![](media/image1.png){width="1.125in" height="1.113888888888889in"}

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]{.smallcaps} [EXECUTIVE SUMMARY 4]{.smallcaps}](#executive-summary)

[1.1 Conclusions and Recommendations
4](#conclusions-and-recommendations)

[1.2 Brief Overview of Clinical Studies
4](#brief-overview-of-clinical-studies)

[1.3 Statistical Issues and Findings
5](#statistical-issues-and-findings)

[2 INTRODUCTION 6](#introduction)

[2.1 Overview 6](#overview)

[2.1.1 History of Drug Development 7](#history-of-drug-development)

[2.1.2 Specific Studies Reviewed 7](#specific-studies-reviewed)

[2.1.3 Major Statistical Issues 7](#major-statistical-issues)

[2.2 Data Sources 8](#data-sources)

[3 STATISTICAL EVALUATION 8](#statistical-evaluation)

[3.1 Evaluation of Efficacy 8](#evaluation-of-efficacy)

[3.1.1 Study Design and Endpoint 8](#study-design-and-endpoint)

[3.1.2 Patient Disposition, Demographic and Baseline Characteristics
9](#patient-disposition-demographic-and-baseline-characteristics)

[3.1.3 Statistical Methodologies 12](#statistical-methodologies)

[3.1.4 Results and Conclusion 13](#results-and-conclusion)

[3.2 Evaluation of Safety 19](#evaluation-of-safety)

[4 FINDINGS IN SPECIAL/SUBGROUP POPULATIONS
23](#findings-in-specialsubgroup-populations)

[4.1 Age, Gender and Ethnic group 23](#age-gender-and-ethnic-group)

[4.2 Other Subgroup Populations 29](#other-subgroup-populations)

[5 SUMMARY AND CONCLUSIONS 29](#summary-and-conclusions)

[5.1 Statistical Issues and Collective Evidence
29](#statistical-issues-and-collective-evidence)

[5.2 Conclusions and Recommendations
30](#conclusions-and-recommendations-1)

**List of Tables**

[Table 1. Patient Participation, Demographic and Baseline
Characteristics (SH-AHS-0003) 9](#__RefHeading___Toc91932352)

[Table 2. Patient Participation, Demographic and Baseline
Characteristics (SH-AHS-0006) 10](#__RefHeading___Toc91932353)

[Table 3. Patient Participation, Demographic and Baseline
Characteristics (SH-AHS-0007) 11](#__RefHeading___Toc91932354)

[Table 4. Patient Participation, Demographic and Baseline
Characteristics (Pooled) 11](#__RefHeading___Toc91932355)

[Table 5. Analysis of the Primary and Secondary Endpoints (SH-AHS-0003)
14](#__RefHeading___Toc91932356)

[Table 6. Analysis of the Priamry and Secondary Endpoints (SH-AHS-0006)
14](#__RefHeading___Toc91932357)

[Table 7. Analysis of the Priamry and Secondary Endpoints (SH-AHS-0007)
15](#__RefHeading___Toc91932358)

[Table 8. Analysis of the Priamry and Secondary Endpoints (Pooled)
15](#__RefHeading___Toc91932359)

[Table 9. Most Commonly Reported AEs (SH-AHS-0003)
19](#__RefHeading___Toc91932360)

[Table 10. Most Commonly Reported AEs (SH-AHS-0006)
20](#__RefHeading___Toc91932361)

[Table 11. Most Commonly Reported AEs (SH-AHS-0007)
21](#__RefHeading___Toc91932362)

[Table 12. Most Commonly Reported AEs (Three Studies Pooled)
21](#__RefHeading___Toc91932363)

[Table 13. Most Commonly Reported AEs (Studies SH-AHS-0003 and
SH-AHS-0006 Combined) 22](#__RefHeading___Toc91932364)

[Table 14. Subgroup Analysis of Time to CV Death or CHF Hospitalization
(SH-AHS-0003) 23](#__RefHeading___Toc91932365)

[Table 15. Subgroup Analysis of Time to CV Death or CHF Hospitalization
(SH-AHS-0006) 24](#OLE_LINK2)

[Table 16. Subgroup Analysis of Time to CV Death or CHF Hospitalization
(SH-AHS-0007) 25](#__RefHeading___Toc91932367)

[Table 17. Subgroup Analysis of Time to CV Death or CHF Hospitalization
(Pooled) 25](#__RefHeading___Toc91932368)

[Table 18. Subgroup Analysis of All-Cause Mortality (Three Studies
Pooled) 26](#__RefHeading___Toc91932369)

[Table 19. Subgroup Analysis of All-Cause Mortality (SH-AHS-0003 and
-0006 Pooled) 27](#__RefHeading___Toc91932370)

**List of Figures**

[Figure 1. Survival Estimate of Time to 1^st^ CV Death or CHF
Hospitalization (SH-AHS-0003) 16](#__RefHeading___Toc91932371)

[Figure 2. Survival Estimate of Time to 1^st^ CV Death or CHF
Hospitalization (SH-AHS-0006) 16](#__RefHeading___Toc91932372)

[Figure 3. Survival Estimate of Time to 1^st^ CV Death or CHF
Hospitalization (SH-AHS-0007) 17](#__RefHeading___Toc91932373)

[Figure 4. Survival Estimate of Time to All Cause Death (Three Studies
Combined) 17](#__RefHeading___Toc91932374)

[Figure 5. Survival Estimate of Time to All Cause Death (Studies 0003
and 0006 Combined) 18](#__RefHeading___Toc91932375)

[Figure 6. Survival Estimate of Time to CV Death (Studies 0003 and 0006
Combined) 18](#__RefHeading___Toc91932376)

[Figure 7. Survival Estimate of Time to Non-CV Death (Studies 0003 and
0006 Combined) 19](#__RefHeading___Toc91932377)

[Figure 8. Time to CV Death or CHF Hospitalization by Ethnicity (Study
SH-AHS-0007) 28](#__RefHeading___Toc91932378)

[Figure 9. Time to CV Death or CHF Hospitalization by Region (Study
SH-AHS-0006) 28](#__RefHeading___Toc91932379)

# EXECUTIVE SUMMARY

## 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%.

## 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.

## 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.

# INTRODUCTION

## 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%.

### 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.

### 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.

### 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.

## Data Sources

This application was submitted electronically. All the materials are
located at
[\\\\Cdsesub1\\n20838\\S_022\\2004-06-30](../../../../../../../../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](../../../../../../../../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](../../../../../../../../n20838/S_022/2004-06-30/crt/datasets)
.

# STATISTICAL EVALUATION

## Evaluation of Efficacy

### 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.

### 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.

[]{#__RefHeading___Toc91932352 .anchor}Table 1. Patient Participation,
Demographic and Baseline Characteristics (SH-AHS-0003)

+----------------------------------------+--------+--------+---------+
|                                        | **Pla  | *      | **      |
|                                        | cebo** | *Cand. | Total** |
|                                        |        | Cil.** |         |
|                                        | **N =  |        | **N =   |
|                                        | 1015** | **N =  | 2028**  |
|                                        |        | 1013** |         |
+========================================+========+========+=========+
| **Disposition N (%)**                  |        |        |         |
+----------------------------------------+--------+--------+---------+
| Completed                              | 1014   | 1011   | 2025    |
|                                        | (99.9) | (99.8) | (99.9)  |
+----------------------------------------+--------+--------+---------+
| Lost to Follow-up                      | 1      | 2      | 3 (0.1) |
|                                        | (0.1)  | (0.2)  |         |
+----------------------------------------+--------+--------+---------+
| **Demographic Characteristics**        |        |        |         |
+----------------------------------------+--------+--------+---------+
| Sex N (%)                              |        |        |         |
+----------------------------------------+--------+--------+---------+
| Male                                   | 691    | 691    | 1382    |
|                                        | (68.1) | (68.2) | (68.1)  |
+----------------------------------------+--------+--------+---------+
| Female                                 | 324    | 322    | 646     |
|                                        | (31.9) | (31.8) | (31.9)  |
+----------------------------------------+--------+--------+---------+
| Age Mean (SD) Years                    | 66.8   | 66.3   | 66.6    |
|                                        | (10.5) | (11.0) | (10.7)  |
+----------------------------------------+--------+--------+---------+
| Ethnicity N (%)                        |        |        |         |
+----------------------------------------+--------+--------+---------+
| European Origin                        | 901    | 895    | 1796    |
|                                        | (88.8) | (88.4) | (88.6)  |
+----------------------------------------+--------+--------+---------+
| Black                                  | 45     | 28     | 73      |
|                                        | (4.4)  | (2.8)  | (3.6)   |
+----------------------------------------+--------+--------+---------+
| South Asia                             | 15     | 22     | 37      |
|                                        | (1.5)  | (2.2)  | (1.8)   |
+----------------------------------------+--------+--------+---------+
| Arab/Middle East                       | 6      | 9      | 15      |
|                                        | (0.6)  | (0.9)  | (0.7)   |
+----------------------------------------+--------+--------+---------+
| Oriental                               | 27     | 29     | 56      |
|                                        | (2.7)  | (2.9)  | (2.8)   |
+----------------------------------------+--------+--------+---------+
| Malay                                  | 10     | 14     | 24      |
|                                        | (1.0)  | (1.4)  | (1.2)   |
+----------------------------------------+--------+--------+---------+
| Other                                  | 11     | 16     | 27      |
|                                        | (1.1)  | (1.6)  | (1.3)   |
+----------------------------------------+--------+--------+---------+
| **Baseline Characteristics**           |        |        |         |
+----------------------------------------+--------+--------+---------+
| Ejection Fraction, Mean (SD)           | 0.30   | 0.30   | 0.30    |
|                                        | (0.07) | (0.08) | (0.07)  |
+----------------------------------------+--------+--------+---------+
| Diabetes Mellitus, N (%)               | 270    | 278    | 548     |
|                                        | (26.6) | (27.4) | (27.0)  |
+----------------------------------------+--------+--------+---------+
| Hypertension, N (%)                    | 515    | 500    | 1015    |
|                                        | (50.7) | (49.4) | (50.0)  |
+----------------------------------------+--------+--------+---------+
| Atrial Fibrillation, N (%)             | 261    | 254    | 515     |
|                                        | (25.7) | (25.1) | (25.4)  |
+----------------------------------------+--------+--------+---------+
| Previous MI, N (%)                     | 618    | 629    | 1247    |
|                                        | (60.9) | (62.1) | (61.5)  |
+----------------------------------------+--------+--------+---------+
| Angina Pectoris, N (%)                 | 592    | 593    | 1185    |
|                                        | (58.3) | (58.5) | (58.4)  |
+----------------------------------------+--------+--------+---------+
| Stroke, N (%)                          | 90     | 85     | 175     |
|                                        | (8.9)  | (8.4)  | (8.6)   |
+----------------------------------------+--------+--------+---------+
| NYHA II, N (%)                         | 479    | 487    | 966     |
|                                        | (47.2) | (48.1) | (47.6)  |
+----------------------------------------+--------+--------+---------+
| NYHA III, N (%)                        | 499    | 490    | 989     |
|                                        | (49.2) | (48.4) | (48.8)  |
+----------------------------------------+--------+--------+---------+
| NYHA IV, N (%)                         | 37     | 36     | 73      |
|                                        | (3.6)  | (3.6)  | (3.6)   |
+----------------------------------------+--------+--------+---------+
| Current Smoker, N (%)                  | 127    | 149    | 276     |
|                                        | (12.5) | (14.7) | (13.8)  |
+----------------------------------------+--------+--------+---------+

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

[]{#__RefHeading___Toc91932353 .anchor}Table 2. Patient Participation,
Demographic and Baseline Characteristics (SH-AHS-0006)

+----------------------------------------+--------+--------+---------+
|                                        | **Pla  | *      | **      |
|                                        | cebo** | *Cand. | Total** |
|                                        |        | Cil.** |         |
|                                        | **N =  |        | **N =   |
|                                        | 1272** | **N =  | 2548**  |
|                                        |        | 1276** |         |
+========================================+========+========+=========+
| **Disposition N (%)**                  |        |        |         |
+----------------------------------------+--------+--------+---------+
| Completed                              | 1271   | 1273   | 2544    |
|                                        | (99.9) | (99.8) | (99.8)  |
+----------------------------------------+--------+--------+---------+
| Lost to Follow-up                      | 1      | 3      | 4 (0.2) |
|                                        | (0.1)  | (0.2)  |         |
+----------------------------------------+--------+--------+---------+
| **Demographic Characteristics**        |        |        |         |
+----------------------------------------+--------+--------+---------+
| Sex N (%)                              |        |        |         |
+----------------------------------------+--------+--------+---------+
| Male                                   | 1000   | 1006   | 2006    |
|                                        | (78.6) | (78.8) | (78.7)  |
+----------------------------------------+--------+--------+---------+
| Female                                 | 272    | 270    | 542     |
|                                        | (21.4) | (21.2) | (21.3)  |
+----------------------------------------+--------+--------+---------+
| Age Mean (SD) Years                    | 64.1   | 64.0   | 64.1    |
|                                        | (11.3) | (10.7) | (11.0)  |
+----------------------------------------+--------+--------+---------+
| Ethnicity N (%)                        |        |        |         |
+----------------------------------------+--------+--------+---------+
| European Origin                        | 1164   | 1143   | 2307    |
|                                        | (91.5) | (89.6) | (90.5)  |
+----------------------------------------+--------+--------+---------+
| Black                                  | 62     | 65     | 127     |
|                                        | (4.9)  | (5.1)  | (5.0)   |
+----------------------------------------+--------+--------+---------+
| South Asia                             | 8      | 19     | 27      |
|                                        | (0.6)  | (1.5)  | (1.1)   |
+----------------------------------------+--------+--------+---------+
| Arab/Middle East                       | 4      | 8      | 12      |
|                                        | (0.3)  | (0.6)  | (0.5)   |
+----------------------------------------+--------+--------+---------+
| Oriental                               | 13     | 22     | 35      |
|                                        | (1.0)  | (1.7)  | (1.4)   |
+----------------------------------------+--------+--------+---------+
| Malay                                  | 7      | 11     | 18      |
|                                        | (0.6)  | (0.9)  | (0.7)   |
+----------------------------------------+--------+--------+---------+
| Other                                  | 14     | 8      | 22      |
|                                        | (1.1)  | (0.6)  | (0.9)   |
+----------------------------------------+--------+--------+---------+
| **Baseline Characteristics**           |        |        |         |
+----------------------------------------+--------+--------+---------+
| Ejection Fraction, Mean (SD)           | 0.28   | 0.28   | 0.28    |
|                                        | (0.07) | (0.08) | (0.07)  |
+----------------------------------------+--------+--------+---------+
| Diabetes Mellitus, N (%)               | 382    | 376    | 758     |
|                                        | (30.0) | (29.5) | (29.7)  |
+----------------------------------------+--------+--------+---------+
| Hypertension, N (%)                    | 619    | 609    | 1228    |
|                                        | (48.7) | (47.7) | (48.2)  |
+----------------------------------------+--------+--------+---------+
| Atrial Fibrillation, N (%)             | 341    | 346    | 687     |
|                                        | (26.8) | (27.1) | (27.0)  |
+----------------------------------------+--------+--------+---------+
| Previous MI, N (%)                     | 703    | 714    | 1417    |
|                                        | (55.3) | (56.0) | (55.6)  |
+----------------------------------------+--------+--------+---------+
| Angina Pectoris, N (%)                 | 684    | 666    | 1350    |
|                                        | (53.8) | (52.2) | (53.0)  |
+----------------------------------------+--------+--------+---------+
| Stroke, N (%)                          | 112    | 108    | 220     |
|                                        | (8.8)  | (8.5)  | (8.6)   |
+----------------------------------------+--------+--------+---------+
| NYHA II, N (%)                         | 302    | 312    | 614     |
|                                        | (23.7) | (24.5) | (24.1)  |
+----------------------------------------+--------+--------+---------+
| NYHA III, N (%)                        | 925    | 931    | 1856    |
|                                        | (72.7) | (73.0) | (72.8)  |
+----------------------------------------+--------+--------+---------+
| NYHA IV, N (%)                         | 45     | 33     | 78      |
|                                        | (3.5)  | (2.6)  | (3.1)   |
+----------------------------------------+--------+--------+---------+
| Current Smoker, N (%)                  | 235    | 194    | 429     |
|                                        | (18.5) | (15.2) | (16.8)  |
+----------------------------------------+--------+--------+---------+

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

[]{#__RefHeading___Toc91932354 .anchor}Table 3. Patient Participation,
Demographic and Baseline Characteristics (SH-AHS-0007)

+----------------------------------------+--------+--------+---------+
|                                        | **Pla  | *      | **      |
|                                        | cebo** | *Cand. | Total** |
|                                        |        | Cil.** |         |
|                                        | **N =  |        | **N =   |
|                                        | 1509** | **N =  | 3023**  |
|                                        |        | 1514** |         |
+========================================+========+========+=========+
| **Disposition N (%)**                  |        |        |         |
+----------------------------------------+--------+--------+---------+
| Completed                              | 1508   | 1512   | 3020    |
|                                        | (99.9) | (99.9) | (99.9)  |
+----------------------------------------+--------+--------+---------+
| Lost to Follow-up                      | 1      | 2      | 3       |
|                                        | (0.01) | (0.01) | (0.01)  |
+----------------------------------------+--------+--------+---------+
| **Demographic Characteristics**        |        |        |         |
+----------------------------------------+--------+--------+---------+
| Sex N (%)                              |        |        |         |
+----------------------------------------+--------+--------+---------+
| Male                                   | 891    | 920    | 1811    |
|                                        | (59.0) | (60.8) | (59.9)  |
+----------------------------------------+--------+--------+---------+
| Female                                 | 618    | 594    | 1212    |
|                                        | (41.0) | (39.2) | (40.1)  |
+----------------------------------------+--------+--------+---------+
| Age Mean (SD) Years                    | 67.1   | 67.2   | 67.2    |
|                                        | (11.1) | (11.1) | (11.1)  |
+----------------------------------------+--------+--------+---------+
| Ethnicity N (%)                        |        |        |         |
+----------------------------------------+--------+--------+---------+
| European Origin                        | 1393   | 1374   | 2767    |
|                                        | (92.3) | (90.8) | (91.5)  |
+----------------------------------------+--------+--------+---------+
| Black                                  | 57     | 69     | 126     |
|                                        | (3.8)  | (4.7)  | (4.2)   |
+----------------------------------------+--------+--------+---------+
| South Asia                             | 11     | 18     | 29      |
|                                        | (0.7)  | (1.2)  | (1.0)   |
+----------------------------------------+--------+--------+---------+
| Arab/Middle East                       | 5      | 5      | 10      |
|                                        | (0.3)  | (0.3)  | (0.3)   |
+----------------------------------------+--------+--------+---------+
| Oriental                               | 22     | 20     | 42      |
|                                        | (1.5)  | (1.3)  | (1.4)   |
+----------------------------------------+--------+--------+---------+
| Malay                                  | 8      | 14     | 22      |
|                                        | (0.5)  | (0.9)  | (0.7)   |
+----------------------------------------+--------+--------+---------+
| Other                                  | 13     | 14     | 27      |
|                                        | (0.9)  | (0.9)  | (0.9)   |
+----------------------------------------+--------+--------+---------+
| **Baseline Characteristics**           |        |        |         |
+----------------------------------------+--------+--------+---------+
| Ejection Fraction, Mean (SD)           | 0.54   | 0.54   | 0.54    |
|                                        | (0.09) | (0.09) | (0.09)  |
+----------------------------------------+--------+--------+---------+
| Diabetes Mellitus, N (%)               | 423    | 434    | 857     |
|                                        | (28.0) | (28.7) | (28.4)  |
+----------------------------------------+--------+--------+---------+
| Hypertension, N (%)                    | 959    | 984    | 1943    |
|                                        | (63.6) | (65.0) | (64.3)  |
+----------------------------------------+--------+--------+---------+
| Atrial Fibrillation, N (%)             | 442    | 439    | 881     |
|                                        | (29.3) | (29.0) | (29.1)  |
+----------------------------------------+--------+--------+---------+
| Previous MI, N (%)                     | 659    | 681    | 1340    |
|                                        | (43.7) | (45.0) | (44.3)  |
+----------------------------------------+--------+--------+---------+
| Angina Pectoris, N (%)                 | 902    | 915    | 1817    |
|                                        | (59.8) | (60.4) | (60.1)  |
+----------------------------------------+--------+--------+---------+
| Stroke, N (%)                          | 128    | 140    | 268     |
|                                        | (8.5)  | (9.2)  | (8.9)   |
+----------------------------------------+--------+--------+---------+
| NYHA II, N (%)                         | 905    | 931    | 1836    |
|                                        | (60.0) | (61.5) | (60.7)  |
+----------------------------------------+--------+--------+---------+
| NYHA III, N (%)                        | 584    | 556    | 1140    |
|                                        | (38.7) | (36.7) | (37.7)  |
+----------------------------------------+--------+--------+---------+
| NYHA IV, N (%)                         | 20     | 27     | 47      |
|                                        | (1.3)  | (1.8)  | (1.6)   |
+----------------------------------------+--------+--------+---------+
| Current Smoker, N (%)                  | 187    | 222    | 409     |
|                                        | (12.4) | (14.7) | (13.5)  |
+----------------------------------------+--------+--------+---------+

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

[]{#__RefHeading___Toc91932355 .anchor}Table 4. Patient Participation,
Demographic and Baseline Characteristics (Pooled)

+----------------------------------------+--------+--------+---------+
|                                        | **Pla  | *      | **      |
|                                        | cebo** | *Cand. | Total** |
|                                        |        | Cil.** |         |
|                                        | **N =  |        | **N =   |
|                                        | 3796** | **N =  | 7599**  |
|                                        |        | 3803** |         |
+========================================+========+========+=========+
| **Disposition N (%)**                  |        |        |         |
+----------------------------------------+--------+--------+---------+
| Completed                              | 3793   | 3796   | 7589    |
|                                        | (99.9) | (99.8) | (99.8)  |
+----------------------------------------+--------+--------+---------+
| Lost to Follow-up                      | 3      | 7      | 10      |
|                                        | (0.01) | (0.02) | (0.02)  |
+----------------------------------------+--------+--------+---------+
| **Demographic Characteristics**        |        |        |         |
+----------------------------------------+--------+--------+---------+
| Sex N (%)                              |        |        |         |
+----------------------------------------+--------+--------+---------+
| Male                                   | 2582   | 2617   | 5199    |
|                                        | (68.0) | (68.8) | (68.4)  |
+----------------------------------------+--------+--------+---------+
| Female                                 | 1214   | 1186   | 2400    |
|                                        | (32.0) | (31.2) | (31.6)  |
+----------------------------------------+--------+--------+---------+
| Age Mean (SD) Years                    | 66.0   | 65.9   | 66.0    |
|                                        | (11.1) | (11.0) | (11.0)  |
+----------------------------------------+--------+--------+---------+
| Ethnicity N (%)                        |        |        |         |
+----------------------------------------+--------+--------+---------+
| European Origin                        | 3458   | 3412   | 6870    |
|                                        | (91.1) | (89.7) | (90.4)  |
+----------------------------------------+--------+--------+---------+
| Black                                  | 164    | 162    | 326     |
|                                        | (4.3)  | (4.3)  | (4.3)   |
+----------------------------------------+--------+--------+---------+
| South Asia                             | 34     | 59     | 93      |
|                                        | (0.9)  | (1.6)  | (1.2)   |
+----------------------------------------+--------+--------+---------+
| Arab/Middle East                       | 15     | 22     | 37      |
|                                        | (0.4)  | (0.6)  | (0.5)   |
+----------------------------------------+--------+--------+---------+
| Oriental                               | 62     | 71     | 133     |
|                                        | (1.6)  | (1.9)  | (1.8)   |
+----------------------------------------+--------+--------+---------+
| Malay                                  | 25     | 39     | 64      |
|                                        | (0.7)  | (1.0)  | (0.8)   |
+----------------------------------------+--------+--------+---------+
| Other                                  | 38     | 38     | 76      |
|                                        | (1.0)  | (1.0)  | (1.0)   |
+----------------------------------------+--------+--------+---------+
| **Baseline Characteristics**           |        |        |         |
+----------------------------------------+--------+--------+---------+
| Ejection Fraction, Mean (SD)           | 0.39   | 0.39   | 0.39    |
|                                        | (0.15) | (0.15) | (0.15)  |
+----------------------------------------+--------+--------+---------+
| Diabetes Mellitus, N (%)               | 1075   | 1088   | 2163    |
|                                        | (28.3) | (28.6) | (28.5)  |
+----------------------------------------+--------+--------+---------+
| Hypertension, N (%)                    | 2093   | 2093   | 4186    |
|                                        | (55.1) | (55.0) | (55.1)  |
+----------------------------------------+--------+--------+---------+
| Atrial Fibrillation, N (%)             | 1044   | 1039   | 2083    |
|                                        | (27.5) | (27.3) | (27.4)  |
+----------------------------------------+--------+--------+---------+
| Previous MI, N (%)                     | 1980   | 2024   | 4004    |
|                                        | (52.2) | (53.2) | (52.7)  |
+----------------------------------------+--------+--------+---------+
| Angina Pectoris, N (%)                 | 2178   | 2174   | 4352    |
|                                        | (57.4) | (57.2) | (57.3)  |
+----------------------------------------+--------+--------+---------+
| Stroke, N (%)                          | 330    | 333    | 663     |
|                                        | (8.7)  | (8.8)  | (8.7)   |
+----------------------------------------+--------+--------+---------+
| NYHA II, N (%)                         | 1686   | 1730   | 3416    |
|                                        | (44.4) | (45.5) | (45.0)  |
+----------------------------------------+--------+--------+---------+
| NYHA III, N (%)                        | 2008   | 1977   | 3985    |
|                                        | (52.9) | (52.0) | (52.4)  |
+----------------------------------------+--------+--------+---------+
| NYHA IV, N (%)                         | 102    | 96     | 198     |
|                                        | (2.7)  | (2.5)  | (2.6)   |
+----------------------------------------+--------+--------+---------+
| Current Smoker, N (%)                  | 549    | 565    | 1114    |
|                                        | (14.5) | (14.9) | (14.7)  |
+----------------------------------------+--------+--------+---------+

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

### 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.

### 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.

[]{#__RefHeading___Toc91932356 .anchor}Table 5. Analysis of the Primary
and Secondary Endpoints (SH-AHS-0003)

+-----------------------------------+--------+-------+-----------+----+
| **Endpoint**                      | **Pa   |       | **Hazard  | *  |
|                                   | tients |       | Ratio     | *P |
|                                   | with   |       | (95%CI)** | -v |
|                                   | e      |       |           | al |
|                                   | vent** |       |           | ue |
|                                   |        |       |           | ** |
+-----------------------------------+--------+-------+-----------+----+
|                                   | Cande  | Pl    |           |    |
|                                   | sartan | acebo |           |    |
|                                   |        |       |           |    |
|                                   | N =    | N =   |           |    |
|                                   | 1013   | 1015  |           |    |
+-----------------------------------+--------+-------+-----------+----+
| **Primary**                       | 334    | 406   | 0.77      | \  |
|                                   |        |       | (0.       | <0 |
| CV death or CHF hospitalization   |        |       | 67--0.89) | .0 |
|                                   |        |       |           | 01 |
+-----------------------------------+--------+-------+-----------+----+
| **Secondary**                     | 371    | 433   | 0.80      | 0  |
|                                   |        |       | (0        | .0 |
| All-cause death or CHF            |        |       | .70-0.92) | 01 |
| hospitalization                   |        |       |           |    |
+-----------------------------------+--------+-------+-----------+----+
| CV death or CHF hospitalization   | 353    | 420   | 0.78      | \  |
| or non-fatal MI                   |        |       | (0        | <0 |
|                                   |        |       | .68-0.90) | .0 |
|                                   |        |       |           | 01 |
+-----------------------------------+--------+-------+-----------+----+
| **Components of the composite     | 219    | 252   | 0.85      | 0  |
| endpoints**                       |        |       | (0        | .0 |
|                                   |        |       | .71-1.02) | 72 |
| CV death                          |        |       |           |    |
+-----------------------------------+--------+-------+-----------+----+
| CHF hospitalization               | 207    | 286   | 0.68      | \  |
|                                   |        |       | (0        | <0 |
|                                   |        |       | .57-0.81) | .0 |
|                                   |        |       |           | 01 |
+-----------------------------------+--------+-------+-----------+----+
| All-cause mortality               | 265    | 296   | 0.87      | 0  |
|                                   |        |       | (0        | .1 |
|                                   |        |       | .74-1.03) | 04 |
+-----------------------------------+--------+-------+-----------+----+
| Nonfatal MI                       | 41     | 36    | 1.11      | 0. |
|                                   |        |       | (0        | 66 |
|                                   |        |       | .71-1.73) |    |
+-----------------------------------+--------+-------+-----------+----+

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.

[]{#__RefHeading___Toc91932357 .anchor}Table 6. Analysis of the Primary
and Secondary Endpoints (SH-AHS-0006)

+-----------------------------------+--------+-------+-----------+----+
| **Endpoint**                      | **Pa   |       | **Hazard  | *  |
|                                   | tients |       | Ratio     | *P |
|                                   | with   |       | (95%CI)** | -v |
|                                   | e      |       |           | al |
|                                   | vent** |       |           | ue |
|                                   |        |       |           | ** |
+-----------------------------------+--------+-------+-----------+----+
|                                   | Cande  | Pl    |           |    |
|                                   | sartan | acebo |           |    |
|                                   |        |       |           |    |
|                                   | N =    | N =   |           |    |
|                                   | 1276   | 1272  |           |    |
+-----------------------------------+--------+-------+-----------+----+
| **Primary**                       | 483    | 538   | 0.85      | 0  |
|                                   |        |       | (0.       | .0 |
| CV death or CHF hospitalization   |        |       | 75--0.96) | 11 |
+-----------------------------------+--------+-------+-----------+----+
| **Secondary**                     | 539    | 587   | 0.87      | 0  |
|                                   |        |       | (0        | .0 |
| All-cause death or CHF            |        |       | .78-0.98) | 21 |
| hospitalization                   |        |       |           |    |
+-----------------------------------+--------+-------+-----------+----+
| CV death or CHF hospitalization   | 495    | 550   | 0.85      | 0  |
| or non-fatal MI                   |        |       | (0        | .0 |
|                                   |        |       | .76-0.96) | 10 |
+-----------------------------------+--------+-------+-----------+----+
| **Components of the composite     | 302    | 347   | 0.84      | 0  |
| endpoints**                       |        |       | (0        | .0 |
|                                   |        |       | .72-0.98) | 29 |
| CV death                          |        |       |           |    |
+-----------------------------------+--------+-------+-----------+----+
| CHF hospitalization               | 309    | 356   | 0.83      | 0  |
|                                   |        |       | (0        | .0 |
|                                   |        |       | .71-0.96) | 13 |
+-----------------------------------+--------+-------+-----------+----+
| All-cause mortality               | 377    | 412   | 0.89      | 0  |
|                                   |        |       | (0        | .0 |
|                                   |        |       | .77-1.02) | 86 |
+-----------------------------------+--------+-------+-----------+----+
| Nonfatal MI                       | 26     | 49    | 0.51      | 0  |
|                                   |        |       | (0        | .0 |
|                                   |        |       | .32-0.82) | 05 |
+-----------------------------------+--------+-------+-----------+----+

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.

[]{#__RefHeading___Toc91932358 .anchor}Table 7. Analysis of the Primary
and Secondary Endpoints (SH-AHS-0007)

+-----------------------------------+--------+-------+-----------+----+
| **Endpoint**                      | **Pa   |       | **Hazard  | *  |
|                                   | tients |       | Ratio     | *P |
|                                   | with   |       | (95%CI)** | -v |
|                                   | e      |       |           | al |
|                                   | vent** |       |           | ue |
|                                   |        |       |           | ** |
+-----------------------------------+--------+-------+-----------+----+
|                                   | Cande  | Pl    |           |    |
|                                   | sartan | acebo |           |    |
|                                   |        |       |           |    |
|                                   | N =    | N =   |           |    |
|                                   | 1514   | 1509  |           |    |
+-----------------------------------+--------+-------+-----------+----+
| **Primary**                       | 333    | 366   | 0.89      | 0. |
|                                   |        |       | (0.       | 12 |
| CV death or CHF hospitalization   |        |       | 77--1.03) |    |
+-----------------------------------+--------+-------+-----------+----+
| **Secondary**                     | 386    | 411   | 0.92      | 0. |
|                                   |        |       | (0        | 22 |
| All-cause death or CHF            |        |       | .80-1.05) |    |
| hospitalization                   |        |       |           |    |
+-----------------------------------+--------+-------+-----------+----+
| CV death or CHF hospitalization   | 365    | 399   | 0.90      | 0. |
| or non-fatal MI                   |        |       | (0        | 13 |
|                                   |        |       | .78-1.03) |    |
+-----------------------------------+--------+-------+-----------+----+
| **Components of the composite     | 170    | 170   | 0.99      | 0. |
| endpoints**                       |        |       | (0        | 92 |
|                                   |        |       | .80-1.22) |    |
| CV death                          |        |       |           |    |
+-----------------------------------+--------+-------+-----------+----+
| CHF hospitalization               | 241    | 276   | 0.85      | 0. |
|                                   |        |       | (0        | 07 |
|                                   |        |       | .72-1.01) |    |
+-----------------------------------+--------+-------+-----------+----+
| All-cause mortality               | 244    | 237   | 1.02      | 0. |
|                                   |        |       | (0        | 84 |
|                                   |        |       | .85-1.22) |    |
+-----------------------------------+--------+-------+-----------+----+
| Nonfatal MI                       | 49     | 63    | 0.77      | 0. |
|                                   |        |       | (0        | 17 |
|                                   |        |       | .53-1.12) |    |
+-----------------------------------+--------+-------+-----------+----+

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.

[]{#__RefHeading___Toc91932359 .anchor}Table 8. Analysis of the Primary
and Secondary Endpoints (Pooled)

+---------------------------------+--------+-------+------------+----+
| **Endpoint**                    | **     |       | **Hazard   | *  |
|                                 | Number |       | Ratio      | *P |
|                                 | of     |       | (95%CI)**  | -v |
|                                 | Pati   |       |            | al |
|                                 | ents** |       |            | ue |
|                                 |        |       |            | ** |
+---------------------------------+--------+-------+------------+----+
|                                 | Cande  | Pl    |            |    |
|                                 | sartan | acebo |            |    |
|                                 |        |       |            |    |
|                                 | n (N)  | n (N) |            |    |
+---------------------------------+--------+-------+------------+----+
| **Primary**                     | 886    | 945   | 0.91       | 0  |
|                                 | (3803) | (     | (          | .0 |
| All-cause death (SH-AHS-0003,   |        | 3796) | 0.83-1.00) | 55 |
| -0006, -0007)                   |        |       |            |    |
+---------------------------------+--------+-------+------------+----+
| **Secondary**                   | 642    | 708   | 0.88       | 0  |
|                                 | (2289) | (     | (          | .0 |
| All-cause death (SH-AHS-0003,   |        | 2287) | 0.79-0.98) | 18 |
| -0006)                          |        |       |            |    |
+---------------------------------+--------+-------+------------+----+
| **Components**                  |        |       |            |    |
+---------------------------------+--------+-------+------------+----+
| CV death (SH-AHS-0003, -0006,   | 691    | 769   | 0.88       | 0  |
| -0007)                          | (3803) | (     | (          | .0 |
|                                 |        | 3796) | 0.79-0.97) | 12 |
| Non-CV death (SH-AHS-0003,      | 195    |       |            | \* |
| -0006, -0007)                   | (3803) | 176   | 1.08       |    |
|                                 |        | (     | (          | 0  |
|                                 |        | 3796) | 0.88-1.33) | .4 |
|                                 |        |       |            | 52 |
|                                 |        |       |            | \* |
+---------------------------------+--------+-------+------------+----+
| CV death (SH-AHS-0003, -0006)   | 521    | 599   | 0.84       | 0  |
|                                 | (2289) | (     | (          | .0 |
| Non-CV death (SH-AHS-0003,      |        | 2287) | 0.75-0.95) | 05 |
| -0006)                          | 121    |       |            | \* |
|                                 | (2289) | 109   | 1.07       |    |
|                                 |        | (     | (          | 0  |
|                                 |        | 2287) | 0.83-1.39) | .5 |
|                                 |        |       |            | 95 |
|                                 |        |       |            | \* |
+---------------------------------+--------+-------+------------+----+
| CV death (SH-AHS-0003)          | 219    | 252   | 0.85       | 0  |
|                                 | (1013) | (     | (          | .0 |
| Non-CV death (SH-AHS-0003)      |        | 1015) | 0.71-1.02) | 72 |
|                                 | 46     |       |            | \* |
|                                 | (1013) | 44    | 1.01       |    |
|                                 |        | (     | (          | 0  |
|                                 |        | 1015) | 0.67-1.53) | .9 |
|                                 |        |       |            | 48 |
|                                 |        |       |            | \* |
+---------------------------------+--------+-------+------------+----+
| CV death (SH-AHS-0006)          | 302    | 347   | 0.84       | 0  |
|                                 | (1276) | (     | (          | .0 |
| Non-CV death (SH-AHS-0006)      |        | 1272) | 0.72-0.98) | 29 |
|                                 | 75     |       |            | \* |
|                                 | (1276) | 65    | 1.11       |    |
|                                 |        | (     | (          | 0  |
|                                 |        | 1272) | 0.80-1.55) | .5 |
|                                 |        |       |            | 29 |
|                                 |        |       |            | \* |
+---------------------------------+--------+-------+------------+----+
| CV death (SH-AHS-0007)          | 170    | 170   | 0.99       | 0  |
|                                 | (1514) | (     | (          | .9 |
| Non-CV death (SH-AHS-0007)      |        | 1509) | 0.80-1.22) | 18 |
|                                 | 74     |       |            | \* |
|                                 | (1514) | 67    | 1.10       |    |
|                                 |        | (     | (          | 0  |
|                                 |        | 1509) | 0.79-1.52) | .5 |
|                                 |        |       |            | 89 |
+---------------------------------+--------+-------+------------+----+

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.

[]{#__RefHeading___Toc91932371 .anchor}Figure 1. Survival Estimate of
Time to 1^st^ CV Death or CHF Hospitalization (SH-AHS-0003)

![](media/image2.png){width="6.490277777777778in"
height="2.6840277777777777in"} Source: Reviewer's analysis.

[]{#__RefHeading___Toc91932372 .anchor}Figure 2. Survival Estimate of
Time to 1^st^ CV Death or CHF Hospitalization (SH-AHS-0006)

![](media/image3.png){width="6.492361111111111in"
height="3.372916666666667in"}

Source: Reviewer's analysis.

[]{#__RefHeading___Toc91932373 .anchor}Figure 3. Survival Estimate of
Time to 1^st^ CV Death or CHF Hospitalization (SH-AHS-0007)

![](media/image4.png){width="6.490277777777778in"
height="3.5597222222222222in"}Source: Reviewer's Analysis.

[]{#__RefHeading___Toc91932374 .anchor}Figure 4. Survival Estimate of
Time to All Cause Death (Three Studies Combined)

![](media/image5.png){width="6.490277777777778in"
height="3.4305555555555554in"}Source: Reviewer's Analysis.

[]{#__RefHeading___Toc91932375 .anchor}Figure 5. Survival Estimate of
Time to All Cause Death (Studies 0003 and 0006 Combined)

![](media/image6.png){width="6.490277777777778in"
height="3.4590277777777776in"}

Source: Reviewer's Analysis.

[]{#__RefHeading___Toc91932376 .anchor}Figure 6. Survival Estimate of
Time to CV Death (Studies 0003 and 0006 Combined)

![](media/image7.png){width="6.490277777777778in"
height="3.5597222222222222in"}

Source: Reviewer's Analysis.

[]{#__RefHeading___Toc91932377 .anchor}Figure 7. Survival Estimate of
Time to Non-CV Death (Studies 0003 and 0006 Combined)

![](media/image8.png){width="6.490277777777778in"
height="3.7104166666666667in"}

Source: Reviewer's Analysis.

## 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.

[]{#__RefHeading___Toc91932360 .anchor}Table 9. Most Commonly Reported
AEs (SH-AHS-0003)

+--------------------------------+--------+--------+--------+--------+
| **Preferred Term**             | **Pla  | **C    | **Pla  | **C    |
|                                | cebo** | andesa | cebo** | andesa |
|                                |        | rtan** |        | rtan** |
|                                | on     | on     | during | during |
|                                | tre    | tre    | study  | study  |
|                                | atment | atment |        |        |
|                                |        |        | (N =   | (N =   |
|                                | (N =   | (N =   | 1015)  | 1013)  |
|                                | 1015)  | 1013)  |        |        |
|                                |        |        | n %    | n %    |
|                                | n %    | n %    |        |        |
+================================+========+========+========+========+
| Cardiac failure/cardiac        | 317    | 234    | 359    | 280    |
| failure aggravated             | (31.2) | (23.1) | (35.4) | (27.6) |
+--------------------------------+--------+--------+--------+--------+
| Hypotension                    | 76     | 190    | 90     | 193    |
|                                | (7.5)  | (18.8) | (8.9)  | (19.1) |
+--------------------------------+--------+--------+--------+--------+
| Angina pectoris/angina         | 110    | 105    | 120    | 127    |
| pectoris aggravated            | (10.8) | (10.4) | (11.8) | (12.5) |
+--------------------------------+--------+--------+--------+--------+
| Renal function abnormal/renal  | 49     | 136    | 50     | 141    |
| dysfunction aggravated         | (4.8)  | (13.4) | (4.9)  | (13.9) |
+--------------------------------+--------+--------+--------+--------+
| Sudden death                   | 85     | 65     | 106    | 80     |
|                                | (8.4)  | (6.4)  | (10.4) | (7.9)  |
+--------------------------------+--------+--------+--------+--------+
| Pneumonia                      | 64     | 65     | 75     | 83     |
|                                | (6.3)  | (6.4)  | (7.4)  | (8.2)  |
+--------------------------------+--------+--------+--------+--------+
| Myocardial infarction          | 58     | 71     | 68     | 85     |
|                                | (5.7)  | (7.0)  | (6.7)  | (8.4)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia ventricular         | 64     | 58     | 79     | 73     |
|                                | (6.3)  | (5.7)  | (7.8)  | (7.2)  |
+--------------------------------+--------+--------+--------+--------+
| Cerebrovascular disorder       | 55     | 41     | 61     | 52     |
|                                | (5.4)  | (4.0)  | (6.0)  | (5.1)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia atrial              | 41     | 44     | 44     | 56     |
|                                | (4.0)  | (4.3)  | (4.3)  | (5.5)  |
+--------------------------------+--------+--------+--------+--------+
| Fibrillation atrial            | 46     | 34     | 57     | 43     |
|                                | (4.5)  | (3.4)  | (5.6)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Chest pain                     | 42     | 37     | 50     | 47     |
|                                | (4.1)  | (3.7)  | (4.9)  | (4.6)  |
+--------------------------------+--------+--------+--------+--------+
| Coronary artery disorder       | 39     | 38     | 48     | 49     |
|                                | (3.8)  | (3.8)  | (4.7)  | (4.8)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia                    | 31     | 28     | 44     | 39     |
| ventricular/arrhythmia         | (3.1)  | (2.8)  | (4.3)  | (3.8)  |
+--------------------------------+--------+--------+--------+--------+
| Cardiomyopathy                 | 29     | 25     | 40     | 37     |
|                                | (2.9)  | (2.5)  | (3.9)  | (3.7)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia supraventricular   | 30     | 27     | 39     | 34     |
|                                | (3.0)  | (2.7)  | (3.8)  | (3.4)  |
+--------------------------------+--------+--------+--------+--------+
| Hyperkalaemia                  | 16     | 54     | 18     | 54     |
|                                | (1.6)  | (5.3)  | (1.8)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Dizziness/vertigo              | 21     | 43     | 23     | 45     |
|                                | (2.1)  | (4.2)  | (2.3)  | (4.4)  |
+--------------------------------+--------+--------+--------+--------+
| Dyspnoea/dyspnoea (aggravated) | 39     | 17     | 43     | 22     |
|                                | (3.8)  | (1.7)  | (4.2)  | (2.2)  |
+--------------------------------+--------+--------+--------+--------+
| Syncope                        | 28     | 26     | 35     | 30     |
|                                | (2.8)  | (2.6)  | (3.4)  | (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.

[]{#__RefHeading___Toc91932361 .anchor}Table 10. Most Commonly Reported
AEs (SH-AHS-0006)

+--------------------------------+--------+--------+--------+--------+
| **Preferred Term**             | **Pla  | **C    | **Pla  | **C    |
|                                | cebo** | andesa | cebo** | andesa |
|                                |        | rtan** |        | rtan** |
|                                | on     | on     | during | during |
|                                | tre    | tre    | study  | study  |
|                                | atment | atment |        |        |
|                                |        |        | (N =   | (N =   |
|                                | (N =   | (N =   | 1272)  | 1276)  |
|                                | 1272)  | 1276)  |        |        |
|                                |        |        | n %    | n %    |
|                                | n %    | n %    |        |        |
+================================+========+========+========+========+
| Cardiac failure/cardiac        | 435    | 350    | 472    | 421    |
| failure aggravated             | (34.2) | (27.4) | (37.1) | (33.0) |
+--------------------------------+--------+--------+--------+--------+
| Hypotension                    | 176    | 288    | 184    | 296    |
|                                | (13.8) | (22.6) | (14.5) | (23.2) |
+--------------------------------+--------+--------+--------+--------+
| Angina pectoris/angina         | 153    | 127    | 169    | 150    |
| pectoris aggravated            | (12.0) | (10.0) | (13.3) | (11.8) |
+--------------------------------+--------+--------+--------+--------+
| Sudden death                   | 140    | 114    | 174    | 143    |
|                                | (11.0) | (8.9)  | (13.7) | (11.2) |
+--------------------------------+--------+--------+--------+--------+
| Renal function abnormal/renal  | 115    | 192    | 119    | 196    |
| dysfunction aggravated         | (9.0)  | (15.0) | (9.4)  | (15.4) |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia ventricular         | 107    | 78     | 121    | 88     |
|                                | (8.4)  | (6.1)  | (9.5)  | (6.9)  |
+--------------------------------+--------+--------+--------+--------+
| Pneumonia                      | 88     | 57     | 108    | 76     |
|                                | (6.9)  | (4.5)  | (8.5)  | (6.0)  |
+--------------------------------+--------+--------+--------+--------+
| Hyperkalaemia                  | 44     | 121    | 46     | 123    |
|                                | (3.5)  | (9.5)  | (3.6)  | (9.6)  |
+--------------------------------+--------+--------+--------+--------+
| Myocardial infarction          | 73     | 60     | 88     | 70     |
|                                | (5.7)  | (4.7)  | (6.9)  | (5.5)  |
+--------------------------------+--------+--------+--------+--------+
| Atrial fibrillation            | 69     | 52     | 73     | 66     |
|                                | (5.4)  | (4.1)  | (5.7)  | (5.2)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia atrial              | 61     | 59     | 71     | 67     |
|                                | (4.8)  | (4.6)  | (5.6)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia                    | 63     | 52     | 68     | 65     |
| ventricular/arrhythmia/        | (5.0)  | (4.1)  | (5.3)  | (5.1)  |
| arrhythmia aggravated          |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Cerebrovascular disorder       | 48     | 55     | 58     | 69     |
|                                | (3.8)  | (4.3)  | (4.6)  | (5.4)  |
+--------------------------------+--------+--------+--------+--------+
| Chest pain                     | 64     | 45     | 71     | 54     |
|                                | (5.0)  | (3.5)  | (5.6)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Coronary artery disorder       | 42     | 58     | 50     | 73     |
|                                | (3.3)  | (4.5)  | (3.9)  | (5.7)  |
+--------------------------------+--------+--------+--------+--------+
| Syncope                        | 45     | 49     | 49     | 59     |
|                                | (3.5)  | (3.8)  | (3.9)  | (4.6)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia supraventricular   | 46     | 47     | 50     | 54     |
|                                | (3.6)  | (3.7)  | (3.9)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Cardiomyopathy                 | 38     | 33     | 48     | 51     |
|                                | (3.0)  | (2.6)  | (3.8)  | (4.0)  |
+--------------------------------+--------+--------+--------+--------+
| Dizziness/vertigo              | 35     | 49     | 40     | 57     |
|                                | (2.8)  | (3.8)  | (3.1)  | (4.5)  |
+--------------------------------+--------+--------+--------+--------+
| Pulmonary oedema               | 41     | 39     | 47     | 48     |
|                                | (3.2)  | (3.1)  | (3.7)  | (3.8)  |
+--------------------------------+--------+--------+--------+--------+
| Renal failure acute            | 29     | 45     | 38     | 54     |
|                                | (2.3)  | (3.5)  | (3.0)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Anaemia                        | 36     | 35     | 43     | 46     |
|                                | (2.8)  | (2.7)  | (3.4)  | (3.6)  |
+--------------------------------+--------+--------+--------+--------+
| Accident and/or injury         | 32     | 34     | 43     | 44     |
|                                | (2.5)  | (2.7)  | (3.4)  | (3.4)  |
+--------------------------------+--------+--------+--------+--------+
| Diabetes mellitus/diabetes     | 41     | 30     | 42     | 37     |
| mellitus aggravated            | (3.2)  | (2.4)  | (3.3)  | (2.9)  |
+--------------------------------+--------+--------+--------+--------+
| Dehydration                    | 18     | 40     | 22     | 55     |
|                                | (1.4)  | (3.1)  | (1.7)  | (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.

[]{#__RefHeading___Toc91932362 .anchor}Table 11. Most Commonly Reported
AEs (SH-AHS-0007)

+--------------------------------+--------+--------+--------+--------+
| **Preferred Term**             | **Pla  | **C    | **Pla  | **C    |
|                                | cebo** | andesa | cebo** | andesa |
|                                |        | rtan** |        | rtan** |
|                                | on     | on     | during | during |
|                                | tre    | tre    | study  | study  |
|                                | atment | atment |        |        |
|                                |        |        | (N =   | (N =   |
|                                | (N =   | (N =   | 1509)  | 1514)  |
|                                | 1509)  | 1514)  |        |        |
|                                |        |        | n %    | n %    |
|                                | n %    | n %    |        |        |
+================================+========+========+========+========+
| Cardiac failure/cardiac        | 321    | 247    | 356    | 300    |
| failure aggravated             | (21.3) | (16.3) | (23.6) | (19.8) |
+--------------------------------+--------+--------+--------+--------+
| Angina pectoris/angina         | 198    | 182    | 217    | 213    |
| pectoris aggravated            | (13.1) | (12.0) | (14.4) | (14.1) |
+--------------------------------+--------+--------+--------+--------+
| Hypotension                    | 120    | 236    | 125    | 247    |
|                                | (8.0)  | (15.6) | (8.3)  | (16.3) |
+--------------------------------+--------+--------+--------+--------+
| Renal function abnormal/renal  | 74     | 146    | 79     | 150    |
| dysfunction aggravated         | (4.9)  | (9.6)  | (5.2)  | (9.9)  |
+--------------------------------+--------+--------+--------+--------+
| Pneumonia                      | 91     | 78     | 116    | 102    |
|                                | (6.0)  | (5.2)  | (7.7)  | (6.7)  |
+--------------------------------+--------+--------+--------+--------+
| Atrial fibrillation            | 103    | 79     | 119    | 93     |
|                                | (6.8)  | (5.2)  | (7.9)  | (6.1)  |
+--------------------------------+--------+--------+--------+--------+
| Myocardial infarction          | 85     | 74     | 101    | 87     |
|                                | (5.6)  | (4.9)  | (6.7)  | (5.7)  |
+--------------------------------+--------+--------+--------+--------+
| Coronary artery disorder       | 89     | 73     | 102    | 83     |
|                                | (5.9)  | (4.8)  | (6.8)  | (5.5)  |
+--------------------------------+--------+--------+--------+--------+
| Cerebrovascular disorder       | 86     | 68     | 97     | 82     |
|                                | (5.7)  | (4.5)  | (6.4)  | (5.4)  |
+--------------------------------+--------+--------+--------+--------+
| Chest pain                     | 71     | 72     | 81     | 82     |
|                                | (4.7)  | (4.8)  | (5.4)  | (5.4)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia supraventricular   | 76     | 55     | 88     | 60     |
|                                | (5.0)  | (3.6)  | (5.8)  | (4.0)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia atrial              | 73     | 53     | 82     | 64     |
|                                | (4.8)  | (3.5)  | (5.4)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Sudden death                   | 57     | 55     | 68     | 68     |
|                                | (3.8)  | (3.6)  | (4.5)  | (4.5)  |
+--------------------------------+--------+--------+--------+--------+
| Accident and/or injury         | 49     | 46     | 63     | 59     |
|                                | (3.2)  | (3.0)  | (4.2)  | (3.9)  |
+--------------------------------+--------+--------+--------+--------+
| Dizziness/vertigo              | 51     | 62     | 52     | 66     |
|                                | (3.4)  | (4.1)  | (3.4)  | (4.4)  |
+--------------------------------+--------+--------+--------+--------+
| Anaemia                        | 35     | 46     | 47     | 63     |
|                                | (2.3)  | (3.0)  | (3.1)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Dyspnoea/dyspnoea (aggravated) | 48     | 39     | 51     | 46     |
|                                | (3.2)  | (2.6)  | (3.4)  | (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.

[]{#__RefHeading___Toc91932363 .anchor}Table 12. Most Commonly Reported
AEs (Three Studies Pooled)

+--------------------------------+--------+--------+--------+--------+
| **Preferred Term**             | **Pla  | **C    | **Pla  | **C    |
|                                | cebo** | andesa | cebo** | andesa |
|                                |        | rtan** |        | rtan** |
|                                | on     | on     | during | during |
|                                | tre    | tre    | study  | study  |
|                                | atment | atment |        |        |
|                                |        |        | (N =   | (N =   |
|                                | (N =   | (N =   | 3796)  | 3803)  |
|                                | 3796)  | 3803)  |        |        |
|                                |        |        | n %    | n %    |
|                                | n %    | n %    |        |        |
+================================+========+========+========+========+
| Cardiac failure/cardiac        | 1073   | 831    | 1187   | 1001   |
| failure aggravated             | (28.3) | (21.9) | (31.3) | (26.3) |
+--------------------------------+--------+--------+--------+--------+
| Hypotension                    | 372    | 714    | 399    | 736    |
|                                | (9.8)  | (18.8) | (10.5) | (19.4) |
+--------------------------------+--------+--------+--------+--------+
| Angina pectoris/angina         | 461    | 414    | 506    | 490    |
| pectoris aggravated            | (12.1) | (10.9) | (13.3) | (12.9) |
+--------------------------------+--------+--------+--------+--------+
| Renal function abnormal/renal  | 238    | 474    | 248    | 487    |
| dysfunction aggravated         | (6.3)  | (12.5) | (6.5)  | (12.8) |
+--------------------------------+--------+--------+--------+--------+
| Sudden death                   | 282    | 234    | 348    | 291    |
|                                | (7.4)  | (6.2)  | (9.2)  | (7.7)  |
+--------------------------------+--------+--------+--------+--------+
| Pneumonia                      | 243    | 200    | 299    | 261    |
|                                | (6.4)  | (5.3)  | (7.9)  | (6.9)  |
+--------------------------------+--------+--------+--------+--------+
| Myocardial infarction          | 216    | 205    | 257    | 242    |
|                                | (5.7)  | (5.4)  | (6.8)  | (6.4)  |
+--------------------------------+--------+--------+--------+--------+
| Atrial fibrillation            | 218    | 165    | 249    | 202    |
|                                | (5.7)  | (4.3)  | (6.6)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia ventricular         | 207    | 159    | 239    | 193    |
|                                | (5.5)  | (4.2)  | (6.3)  | (5.1)  |
+--------------------------------+--------+--------+--------+--------+
| Cerebrovascular disorder       | 189    | 164    | 216    | 203    |
|                                | (5.0)  | (4.3)  | (5.7)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Coronary artery disorder       | 170    | 169    | 200    | 205    |
|                                | (4.5)  | (4.4)  | (5.3)  | (5.4)  |
+--------------------------------+--------+--------+--------+--------+
| Chest pain                     | 177    | 154    | 202    | 183    |
|                                | (4.7)  | (4.0)  | (5.3)  | (4.8)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia atrial              | 175    | 156    | 197    | 187    |
|                                | (4.6)  | (4.1)  | (5.2)  | (4.9)  |
+--------------------------------+--------+--------+--------+--------+
| Hyperkalaemia                  | 78     | 238    | 84     | 242    |
|                                | (2.1)  | (6.3)  | (2.2)  | (6.4)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia supraventricular   | 152    | 129    | 177    | 148    |
|                                | (4.0)  | (3.4)  | (4.7)  | (3.9)  |
+--------------------------------+--------+--------+--------+--------+
| Dizziness/vertigo              | 107    | 154    | 115    | 168    |
|                                | (2.8)  | (4.0)  | (3.0)  | (4.4)  |
+--------------------------------+--------+--------+--------+--------+
| Accident and/or injury         | 112    | 99     | 143    | 125    |
|                                | (3.0)  | (2.6)  | (3.8)  | (3.3)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia                    | 110    | 100    | 132    | 128    |
| ventricular/arrhythmia/        | (2.9)  | (2.6)  | (3.5)  | (3.4)  |
| arrhythmia aggravated          |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Syncope                        | 105    | 121    | 119    | 139    |
|                                | (2.8)  | (3.2)  | (3.1)  | (3.7)  |
+--------------------------------+--------+--------+--------+--------+
| Anaemia                        | 87     | 110    | 110    | 145    |
|                                | (2.3)  | (2.9)  | (2.9)  | (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.

[]{#__RefHeading___Toc91932364 .anchor}Table 13. Most Commonly Reported
AEs (Studies SH-AHS-0003 and SH-AHS-0006 Combined)

+--------------------------------+--------+--------+--------+--------+
| **Preferred Term**             | **Pla  | **C    | **Pla  | **C    |
|                                | cebo** | andesa | cebo** | andesa |
|                                |        | rtan** |        | rtan** |
|                                | on     | on     | during | during |
|                                | tre    | tre    | study  | study  |
|                                | atment | atment |        |        |
|                                |        |        | (N =   | (N =   |
|                                | (N =   | (N =   | 2287)  | 2289)  |
|                                | 2287)  | 2289)  |        |        |
|                                |        |        | n %    | n %    |
|                                | n %    | n %    |        |        |
+================================+========+========+========+========+
| Cardiac failure/cardiac        | 752    | 584    | 831    | 701    |
| failure aggravated             | (32.9) | (25.5) | (36.3) | (30.6) |
+--------------------------------+--------+--------+--------+--------+
| Hypotension                    | 252    | 478    | 274    | 489    |
|                                | (11.0) | (20.9) | (12.0) | (21.4) |
+--------------------------------+--------+--------+--------+--------+
| Angina pectoris/angina         | 263    | 232    | 289    | 277    |
| pectoris aggravated            | (11.5) | (10.1) | (12.6) | (12.1) |
+--------------------------------+--------+--------+--------+--------+
| Renal function abnormal/renal  | 164    | 328    | 169    | 143    |
| dysfunction aggravated         | (7.2)  | (14.3) | (13.7) | (11.2) |
+--------------------------------+--------+--------+--------+--------+
| Sudden death                   | 225    | 179    | 280    | 223    |
|                                | (9.8)  | (7.8)  | (12.2) | (9.7)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia ventricular         | 171    | 136    | 200    | 161    |
|                                | (7.5)  | (5.9)  | (8.7)  | (7.0)  |
+--------------------------------+--------+--------+--------+--------+
| Pneumonia                      | 152    | 122    | 183    | 159    |
|                                | (6.6)  | (5.3)  | (8.0)  | (6.9)  |
+--------------------------------+--------+--------+--------+--------+
| Myocardial infarction          | 131    | 131    | 156    | 155    |
|                                | (5.7)  | (5.7)  | (6.8)  | (6.8)  |
+--------------------------------+--------+--------+--------+--------+
| Hyperkalaemia                  | 60     | 175    | 64     | 177    |
|                                | (2.6)  | (7.6)  | (2.8)  | (7.7)  |
+--------------------------------+--------+--------+--------+--------+
| Cerebrovascular disorder       | 103    | 96     | 119    | 121    |
|                                | (4.5)  | (4.2)  | (5.2)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Fibrillation atrial            | 115    | 86     | 130    | 109    |
|                                | (5.0)  | (3.8)  | (5.7)  | (4.8)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia atrial              | 102    | 103    | 115    | 123    |
|                                | (4.5)  | (4.5)  | (5.0)  | (5.4)  |
+--------------------------------+--------+--------+--------+--------+
| Chest pain                     | 106    | 82     | 121    | 101    |
|                                | (4.6)  | (3.6)  | (5.3)  | (4.4)  |
+--------------------------------+--------+--------+--------+--------+
| Coronary artery disorder       | 81     | 96     | 98     | 122    |
|                                | (3.5)  | (4.2)  | (4.3)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia                    | 94     | 80     | 112    | 104    |
| ventricular/arrhythmia/        | (4.1)  | (3.5)  | (4.9)  | (4.5)  |
| arrhythmia aggravated          |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia supraventricular   | 76     | 74     | 89     | 88     |
|                                | (3.3)  | (3.2)  | (3.9)  | (3.8)  |
+--------------------------------+--------+--------+--------+--------+
| Cardiomyopathy                 | 67     | 58     | 88     | 88     |
|                                | (2.9)  | (2.5)  | (3.8)  | (3.8)  |
+--------------------------------+--------+--------+--------+--------+
| Syncope                        | 73     | 75     | 84     | 89     |
|                                | (3.2)  | (3.3)  | (3.7)  | (3.9)  |
+--------------------------------+--------+--------+--------+--------+
| Dizziness/vertigo              | 56     | 92     | 63     | 102    |
|                                | (2.4)  | (4.0)  | (2.8)  | (4.5)  |
+--------------------------------+--------+--------+--------+--------+
| Pulmonary oedema               | 67     | 59     | 77     | 75     |
|                                | (2.9)  | (2.6)  | (3.4)  | (3.3)  |
+--------------------------------+--------+--------+--------+--------+
| Accident and/or injury         | 63     | 53     | 80     | 66     |
|                                | (2.8)  | (2.3)  | (3.5)  | (2.9)  |
+--------------------------------+--------+--------+--------+--------+
| Anaemia                        | 52     | 64     | 63     | 82     |
|                                | (2.3)  | (2.8)  | (2.8)  | (3.6)  |
+--------------------------------+--------+--------+--------+--------+
| Renal failure acute            | 41     | 69     | 57     | 85     |
|                                | (1.8)  | (3.0)  | (2.5)  | (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.

# FINDINGS IN SPECIAL/SUBGROUP POPULATIONS

## 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.

[]{#__RefHeading___Toc91932365 .anchor}Table 14. Subgroup Analysis of
Time to CV Death or CHF Hospitalization (SH-AHS-0003)

+---------+-------------+----+---------+--------+---------------+----+
| **Var   | **Group**   | *  | *       | **Pla  | **Hazard      | *  |
| iable** |             | *T | *Candes | cebo** | Ratio (95%    | *P |
|         |             | ot | artan** |        | CI)**         | -v |
|         |             | al |         | **\#   |               | al |
|         |             | ** | **\# of | of     |               | ue |
|         |             |    | e       | Ev     |               | ** |
|         |             | *  | vents** | ents** |               |    |
|         |             | *N |         |        |               |    |
|         |             | ** |         |        |               |    |
+=========+=============+====+=========+========+===============+====+
| Age     | \< 65       | 8  | 120     | 116    | 0.973 (0.754, | 0  |
| (Years) |             | 04 |         |        | 1.256)        | .8 |
|         |             |    |         |        |               | 33 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 65 -\<  | 7  | 123     | 165    | 0.711 (0.563, | 0  |
|         | 75          | 52 |         |        | 0.898)        | .0 |
|         |             |    |         |        |               | 04 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 4  | 91      | 125    | 0.647 (0.494, | 0  |
|         |             | 72 |         |        | 0.848)        | .0 |
|         |             |    |         |        |               | 02 |
+---------+-------------+----+---------+--------+---------------+----+
| Age     | \< 75       | 15 | 243     | 281    | 0.818 (0.689, | 0  |
| (Years) |             | 56 |         |        | 0.971)        | .0 |
|         |             |    |         |        |               | 22 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 4  | 91      | 125    | 0.647 (0.494, | 0  |
|         |             | 72 |         |        | 0.848)        | .0 |
|         |             |    |         |        |               | 02 |
+---------+-------------+----+---------+--------+---------------+----+
| Sex     | Male        | 13 | 231     | 285    | 0.750 (0.630, | 0  |
|         |             | 82 |         |        | 0.892)        | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Female      | 6  | 103     | 121    | 0.813 (0.625, | 0  |
|         |             | 46 |         |        | 1.057)        | .1 |
|         |             |    |         |        |               | 22 |
+---------+-------------+----+---------+--------+---------------+----+
| Ethnic  | European    | 17 | 286     | 354    | 0.750 (0.642, | \  |
| Group   |             | 96 |         |        | 0.877)        | <0 |
|         |             |    |         |        |               | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Black       | 73 | 6       | 19     | 0.450 (0.179, | 0  |
|         |             |    |         |        | 1.127)        | .0 |
|         |             |    |         |        |               | 88 |
+---------+-------------+----+---------+--------+---------------+----+
|         | South Asian | 37 | 14      | 9      | 1.211 (0.523, | 0  |
|         |             |    |         |        | 2.803)        | .6 |
|         |             |    |         |        |               | 55 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Arab/Middle | 15 | 3       | 2      | 1.142 (0.191, | 0  |
|         | East        |    |         |        | 6.850)        | .8 |
|         |             |    |         |        |               | 84 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Oriental    | 56 | 14      | 9      | 1.672 (0.721, | 0  |
|         |             |    |         |        | 3.875)        | .2 |
|         |             |    |         |        |               | 31 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Malay       | 24 | 7       | 6      | 0.850 (0.285, | 0  |
|         |             |    |         |        | 2.533)        | .7 |
|         |             |    |         |        |               | 70 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 27 | 4       | 7      | 0.277 (0.081, | 0  |
|         |             |    |         |        | 0.953)        | .0 |
|         |             |    |         |        |               | 42 |
+---------+-------------+----+---------+--------+---------------+----+
| Region  | Western     | 9  | 146     | 173    | 0.787 (0.632, | 0  |
|         | Europe      | 24 |         |        | 0.981)        | .0 |
|         |             |    |         |        |               | 33 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Eastern     | 1  | 32      | 44     | 0.733 (0.465, | 0  |
|         | Europe      | 98 |         |        | 1.157)        | .1 |
|         |             |    |         |        |               | 82 |
+---------+-------------+----+---------+--------+---------------+----+
|         | North       | 6  | 114     | 141    | 0.765 (0.598, | 0  |
|         | America (US | 77 |         |        | 0.979)        | .0 |
|         | and Canada) |    |         |        |               | 34 |
+---------+-------------+----+---------+--------+---------------+----+
|         | USA         | 4  | 82      | 99     | 0.811 (0.605, | 0  |
|         |             | 70 |         |        | 1.087)        | .1 |
|         |             |    |         |        |               | 62 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Asia        | 73 | 24      | 16     | 1.168 (0.620, | 0  |
|         |             |    |         |        | 2.201)        | .6 |
|         |             |    |         |        |               | 31 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Russia      | 53 | 5       | 9      | 0.552 (0.185, | 0  |
|         |             |    |         |        | 1.649)        | .2 |
|         |             |    |         |        |               | 87 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 1  | 13      | 23     | 0.457 (0.231, | 0  |
|         |             | 03 |         |        | 0.902)        | .0 |
|         |             |    |         |        |               | 24 |
+---------+-------------+----+---------+--------+---------------+----+
| NYHA    | II          | 9  | 115     | 147    | 0.720 (0.564, | 0  |
|         |             | 66 |         |        | 0.920)        | .0 |
|         |             |    |         |        |               | 08 |
+---------+-------------+----+---------+--------+---------------+----+
|         | III         | 9  | 195     | 234    | 0.790 (0.653, | 0  |
|         |             | 89 |         |        | 0.955)        | .0 |
|         |             |    |         |        |               | 15 |
+---------+-------------+----+---------+--------+---------------+----+
|         | IV          | 73 | 24      | 25     | 0.817 (0.465, | 0  |
|         |             |    |         |        | 1.436)        | .4 |
|         |             |    |         |        |               | 83 |
+---------+-------------+----+---------+--------+---------------+----+
| LVEF    | \< 0.25     | 4  | 110     | 118    | 0.756 (0.583, | 0  |
|         |             | 53 |         |        | 0.981)        | .0 |
|         |             |    |         |        |               | 35 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 0.25    | 15 | 224     | 288    | 0.750 (0.630, | 0  |
|         |             | 74 |         |        | 0.894)        | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+

Source: Table 107 of the Sponsor's clinical study report of study
SH-AHS-0003, independently confirmed by this reviewer. The nominal
P-value, hazard ratio and CI were from Cox regression model.

[]{#OLE_LINK2 .anchor}

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

+---------+-------------+----+---------+--------+----------------+----+
| **Var   | **Group**   | *  | *       | **Pla  | **Hazard Ratio | *  |
| iable** |             | *T | *Candes | cebo** | (95% CI)**     | *P |
|         |             | ot | artan** |        |                | -v |
|         |             | al |         | **\#   |                | al |
|         |             | ** | **\# of | of     |                | ue |
|         |             |    | e       | Ev     |                | ** |
|         |             | *  | vents** | ents** |                |    |
|         |             | *N |         |        |                |    |
|         |             | ** |         |        |                |    |
+=========+=============+====+=========+========+================+====+
| Age     | \< 65       | 12 | 192     | 211    | 0.879 (0.723,  | 0  |
| (Years) |             | 68 |         |        | 1.069)         | .1 |
|         |             |    |         |        |                | 97 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 65 -\<  | 8  | 176     | 193    | 0.782 (0.637,  | 0  |
|         | 75          | 23 |         |        | 0.959)         | .0 |
|         |             |    |         |        |                | 18 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 4  | 115     | 134    | 0.945 (0.736,  | 0  |
|         |             | 57 |         |        | 1.212)         | .6 |
|         |             |    |         |        |                | 54 |
+---------+-------------+----+---------+--------+----------------+----+
| Age     | \< 75       | 20 | 368     | 404    | 0.842 (0.732,  | 0  |
| (Years) |             | 91 |         |        | 0.970)         | .0 |
|         |             |    |         |        |                | 17 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 4  | 115     | 134    | 0.945 (0.736,  | 0  |
|         |             | 57 |         |        | 1.212)         | .6 |
|         |             |    |         |        |                | 54 |
+---------+-------------+----+---------+--------+----------------+----+
| Sex     | Male        | 20 | 387     | 427    | 0.862 (0.752,  | 0  |
|         |             | 06 |         |        | 0.990)         | .0 |
|         |             |    |         |        |                | 35 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Female      | 5  | 96      | 111    | 0.815 (0.620,  | 0  |
|         |             | 42 |         |        | 1.072)         | .1 |
|         |             |    |         |        |                | 43 |
+---------+-------------+----+---------+--------+----------------+----+
| Ethnic  | European    | 23 | 427     | 490    | 0.845 (0.742,  | 0  |
| Group   |             | 07 |         |        | 0.962)         | .0 |
|         |             |    |         |        |                | 11 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Black       | 1  | 24      | 29     | 0.655 (0.381,  | 0  |
|         |             | 27 |         |        | 1.126)         | .1 |
|         |             |    |         |        |                | 26 |
+---------+-------------+----+---------+--------+----------------+----+
|         | South Asian | 27 | 11      | 4      | 1.264 (0.400,  | 0  |
|         |             |    |         |        | 3.998)         | .6 |
|         |             |    |         |        |                | 90 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Arab/Middle | 12 | 3       | 0      |                |    |
|         | East        |    |         |        |                |    |
+---------+-------------+----+---------+--------+----------------+----+
|         | Oriental    | 35 | 10      | 4      | 1.804 (0.564,  | 0  |
|         |             |    |         |        | 5.768)         | .3 |
|         |             |    |         |        |                | 20 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Malay       | 18 | 5       | 3      | 1.104 (0.263,  | 0  |
|         |             |    |         |        | 4.636)         | .8 |
|         |             |    |         |        |                | 92 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 22 | 3       | 8      | 0.573 (0.152,  | 0  |
|         |             |    |         |        | 2.165)         | .4 |
|         |             |    |         |        |                | 12 |
+---------+-------------+----+---------+--------+----------------+----+
| Region  | Western     | 11 | 194     | 255    | 0.739 (0.613,  | 0  |
|         | Europe      | 93 |         |        | 0.891)         | .0 |
|         |             |    |         |        |                | 02 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Eastern     | 2  | 41      | 43     | 0.825 (0.538,  | 0  |
|         | Europe      | 19 |         |        | 1.266)         | .3 |
|         |             |    |         |        |                | 78 |
+---------+-------------+----+---------+--------+----------------+----+
|         | North       | 9  | 205     | 204    | 0.984 (0.811,  | 0  |
|         | America (US | 54 |         |        | 1.194)         | .8 |
|         | and Canada) |    |         |        |                | 70 |
+---------+-------------+----+---------+--------+----------------+----+
|         | USA         | 5  | 128     | 128    | 1.019 (0.798,  | 0  |
|         |             | 97 |         |        | 1.303)         | .8 |
|         |             |    |         |        |                | 77 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Asia        | 59 | 19      | 8      | 1.282 (0.561,  | 0  |
|         |             |    |         |        | 2.930)         | .5 |
|         |             |    |         |        |                | 56 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Russia      | 15 | 2       | 5      | 0.787 (0.152,  | 0  |
|         |             |    |         |        | 4.073)         | .7 |
|         |             |    |         |        |                | 75 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 1  | 22      | 23     | 0.800 (0.446,  | 0  |
|         |             | 08 |         |        | 1.435)         | .4 |
|         |             |    |         |        |                | 54 |
+---------+-------------+----+---------+--------+----------------+----+
| ACE at  | Recommended | 12 | 232     | 275    | 0.794 (0.666,  | 0  |
| b       | Dose        | 91 |         |        | 0.945)         | .0 |
| aseline |             |    |         |        |                | 10 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Not         | 12 | 251     | 263    | 0.915 (0.770,  | 0  |
|         | Recommended | 57 |         |        | 1.088)         | .3 |
|         | Dose        |    |         |        |                | 14 |
+---------+-------------+----+---------+--------+----------------+----+
| ACE     | Recommended | 15 | 270     | 330    | 0.810 (0.689,  | 0  |
| During  | Dose        | 35 |         |        | 0.951)         | .0 |
| Study   |             |    |         |        |                | 10 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Not         | 10 | 213     | 208    | 0.910 (0.751,  | 0  |
|         | Recommended | 12 |         |        | 1.101)         | .3 |
|         | Dose        |    |         |        |                | 31 |
+---------+-------------+----+---------+--------+----------------+----+
| NYHA    | II          | 6  | 93      | 104    | 0.841 (0.636,  | 0  |
|         |             | 14 |         |        | 1.112)         | .2 |
|         |             |    |         |        |                | 25 |
+---------+-------------+----+---------+--------+----------------+----+
|         | III         | 18 | 367     | 399    | 0.868 (0.753,  | 0  |
|         |             | 56 |         |        | 1.000)         | .0 |
|         |             |    |         |        |                | 51 |
+---------+-------------+----+---------+--------+----------------+----+
|         | IV          | 78 | 23      | 35     | 0.847 (0.500,  | 0  |
|         |             |    |         |        | 1.435)         | .5 |
|         |             |    |         |        |                | 36 |
+---------+-------------+----+---------+--------+----------------+----+
| LVEF    | \< 0.25     | 7  | 186     | 203    | 0.851 (0.698,  | 0  |
|         |             | 70 |         |        | 1.039)         | .1 |
|         |             |    |         |        |                | 13 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 0.25    | 17 | 297     | 335    | 0.849 (0.726,  | 0  |
|         |             | 78 |         |        | 0.993)         | .0 |
|         |             |    |         |        |                | 40 |
+---------+-------------+----+---------+--------+----------------+----+

Source: Table 102 of the Sponsor's clinical study report of study
SH-AHS-0006, independently confirmed by this reviewer. The nominal
P-value, hazard ratio and CI were from Cox regression model.

[]{#__RefHeading___Toc91932367 .anchor}Table 16. Subgroup Analysis of
Time to CV Death or CHF Hospitalization (SH-AHS-0007)

+---------+-------------+----+---------+--------+----------------+----+
| **Var   | **Group**   | *  | *       | **Pla  | **Hazard Ratio | *  |
| iable** |             | *T | *Candes | cebo** | (95% CI)**     | *P |
|         |             | ot | artan** |        |                | -v |
|         |             | al |         | **\#   |                | al |
|         |             | ** | **\# of | of     |                | ue |
|         |             |    | e       | Ev     |                | ** |
|         |             | *  | vents** | ents** |                |    |
|         |             | *N |         |        |                |    |
|         |             | ** |         |        |                |    |
+=========+=============+====+=========+========+================+====+
| Age     | \< 65       | 11 | 72      | 86     | 0.901 (0.659,  | 0  |
| (Years) |             | 84 |         |        | 1.232)         | .5 |
|         |             |    |         |        |                | 13 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 65 -\<  | 10 | 117     | 118    | 0.901 (0.698,  | 0  |
|         | 75          | 32 |         |        | 1.164)         | .4 |
|         |             |    |         |        |                | 24 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 8  | 144     | 162    | 0.815 (0.651,  | 0  |
|         |             | 07 |         |        | 1.020)         | .0 |
|         |             |    |         |        |                | 74 |
+---------+-------------+----+---------+--------+----------------+----+
| Age     | \< 75       | 22 | 189     | 204    | 0.923 (0.757,  | 0  |
| (Years) |             | 16 |         |        | 1.125)         | .4 |
|         |             |    |         |        |                | 29 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 8  | 144     | 162    | 0.815 (0.651,  | 0  |
|         |             | 07 |         |        | 1.020)         | .0 |
|         |             |    |         |        |                | 74 |
+---------+-------------+----+---------+--------+----------------+----+
| Sex     | Male        | 18 | 195     | 205    | 0.909 (0.747,  | 0  |
|         |             | 11 |         |        | 1.106)         | .3 |
|         |             |    |         |        |                | 41 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Female      | 12 | 138     | 161    | 0.867 (0.691,  | 0  |
|         |             | 12 |         |        | 1.089)         | .2 |
|         |             |    |         |        |                | 20 |
+---------+-------------+----+---------+--------+----------------+----+
| Ethnic  | European    | 27 | 289     | 336    | 0.845 (0.722,  | 0  |
| Group   |             | 67 |         |        | 0.989)         | .0 |
|         |             |    |         |        |                | 36 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Black       | 1  | 16      | 11     | 1.203 (0.558,  | 0  |
|         |             | 26 |         |        | 2.592)         | .6 |
|         |             |    |         |        |                | 37 |
+---------+-------------+----+---------+--------+----------------+----+
|         | South Asian | 29 | 6       | 2      | 2.263 (0.456,  | 0  |
|         |             |    |         |        | 11.242)        | .3 |
|         |             |    |         |        |                | 18 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Arab/Middle | 10 | 2       | 2      | 1.291 (0.180,  | 0  |
|         | East        |    |         |        | 9.240)         | .7 |
|         |             |    |         |        |                | 99 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Oriental    | 42 | 10      | 4      | 3.730 (1.166,  | 0  |
|         |             |    |         |        | 11.928)        | .0 |
|         |             |    |         |        |                | 26 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Malay       | 22 | 5       | 5      | 0.508 (0.147,  | 0  |
|         |             |    |         |        | 1.757)         | .2 |
|         |             |    |         |        |                | 85 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 27 | 5       | 6      | 0.836 (0.255,  | 0  |
|         |             |    |         |        | 2.744)         | .7 |
|         |             |    |         |        |                | 68 |
+---------+-------------+----+---------+--------+----------------+----+
| Region  | Western     | 13 | 125     | 143    | 0.872 (0.686,  | 0  |
|         | Europe      | 77 |         |        | 1.108)         | .2 |
|         |             |    |         |        |                | 62 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Eastern     | 1  | 18      | 12     | 1.388 (0.669,  | 0  |
|         | Europe      | 96 |         |        | 2.882)         | .3 |
|         |             |    |         |        |                | 79 |
+---------+-------------+----+---------+--------+----------------+----+
|         | North       | 11 | 142     | 167    | 0.827 (0.661,  | 0  |
|         | America (US | 12 |         |        | 1.034)         | .0 |
|         | and Canada) |    |         |        |                | 96 |
+---------+-------------+----+---------+--------+----------------+----+
|         | USA         | 7  | 95      | 105    | 0.853 (0.646,  | 0  |
|         |             | 34 |         |        | 1.126)         | .2 |
|         |             |    |         |        |                | 61 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Asia        | 70 | 17      | 9      | 1.555 (0.693,  | 0  |
|         |             |    |         |        | 3.494)         | .2 |
|         |             |    |         |        |                | 85 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Russia      | 1  | 9       | 10     | 0.816 (0.331,  | 0  |
|         |             | 32 |         |        | 2.008)         | .6 |
|         |             |    |         |        |                | 58 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 1  | 22      | 25     | 0.889 (0.501,  | 0  |
|         |             | 36 |         |        | 1.578)         | .6 |
|         |             |    |         |        |                | 89 |
+---------+-------------+----+---------+--------+----------------+----+
| ACE at  | Recommended | 3  | 43      | 41     | 0.855 (0.557,  | 0  |
| b       | Dose        | 06 |         |        | 1.311)         | .4 |
| aseline |             |    |         |        |                | 73 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Not         | 27 | 290     | 325    | 0.887 (0.757,  | 0  |
|         | Recommended | 17 |         |        | 1.039)         | .1 |
|         | Dose        |    |         |        |                | 37 |
+---------+-------------+----+---------+--------+----------------+----+
| ACE     | Recommended | 5  | 63      | 79     | 0.810 (0.582,  | 0  |
| During  | Dose        | 19 |         |        | 1.129)         | .2 |
| Study   |             |    |         |        |                | 13 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Not         | 4  | 70      | 82     | 0.882 (0.641,  | 0  |
|         | Recommended | 96 |         |        | 1.214)         | .4 |
|         | Dose        |    |         |        |                | 41 |
+---------+-------------+----+---------+--------+----------------+----+
| NYHA    | II          | 18 | 151     | 164    | 0.883 (0.708,  | 0  |
|         |             | 36 |         |        | 1.101)         | .2 |
|         |             |    |         |        |                | 69 |
+---------+-------------+----+---------+--------+----------------+----+
|         | III         | 11 | 166     | 195    | 0.870 (0.707,  | 0  |
|         |             | 40 |         |        | 1.070)         | .1 |
|         |             |    |         |        |                | 88 |
+---------+-------------+----+---------+--------+----------------+----+
|         | IV          | 47 | 16      | 7      | 1.602 (0.657,  | 0  |
|         |             |    |         |        | 3.905)         | .3 |
|         |             |    |         |        |                | 00 |
+---------+-------------+----+---------+--------+----------------+----+
| LVEF    | \< 0.50     | 10 | 106     | 131    | 0.778 (0.602,  | 0  |
|         |             | 72 |         |        | 1.005)         | .0 |
|         |             |    |         |        |                | 55 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 0.50    | 19 | 227     | 235    | 0.951 (0.793,  | 0  |
|         |             | 51 |         |        | 1.142)         | .5 |
|         |             |    |         |        |                | 92 |
+---------+-------------+----+---------+--------+----------------+----+

Source: Table 102 of the Sponsor's clinical study report of study
SH-AHS-0007, independently confirmed by this reviewer. The nominal
P-value, hazard ratio and CI were from Cox regression model.

[]{#__RefHeading___Toc91932368 .anchor}Table 17. Subgroup Analysis of
Time to CV Death or CHF Hospitalization (Pooled)

+---------+-------------+----+---------+--------+---------------+----+
| **Var   | **Group**   | *  | *       | **Pla  | **Hazard      | *  |
| iable** |             | *T | *Candes | cebo** | Ratio (95%    | *P |
|         |             | ot | artan** |        | CI)**         | -v |
|         |             | al |         | **\#   |               | al |
|         |             | ** | **\# of | of     |               | ue |
|         |             |    | e       | Ev     |               | ** |
|         |             | *  | vents** | ents** |               |    |
|         |             | *N |         |        |               |    |
|         |             | ** |         |        |               |    |
+=========+=============+====+=========+========+===============+====+
| All     | All         | 75 | 1150    | 1310   | 0.836 (0.772, | \  |
|         |             | 99 |         |        | 0.905)        | <0 |
|         |             |    |         |        |               | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
| Age     | \< 65       | 32 | 384     | 413    | 0.910 (0.792, | 0  |
| (Years) |             | 56 |         |        | 1.046)        | .1 |
|         |             |    |         |        |               | 85 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 65 -\<  | 26 | 416     | 476    | 0.787 (0.690, | \  |
|         | 75          | 07 |         |        | 0.898)        | <0 |
|         |             |    |         |        |               | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 17 | 350     | 421    | 0.802 (0.696, | 0  |
|         |             | 36 |         |        | 0.924)        | .0 |
|         |             |    |         |        |               | 02 |
+---------+-------------+----+---------+--------+---------------+----+
| Age     | \< 75       | 58 | 800     | 889    | 0.853 (0.775, | 0  |
| (Years) |             | 63 |         |        | 0.938)        | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 17 | 350     | 421    | 0.802 (0.696, | 0  |
|         |             | 36 |         |        | 0.924)        | .0 |
|         |             |    |         |        |               | 02 |
+---------+-------------+----+---------+--------+---------------+----+
| Sex     | Male        | 51 | 813     | 917    | 0.837 (0.762, | \  |
|         |             | 99 |         |        | 0.920)        | <0 |
|         |             |    |         |        |               | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Female      | 24 | 337     | 393    | 0.835 (0.722, | 0  |
|         |             | 00 |         |        | 0.966)        | .0 |
|         |             |    |         |        |               | 15 |
+---------+-------------+----+---------+--------+---------------+----+
| Ethnic  | European    | 68 | 1002    | 1180   | 0.816 (0.750, | \  |
| Group   |             | 70 |         |        | 0.888)        | <0 |
|         |             |    |         |        |               | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Black       | 3  | 46      | 59     | 0.714 (0.484, | 0  |
|         |             | 26 |         |        | 1.054)        | .0 |
|         |             |    |         |        |               | 90 |
+---------+-------------+----+---------+--------+---------------+----+
|         | South Asian | 93 | 31      | 15     | 1.362 (0.731, | 0  |
|         |             |    |         |        | 2.538)        | .3 |
|         |             |    |         |        |               | 30 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Arab/Middle | 37 | 8       | 4      | 1.724 (0.511, | 0  |
|         | East        |    |         |        | 5.821)        | .3 |
|         |             |    |         |        |               | 80 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Oriental    | 1  | 34      | 17     | 2.135 (1.185, | 0  |
|         |             | 33 |         |        | 3.845)        | .0 |
|         |             |    |         |        |               | 12 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Malay       | 64 | 17      | 14     | 0.769 (0.378, | 0  |
|         |             |    |         |        | 1.566)        | .4 |
|         |             |    |         |        |               | 69 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 76 | 12      | 21     | 0.504 (0.243, | 0  |
|         |             |    |         |        | 1.046)        | .0 |
|         |             |    |         |        |               | 66 |
+---------+-------------+----+---------+--------+---------------+----+
| Region  | Western     | 34 | 465     | 571    | 0.787 (0.696, | \  |
|         | Europe      | 94 |         |        | 0.889)        | <0 |
|         |             |    |         |        |               | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Eastern     | 6  | 91      | 99     | 0.854 (0.643, | 0  |
|         | Europe      | 13 |         |        | 1.136)        | .2 |
|         |             |    |         |        |               | 79 |
+---------+-------------+----+---------+--------+---------------+----+
|         | North       | 27 | 461     | 512    | 0.872 (0.769, | 0  |
|         | America (US | 43 |         |        | 0.989)        | .0 |
|         | and Canada) |    |         |        |               | 33 |
+---------+-------------+----+---------+--------+---------------+----+
|         | USA         | 18 | 305     | 332    | 0.904 (0.773, | 0  |
|         |             | 01 |         |        | 1.056)        | .2 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Asia        | 2  | 60      | 33     | 1.299 (0.848, | 0  |
|         |             | 02 |         |        | 1.991)        | .2 |
|         |             |    |         |        |               | 30 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Russia      | 2  | 16      | 24     | 0.707 (0.374, | 0  |
|         |             | 00 |         |        | 1.340)        | .2 |
|         |             |    |         |        |               | 88 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 3  | 57      | 71     | 0.712 (0.502, | 0  |
|         |             | 47 |         |        | 1.010)        | .0 |
|         |             |    |         |        |               | 57 |
+---------+-------------+----+---------+--------+---------------+----+
| NYHA    | II          | 34 | 359     | 415    | 0.814 (0.707, | 0  |
|         |             | 16 |         |        | 0.938)        | .0 |
|         |             |    |         |        |               | 04 |
+---------+-------------+----+---------+--------+---------------+----+
|         | III         | 39 | 728     | 828    | 0.846 (0.766, | 0  |
|         |             | 85 |         |        | 0.935)        | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | IV          | 1  | 63      | 67     | 0.930 (0.656, | 0  |
|         |             | 98 |         |        | 1.317)        | .6 |
|         |             |    |         |        |               | 82 |
+---------+-------------+----+---------+--------+---------------+----+
| LVEF    | \< 0.50     | 56 | 923     | 1075   | 0.813 (0.744, | \  |
|         |             | 45 |         |        | 0.887)        | <0 |
|         |             |    |         |        |               | .0 |
|         |             |    |         |        |               | 01 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 0.50    | 19 | 227     | 235    | 0.951 (0.793, | 0  |
|         |             | 53 |         |        | 1.142)        | .5 |
|         |             |    |         |        |               | 92 |
+---------+-------------+----+---------+--------+---------------+----+

Source: Table 12.1.9.4.40 of the Sponsor's clinical study report,
Appendix 12.1.3, independently confirmed by this reviewer. The nominal
P-value, hazard ratio and CI were from Cox regression model.

[]{#__RefHeading___Toc91932369 .anchor}Table 18. Subgroup Analysis of
All-Cause Mortality (Three Studies Pooled)

+---------+-------------+----+---------+--------+---------------+----+
| **Var   | **Group**   | *  | *       | **Pla  | **Hazard      | *  |
| iable** |             | *T | *Candes | cebo** | Ratio (95%    | *P |
|         |             | ot | artan** |        | CI)**         | -v |
|         |             | al |         | **\#   |               | al |
|         |             | ** | **\# of | of     |               | ue |
|         |             |    | e       | Ev     |               | ** |
|         |             | *  | vents** | ents** |               |    |
|         |             | *N |         |        |               |    |
|         |             | ** |         |        |               |    |
+=========+=============+====+=========+========+===============+====+
| Age     | \< 65       | 32 | 233     | 266    | 0.858 (0.719, | 0  |
| (Years) |             | 56 |         |        | 1.022)        | .0 |
|         |             |    |         |        |               | 87 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 65 -\<  | 26 | 348     | 330    | 0.984 (0.847, | 0  |
|         | 75          | 07 |         |        | 1.144)        | .8 |
|         |             |    |         |        |               | 37 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 17 | 305     | 349    | 0.887 (0.761, | 0  |
|         |             | 36 |         |        | 1.035)        | .1 |
|         |             |    |         |        |               | 27 |
+---------+-------------+----+---------+--------+---------------+----+
| Age     | \< 75       | 58 | 581     | 596    | 0.939 (0.838, | 0  |
| (Years) |             | 63 |         |        | 1.053)        | .2 |
|         |             |    |         |        |               | 82 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 17 | 305     | 349    | 0.887 (0.761, | 0  |
|         |             | 36 |         |        | 1.035)        | .1 |
|         |             |    |         |        |               | 27 |
+---------+-------------+----+---------+--------+---------------+----+
| Sex     | Male        | 51 | 638     | 678    | 0.911 (0.817, | 0  |
|         |             | 99 |         |        | 1.015)        | .0 |
|         |             |    |         |        |               | 90 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Female      | 24 | 248     | 267    | 0.924 (0.778, | 0  |
|         |             | 00 |         |        | 1.099)        | .3 |
|         |             |    |         |        |               | 73 |
+---------+-------------+----+---------+--------+---------------+----+
| Ethnic  | European    | 68 | 790     | 856    | 0.914 (0.829, | 0  |
| Group   |             | 70 |         |        | 1.006)        | .0 |
|         |             |    |         |        |               | 67 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Black       | 3  | 27      | 30     | 0.889 (0.527, | 0  |
|         |             | 26 |         |        | 1.499)        | .6 |
|         |             |    |         |        |               | 58 |
+---------+-------------+----+---------+--------+---------------+----+
|         | South Asian | 93 | 18      | 14     | 0.659 (0.325, | 0  |
|         |             |    |         |        | 1.338)        | .2 |
|         |             |    |         |        |               | 49 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Arab/Middle | 37 | 5       | 2      | 1.786 (0.340, | 0  |
|         | East        |    |         |        | 9.369)        | .4 |
|         |             |    |         |        |               | 93 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Oriental    | 1  | 24      | 13     | 1.619 (0.819, | 0  |
|         |             | 33 |         |        | 3.199)        | .1 |
|         |             |    |         |        |               | 66 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Malay       | 64 | 16      | 14     | 0.729 (0.355, | 0  |
|         |             |    |         |        | 1.499)        | .3 |
|         |             |    |         |        |               | 90 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 76 | 6       | 16     | 0.315 (0.121, | 0  |
|         |             |    |         |        | 0.820)        | .0 |
|         |             |    |         |        |               | 18 |
+---------+-------------+----+---------+--------+---------------+----+
| Region  | Western     | 34 | 405     | 440    | 0.917 (0.801, | 0  |
|         | Europe      | 94 |         |        | 1.049)        | .2 |
|         |             |    |         |        |               | 07 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Eastern     | 6  | 70      | 79     | 0.847 (0.614, | 0  |
|         | Europe      | 13 |         |        | 1.169)        | .3 |
|         |             |    |         |        |               | 13 |
+---------+-------------+----+---------+--------+---------------+----+
|         | North       | 27 | 306     | 330    | 0.919 (0.786, | 0  |
|         | America (US | 43 |         |        | 1.073)        | .2 |
|         | and Canada) |    |         |        |               | 84 |
+---------+-------------+----+---------+--------+---------------+----+
|         | USA         | 18 | 199     | 215    | 0.927 (0.764, | 0  |
|         |             | 01 |         |        | 1.124)        | .4 |
|         |             |    |         |        |               | 42 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Asia        | 2  | 44      | 31     | 0.898 (0.566, | 0  |
|         |             | 02 |         |        | 1.425)        | .6 |
|         |             |    |         |        |               | 48 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Russia      | 2  | 16      | 13     | 1.470 (0.700, | 0  |
|         |             | 00 |         |        | 3.089)        | .3 |
|         |             |    |         |        |               | 09 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 3  | 45      | 52     | 0.760 (0.509, | 0  |
|         |             | 47 |         |        | 1.133)        | .1 |
|         |             |    |         |        |               | 78 |
+---------+-------------+----+---------+--------+---------------+----+
| NYHA    | II          | 34 | 281     | 282    | 0.961 (0.815, | 0  |
|         |             | 16 |         |        | 1.134)        | .6 |
|         |             |    |         |        |               | 37 |
+---------+-------------+----+---------+--------+---------------+----+
|         | III         | 39 | 553     | 611    | 0.890 (0.793, | 0  |
|         |             | 85 |         |        | 0.999)        | .0 |
|         |             |    |         |        |               | 47 |
+---------+-------------+----+---------+--------+---------------+----+
|         | IV          | 1  | 52      | 52     | 1.037 (0.703, | 0  |
|         |             | 98 |         |        | 1.528)        | .8 |
|         |             |    |         |        |               | 56 |
+---------+-------------+----+---------+--------+---------------+----+
| LVEF    | \< 0.25     | 12 | 225     | 261    | 0.781 (0.653, | 0  |
|         |             | 23 |         |        | 0.934)        | .0 |
|         |             |    |         |        |               | 07 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 0.25    | 63 | 660     | 684    | 0.956 (0.859, | 0  |
|         |             | 75 |         |        | 1.064)        | .4 |
|         |             |    |         |        |               | 10 |
+---------+-------------+----+---------+--------+---------------+----+

Source: Table 12.1.9.4.49 of the Sponsor's clinical study report,
Appendix 12.1.3, independently confirmed by this reviewer. The nominal
P-value, hazard ratio and CI were from Cox regression model.

[]{#__RefHeading___Toc91932370 .anchor}Table 19. Subgroup Analysis of
All-Cause Mortality (SH-AHS-0003 and -0006 Pooled)

+---------+-------------+----+---------+--------+---------------+----+
| **Var   | **Group**   | *  | *       | **Pla  | **Hazard      | *  |
| iable** |             | *T | *Candes | cebo** | Ratio (95%    | *P |
|         |             | ot | artan** |        | CI)**         | -v |
|         |             | al |         | **\#   |               | al |
|         |             | ** | **\# of | of     |               | ue |
|         |             |    | e       | Ev     |               | ** |
|         |             | *  | vents** | ents** |               |    |
|         |             | *N |         |        |               |    |
|         |             | ** |         |        |               |    |
+=========+=============+====+=========+========+===============+====+
| Age     | \< 65       | 20 | 198     | 223    | 0.853 (0.705, | 0  |
| (Years) |             | 72 |         |        | 1.033)        | .1 |
|         |             |    |         |        |               | 05 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 65 -\<  | 15 | 253     | 259    | 0.916 (0.770, | 0  |
|         | 75          | 75 |         |        | 1.089)        | .3 |
|         |             |    |         |        |               | 20 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 9  | 191     | 226    | 0.894 (0.737, | 0  |
|         |             | 29 |         |        | 1.084)        | .2 |
|         |             |    |         |        |               | 55 |
+---------+-------------+----+---------+--------+---------------+----+
| Age     | \< 75       | 36 | 451     | 482    | 0.892 (0.784, | 0  |
| (Years) |             | 47 |         |        | 1.014)        | .0 |
|         |             |    |         |        |               | 80 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 75      | 9  | 191     | 226    | 0.894 (0.737, | 0  |
|         |             | 29 |         |        | 1.084)        | .2 |
|         |             |    |         |        |               | 55 |
+---------+-------------+----+---------+--------+---------------+----+
| Sex     | Male        | 33 | 494     | 541    | 0.884 (0.783, | 0  |
|         |             | 88 |         |        | 0.999)        | .0 |
|         |             |    |         |        |               | 48 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Female      | 11 | 148     | 167    | 0.864 (0.692, | 0  |
|         |             | 88 |         |        | 1.078)        | .1 |
|         |             |    |         |        |               | 95 |
+---------+-------------+----+---------+--------+---------------+----+
| Ethnic  | European    | 41 | 575     | 637    | 0.890 (0.795, | 0  |
| Group   |             | 03 |         |        | 0.996)        | .0 |
|         |             |    |         |        |               | 42 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Black       | 2  | 18      | 27     | 0.683 (0.375, | 0  |
|         |             | 00 |         |        | 1.244)        | .2 |
|         |             |    |         |        |               | 13 |
+---------+-------------+----+---------+--------+---------------+----+
|         | South Asian | 64 | 14      | 12     | 0.578 (0.265, | 0  |
|         |             |    |         |        | 1.264)        | .1 |
|         |             |    |         |        |               | 70 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Arab/Middle | 27 | 4       | 1      | 2.330 (0.260, | 0  |
|         | East        |    |         |        | 20.886)       | .4 |
|         |             |    |         |        |               | 50 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Oriental    | 91 | 17      | 10     | 1.298 (0.592, | 0  |
|         |             |    |         |        | 2.848)        | .5 |
|         |             |    |         |        |               | 15 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Malay       | 42 | 11      | 9      | 0.866 (0.358, | 0  |
|         |             |    |         |        | 2.095)        | .7 |
|         |             |    |         |        |               | 50 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 49 | 3       | 12     | 0.193 (0.053, | 0  |
|         |             |    |         |        | 0.704)        | .0 |
|         |             |    |         |        |               | 13 |
+---------+-------------+----+---------+--------+---------------+----+
| Region  | Western     | 21 | 299     | 330    | 0.900 (0.769, | 0  |
|         | Europe      | 17 |         |        | 1.052)        | .1 |
|         |             |    |         |        |               | 86 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Eastern     | 4  | 56      | 72     | 0.747 (0.527, | 0  |
|         | Europe      | 17 |         |        | 1.060)        | .1 |
|         |             |    |         |        |               | 03 |
+---------+-------------+----+---------+--------+---------------+----+
|         | North       | 16 | 221     | 238    | 0.916 (0.763, | 0  |
|         | America (US | 31 |         |        | 1.100)        | .3 |
|         | and Canada) |    |         |        |               | 48 |
+---------+-------------+----+---------+--------+---------------+----+
|         | USA         | 10 | 147     | 153    | 0.979 (0.780, | 0  |
|         |             | 67 |         |        | 1.227)        | .8 |
|         |             |    |         |        |               | 52 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Asia        | 1  | 30      | 22     | 0.796 (0.458, | 0  |
|         |             | 32 |         |        | 1.382)        | .4 |
|         |             |    |         |        |               | 18 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Russia      | 68 | 7       | 8      | 1.319 (0.472, | 0  |
|         |             |    |         |        | 3.685)        | .5 |
|         |             |    |         |        |               | 97 |
+---------+-------------+----+---------+--------+---------------+----+
|         | Other       | 2  | 29      | 38     | 0.621 (0.383, | 0  |
|         |             | 11 |         |        | 1.008)        | .0 |
|         |             |    |         |        |               | 54 |
+---------+-------------+----+---------+--------+---------------+----+
| NYHA    | II          | 15 | 158     | 171    | 0.888 (0.715, | 0  |
|         |             | 80 |         |        | 1.103)        | .2 |
|         |             |    |         |        |               | 83 |
+---------+-------------+----+---------+--------+---------------+----+
|         | III         | 28 | 442     | 490    | 0.874 (0.769, | 0  |
|         |             | 45 |         |        | 0.994)        | .0 |
|         |             |    |         |        |               | 41 |
+---------+-------------+----+---------+--------+---------------+----+
|         | IV          | 1  | 42      | 47     | 0.989 (0.650, | 0  |
|         |             | 51 |         |        | 1.503)        | .9 |
|         |             |    |         |        |               | 57 |
+---------+-------------+----+---------+--------+---------------+----+
| LVEF    | \< 0.25     | 12 | 225     | 261    | 0.781 (0.653, | 0  |
|         |             | 23 |         |        | 0.934)        | .0 |
|         |             |    |         |        |               | 07 |
+---------+-------------+----+---------+--------+---------------+----+
|         | \>= 0.25    | 33 | 416     | 447    | 0.923 (0.807, | 0  |
|         |             | 52 |         |        | 1.054)        | .2 |
|         |             |    |         |        |               | 37 |
+---------+-------------+----+---------+--------+---------------+----+

Source: Table 12.1.9.4.135 of the Sponsor's clinical study report,
Appendix 12.1.3, independently confirmed by this reviewer. The nominal
P-value, hazard ratio and CI were from Cox regression model.

[]{#__RefHeading___Toc91932378 .anchor}Figure 8. Time to CV Death or CHF
Hospitalization by Ethnicity (Study SH-AHS-0007)

![](media/image9.wmf){width="5.997222222222222in"
height="3.109027777777778in"}

Source: Reviewer's analysis.

[]{#__RefHeading___Toc91932379 .anchor}Figure 9. Time to CV Death or CHF
Hospitalization by Region (Study SH-AHS-0006)

![](media/image10.wmf){width="5.993055555555555in"
height="2.9347222222222222in"}

Source: Reviewer's analysis.

## Other Subgroup Populations

The results of subgroup analysis of the primary endpoint by region,
classification of NYHA and LVEF are presented in Tables 14 - 19. For
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
Asia subgroup in each of the three studies, the USA subgroup in Study
SH-AHS-0006 and Eastern Europe in Study SH-AHS-0007. The sample sizes
were small in Asia and Eastern Europe. The estimate of the hazard ratio
was 1.02 in the USA subgroup (0.98 in North America) in Study
SH-AHS-0006 (Table 15), which seemed not to be consistent with the
overall results. However, as Figure 9 indicates, North America does not
deviate from other regions dramatically in Study SH-AHS-0006. In the
other two studies, the results in the USA were quite consistent with the
overall results. When the three studies were combined, the hazard ratio
in the USA group was consistent with the overall results (Table 17).

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

# SUMMARY AND CONCLUSIONS

## Statistical Issues and Collective Evidence

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. It
seemed that both CV death and CHF hospitalization contributed the
benefits. 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.

Studies SH-AHS-0006 (Added) and SH-AHS-0007 (Preserved) have the same
primary and secondary endpoints as Study SH-AHS-0003. In Study
SH-AHS-0006, 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, 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 of the
all-cause mortality. The secondary endpoint had a 12% relative risk
reduction with a nominal p-value = 0.018. The results of the primary and
secondary endpoints 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 CV death or non-CV death
in Study SH-AHS-0007 (the relative risks were 0.99 (P = 0.92) and 1.10
(P = 0.59) for CV deaths and non-CV deaths, respectively), but it had
relative risk reductions of 15% (P = 0.072) and 16% (P = 0.029) in CV
death in Studies SH-AHS-0003 and SH-AHS-0006, respectively. The relative
risk reductions were very consistent in the two studies, and the nominal
p-value was less than 0.05 in Study SH-AHS-006. The nominal p-value was
bigger than 0.05 in Study SH-AHS-003, 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 was 16% in CV mortality with
a nominal p-value = 0.005. No effects were observed for non-CV deaths in
the two studies (the relative risks were 1.01 (P = 0.95) and 1.11 (P =
0.53) in Studies SH-AHS-0003 and SH-AHS-0006, respectively).

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.

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 oriental subgroup in the other two studies. 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).

## Conclusions and Recommendations

Candesartan significantly reduced the risk of CV death or CHF
hospitalization in patients with depressed LV systolic function and EF
\< 40% treated with or without an ACE inhibitor. 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 the same patient population. In patients with preserved
LV systolic function and EF \> 40%, Candesartan failed to show that it
significantly reduced 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.

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

Candesartan probably significantly reduced the risk of CV mortality 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 all-cause or CV mortality in patients with preserved
LV systolic function and EF \> 40%.