

  57 (2.5)

  85 (3.7)

Source: Table 146 of the Sponsor’s clinical study report of study SH-AHS-pooled.

On treatment = on treatment with investigational product; During study = total study period, irrespective of treatment with investigational product or not.

4       FINDINGS IN SPECIAL/SUBGROUP POPULATIONS

4.1      Age, Gender and Ethnic group

 

Subgroup analysis of the primary endpoint was performed by age, gender and ethnic group.  For the analysis of time to CV death or CHF hospitalization, the results are presented in Tables 14, 15, 16 and 17 for Studies SH-AHS-0003, SH-AHS-0006, SH-AHS-0007 and three studies combined, respectively.  For the analysis of all-cause mortality, the results are in Tables 18 and 19 for three studies combined and two studies (SH-AHS-0003 and SH-AHS-0006) combined, respectively. 

 

For the time to CV death or CHF hospitalization, the hazard ratios were less than 1 (in favor of Candesartan) in all the subgroups except for the oriental, South Asian, Arab/Middle East subgroups in each of the three studies, and for blacks in Study SH-AHS-0007.  The sample sizes were small in these subgroups, and the nominal p-values were larger than 0.05 except for the oriental group in Study SH-AHS-0007.  The hazard ratio was 3.73 with a nominal p-value = 0.026 in the oriental subgroup of Study SH-AHS-0007 (Table 16 and Figure 8), and the hazard ratios were bigger than 1 in the oriental subgroup in the other two studies with the nominal p-values larger than 0.05.  The hazard ratio was 2.14 with a nominal p-value = 0.012 in the oriental subgroup when the three studies were combined (Table 17). 

 

For all-cause mortality, the hazard ratios were less than 1 (in favor of Candesartan) in all the subgroups except for the oriental, Arab/Middle East subgroups in the three studies combined and two studies combined (SH-AHS-0003 and SH-AHS-0006).   Again, the sample sizes were small in these subgroups and the nominal p-values were larger than 0.05.

 

Table 14. Subgroup Analysis of Time to CV Death or CHF Hospitalization (SH-AHS-0003)

 

Variable

 

Group

Total

N

Candesartan

# of events

Placebo

# of Events

 

Hazard Ratio (95% CI)

P-value

Age(Years)

< 65

804

120

116

0.973 (0.754, 1.256)

0.833

 

>= 65 -< 75

752

123

165

0.711 (0.563, 0.898)

0.004

 

>= 75

472

91

125

0.647 (0.494, 0.848)

0.002

Age (Years)

< 75

1556