![](media/image1.png)

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

**Drug Name:** Candesartan Cilexetil (ATACAND) Tablets

**Indication(s):** Treatment of Heart Failure in Patients Treated with
ACE Inhibitors

**Applicant:** Astra Zeneca

**Review Priority:** Priority

**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. (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 5](#introduction)

[2.1 Overview 5](#overview)

[2.1.1 History of Drug Development 5](#history-of-drug-development)

[2.1.2 Specific Studies Reviewed 5](#specific-studies-reviewed)

[2.1.3 Major Statistical Issues 6](#major-statistical-issues)

[2.2 Data Sources 6](#data-sources)

[3 STATISTICAL EVALUATION 6](#statistical-evaluation)

[3.1 Evaluation of Efficacy 6](#evaluation-of-efficacy)

[3.1.1 Study Design and Endpoint 6](#study-design-and-endpoint)

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

[3.1.3 Statistical Methodologies 8](#statistical-methodologies)

[3.1.4 Results and Conclusion 8](#results-and-conclusion)

[3.2 Evaluation of Safety 10](#evaluation-of-safety)

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

[4.1 Age, Gender and Ethnic group 13](#age-gender-and-ethnic-group)

[4.2 Other Subgroup Populations 15](#other-subgroup-populations)

[5 SUMMARY AND CONCLUSIONS 15](#summary-and-conclusions)

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

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

**List of Tables**

[Table 1. Patient Participation, Demographic and Baseline
Characteristics 7](#__RefHeading___Toc86725482)

[Table 2. Analysis of the Priamry and Secondary Endpoints
9](#__RefHeading___Toc86725483)

[Table 3. Some Sugroup Analysis of the Primary Endpoint
10](#__RefHeading___Toc86725484)

[Table 4. Most Commonly Reported AEs 11](#__RefHeading___Toc86725485)

[Table 5. Number of Patients with Most Commonly Reported AEs Leading to
Death 11](#__RefHeading___Toc86725486)

[Table 6. Number of Patients with Most Commonly Reported SAEs Other Than
Death 12](#__RefHeading___Toc86725487)

[Table 7. Subgroup Analysis of Time to the First CV Death or CHF
hospitalization 13](#__RefHeading___Toc86725488)

[Table 8. Subgroup Analysis of Time to the All-cause Death or CHF
hospitalization 13](#__RefHeading___Toc86725489)

[Table 9. Subgroup Analysis of Time to the CV Death or CHF
hospitalization or Nonfatal MI 14](#__RefHeading___Toc86725490)

**List of Figures**

[Figure 1. Kaplan-Meier Estimate of Time to 1^st^ CV Death or CHF
Hospitalization 9](#__RefHeading___Toc86725491)

[Figure 2. Plot of Testing of the Proportional Hazards Assumption
10](#__RefHeading___Toc86725492)

# 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 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.

The benefits of Candesartan appeared to be very small in North America
relative to Western Europe (Table 7). The secondary endpoints showed
similar results (Tables 8 and 9).

## Brief Overview of Clinical Studies

This review is based on Study SH-AHS-0006, which is one of the three
pivotal studies for the CHARM (Candesartan in Heart Failure Assessment
of Reduction in Mortality and mobility) program. The CHARM 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. SH-AHS-0006 studied patients with heart failure who
were treated with ACE inhibitors and had depressed LV systolic function,
SH-AHS-0003 treated patients with heart failure who were ACE inhibitor
intolerant and had depressed LV function, and SH-AHS-0007 had patients
with heart failure and preserved LV systolic function. 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 individual 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.

This indication for the patients treated with an ACE inhibitor
(SH-AHS-0006) was granted with priority review status and this review
was based on this study. A separate review will consider the other
indications.

This study (SH-AHS-0006) 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% treated with an ACE inhibitor. A total of 2548 patients
were randomized in a 1:1 ratio into Candesartan group (n = 1276) and
placebo group (n = 1272). All patients remained in the study until the
last randomized patient had been in the CHARM program for two years.
Patient follow-up time ranged from 41 to 48 months, with the median
follow-up time around 41 months.

## Statistical Issues and Findings

Candesartan significantly reduced CV death or CHF hospitalization with a
relative risk reduction of 15% over placebo. The relative risk
reductions were 2% in North America and 26% in Western Europe,
respectively.

It also significantly reduced the all-cause death or CHF hospitalization
with a 13% relative risk reduction. It significantly reduced the
relative risk of CV death or CHF hospitalization or non-fatal MI, with a
15% relative risk reduction.

# 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. Study SH-AHS-0006 (CHARM-Added trial)
studied the patients with depressed LV systolic function and EF \<40%
treated with an ACE inhibitor. The patients in Study SH-AHS-0003
(CHARM-Alternative) were ACE inhibitor intolerant with depressed LV
systolic function and EF \<40%. Study SH-AHS-0007 (CHARM-Preserved)
studied 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.

### Specific Studies Reviewed

Study SH-AHS-0006 was fully reviewed for this priority review. This
study enrolled patients with depressed LV systolic function (EF\<= 40%)
treated with ACE inhibitors. It is also called CHARM-added trial.

### Major Statistical Issues

The primary endpoint of this study is the composite of CV mortality and
CV hospitalization for the management of CHF, and this single study is
intended for the indication that Candesartan reduces the risk of the
composite endpoint when compared with placebo. The data from this study,
together with the other two studies 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 test of the primary endpoint is tested at alpha =
0.05 in this study, and the analysis for all-cause mortality is also
performed at alpha = 0.05 level based on the pooled data. Since this is
a single study, the evidence for the indication of the primary endpoint
should be strong and the p-value should be smaller. Some adjustment of
the p-value should be made for the all-cause mortality for the pooled
data of the 3 studies. Six interim analyses were conducted on all-cause
mortality, which was not the primary endpoint. It is not clear how the
interim analyses would affect the alpha level for the analysis of the
primary endpoint. Since the Type I error rates allocated for the interim
analyses were very small, the effect should be 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 this study 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\\SH-AHS-0006](../../../../../../../../n20838/S_022/2004-06-30/crt/datasets/SH-AHS-0006).

# STATISTICAL EVALUATION

## Evaluation of Efficacy

### Study Design and Endpoint

This was a randomized, double-blind, placebo controlled, parallel group,
multicenter study to evaluate the influence of Candesartan with a target
dose of 32 mg once daily on mortality and morbidity in patients with
depressed LV systolic function and EF \< 40% treated with an ACE
inhibitor. The patient population was male and female patients, over or
equal to 18 years of age, with symptomatic CHF corresponding to NYHA
class II-IV and with depressed LV systolic function and treated with ACE
inhibitors. A total of 2548 patients were randomized in a 1-1 ratio into
Candesartan group (n = 1276) or placebo group (n = 1272). All patients
remained in the study until the last randomized patient had been in the
CHARM program for two years. 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. The first patient was randomized on March 22, 1999
and the last patient was completed on March 31, 2003.

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.

### Patient Disposition, Demographic and Baseline Characteristics

Table 1 is the summary of the patient participation, demographic and
baseline characteristics. Almost everybody completed the study, with
99.8% of the patients completed the study in the Candesartan group and
99.9% of the patients completed in the placebo group, respectively. The
demographic and baseline characteristics seem to be comparable between
the two treatment groups for the variables listed in the table.

[]{#__RefHeading___Toc86725482 .anchor}Table 1. Patient Participation,
Demographic and Baseline Characteristics

+----------------------------------------+--------+--------+---------+
|                                        | **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.

### Statistical Methodologies

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 was 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 primary and two secondary endpoints were analyzed based on the
principal 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.

### Results and Conclusion

Table 2 presents the results of the analysis of the primary endpoint and
two secondary endpoints, including the analysis of the components of the
composite endpoints. For the primary endpoint, time to the first CV
death or CHF hospitalization, Candesartan had a relative risk reduction
of 15% over placebo, with p-value = 0.011. Candesartan also reduced the
risk of the two secondary endpoints. The relative risk reduction was 13%
(nominal P = 0.021) for all-cause death or CHF hospitalization and 15%
(nominal P = 0.010) for CV death or CHF hospitalization or nonfatal MI.
It seemed that each individual component contributed to the benefit of
Candesartan.

[]{#__RefHeading___Toc86725483 .anchor}Table 2. Analysis of the Priamry
and Secondary Endpoints

+-----------------------------------+---------+-------+-----------+----+
| **Endpoint**                      | **No.   |       | **Hazard  | *  |
|                                   | of      |       | Ratio     | *P |
|                                   | P       |       | (95%CI)** | -v |
|                                   | atients |       |           | al |
|                                   | with    |       |           | ue |
|                                   | event** |       |           | ** |
+-----------------------------------+---------+-------+-----------+----+
|                                   | Cand    | Pl    |           |    |
|                                   | esartan | 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.

Figures 1 is the Kaplan-Meier estimates for time to the first CV death
or CHF hospitalization. It seemed that the benefit of Candesartan
appeared early and was maintained throughout the study period. Based on
Figure 2, it appeared that it was reasonable to use the proportional
hazards model, although the proportion might not be a constant over
time.

[]{#__RefHeading___Toc86725491 .anchor}Figure 1. Kaplan-Meier Estimate
of Time to 1^st^ CV Death or CHF Hospitalization

![](media/image2.png){width="6.492361111111111in" height="3.875in"}

Source: Reviewer's analysis.

[]{#__RefHeading___Toc86725492 .anchor}Figure 2. Plot of Testing of the
Proportional Hazards Assumption

![](media/image3.png){width="6.430555555555555in"
height="3.308333333333333in"}

Source: Reviewer's Analysis.

The results of the analysis of the primary endpoint for some subgroups
are in Table 3. Based on Table 3, it seemed that Candesartan was more
effective when the patients took recommended ACE inhibitor doses.

[]{#__RefHeading___Toc86725484 .anchor}Table 3. Some Sugroup Analysis of
the Primary Endpoint

+------------------------------------+--------+------+-----------+----+
| **Subgroup**                       | *      |      | **Hazard  | *  |
|                                    | *Total |      | Ratio     | *P |
|                                    | N (n   |      | (95%CI)** | -v |
|                                    | with   |      |           | al |
|                                    | eve    |      |           | ue |
|                                    | nts)** |      |           | ** |
+------------------------------------+--------+------+-----------+----+
|                                    | Cande  | Pla  |           |    |
|                                    | sartan | cebo |           |    |
|                                    |        |      |           |    |
|                                    | N (n)  | N    |           |    |
|                                    |        | (n)  |           |    |
+------------------------------------+--------+------+-----------+----+
| Patients with recommended ACE      | 643    | 648  | 0.79      | 0  |
| inhibitors at baseline             | (232)  | (    | (0        | .0 |
|                                    |        | 275) | .67-0.95) | 10 |
+------------------------------------+--------+------+-----------+----+
| Patients without recommended ACE   | 633    | 624  | 0.92      | 0  |
| inhibitors at baseline             | (251)  | (    | (0        | .3 |
|                                    |        | 263) | .77-1.09) | 14 |
+------------------------------------+--------+------+-----------+----+
| Patients with recommended ACE      | 748    | 787  | 0.81      | 0  |
| inhibitors during study            | (270)  | (    | (0        | .0 |
|                                    |        | 330) | .69-0.95) | 10 |
+------------------------------------+--------+------+-----------+----+
| Patients without recommended ACE   | 528    | 485  | 0.91      | 0  |
| inhibitor during study             | (213)  | (    | (0        | .3 |
|                                    |        | 208) | .75-1.10) | 45 |
+------------------------------------+--------+------+-----------+----+

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 with
treatment as the only independent variable.

## Evaluation of Safety

The most commonly reported adverse events (AE) are in Table 5. Table 6
lists the most commonly reported AEs leading to death, and the most
commonly reported severe AEs other than death are reported in Table 7.
Tables 5 and 7 use a cut-off of 3% AEs in the total population during
the study (N = 2548), and Table 6 uses a cut-off of 0.3% in the total
population during the study (N = 2548). Candesartan reduced the risk of
death, so there are fewer deaths in the Candesartan group. 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 occurred in 23% and 15% of the patients in
Candesartan group and Placebo group, respectively, and renal function
abnormal/renal dysfunction aggravated occurred in 15% and 9% of the
patients in Candesartan group and Placebo group, respectively. The two
AEs also occurred more often in the Candesartan group among the most
often reported non-fatal SAEs.

[]{#__RefHeading___Toc86725485 .anchor}Table 4. Most Commonly Reported
AEs

+--------------------------------+--------+--------+--------+--------+
| **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___Toc86725486 .anchor}Table 5. Number of Patients with
Most Commonly Reported AEs Leading to Death

+--------------------------------+--------+--------+--------+--------+
| **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 %    |        |        |
+================================+========+========+========+========+
| Sudden death                   | 139    | 113    | 174    | 143    |
|                                | (10.9) | (8.9)  | (13.7) | (11.2) |
+--------------------------------+--------+--------+--------+--------+
| Cardiac failure/cardiac        | 61     | 28     | 112    | 74     |
| failure aggravated             | (4.8)  | (2.2)  | (8.8)  | (5.8)  |
+--------------------------------+--------+--------+--------+--------+
| Myocardial infarction          | 12     | 15     | 20     | 21     |
|                                | (0.9)  | (1.2)  | (1.6)  | (1.6)  |
+--------------------------------+--------+--------+--------+--------+
| Death                          | 5      | 7      | 13     | 19     |
|                                | (0.4)  | (0.5)  | (1.0)  | (1.5)  |
+--------------------------------+--------+--------+--------+--------+
| Pneumonia                      | 11     | 3      | 19     | 10     |
|                                | (0.9)  | (0.2)  | (1.5)  | (0.8)  |
+--------------------------------+--------+--------+--------+--------+
| Cardiac arrest                 | 8      | 8      | 13     | 13     |
|                                | (0.6)  | (0.6)  | (1.0)  | (1.0)  |
+--------------------------------+--------+--------+--------+--------+
| Fibrillation ventricular       | 14     | 6      | 16     | 9      |
|                                | (1.1)  | (0.5)  | (1.3)  | (0.7)  |
+--------------------------------+--------+--------+--------+--------+
| Cerebrovascular disorder       | 7      | 8      | 11     | 12     |
|                                | (0.6)  | (0.6)  | (0.9)  | (0.9)  |
+--------------------------------+--------+--------+--------+--------+
| Sepsis                         | 6      | 5      | 10     | 11     |
|                                | (0.5)  | (0.4)  | (0.8)  | (0.9)  |
+--------------------------------+--------+--------+--------+--------+
| Cardiomyopathy                 | 3      | 2      | 8      | 8      |
|                                | (0.2)  | (0.2)  | (0.6)  | (0.6)  |
+--------------------------------+--------+--------+--------+--------+
| Pulmonary carcinoma            | 4      | 5      | 5      | 10     |
|                                | (0.3)  | (0.4)  | (0.4)  | (0.8)  |
+--------------------------------+--------+--------+--------+--------+
| Pulmonary oedema               | 4      | 3      | 8      | 6      |
|                                | (0.3)  | (0.2)  | (0.6)  | (0.5)  |
+--------------------------------+--------+--------+--------+--------+
| Renal failure nos              | 3      | 0 (0)  | 8      | 4      |
|                                | (0.2)  |        | (0.6)  | (0.3)  |
+--------------------------------+--------+--------+--------+--------+
| Accident and/or injury         | 3      | 3      | 5      | 5      |
|                                | (0.2)  | (0.2)  | (0.4)  | (0.4)  |
+--------------------------------+--------+--------+--------+--------+
| Renal failure acute            | 3      | 2      | 5      | 5      |
|                                | (0.2)  | (0.2)  | (0.4)  | (0.4)  |
+--------------------------------+--------+--------+--------+--------+
| Multiorgan failure             | 0 (0)  | 1      | 4      | 4      |
|                                |        | (0.1)  | (0.3)  | (0.3)  |
+--------------------------------+--------+--------+--------+--------+
| Colon carcinoma                | 0 (0)  | 1      | 0 (0)  | 7      |
|                                |        | (0.1)  |        | (0.5)  |
+--------------------------------+--------+--------+--------+--------+
| Coronary artery disorder       | 2      | 1      | 2      | 5      |
|                                | (0.2)  | (0.1)  | (0.2)  | (0.4)  |
+--------------------------------+--------+--------+--------+--------+
| Renal function abnormal        | 2      | 0 (0)  | 5      | 2      |
|                                | (0.2)  |        | (0.4)  | (0.2)  |
+--------------------------------+--------+--------+--------+--------+

Source: Table 67 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___Toc86725487 .anchor}Table 6. Number of Patients with
Most Commonly Reported SAEs Other Than Death

+--------------------------------+--------+--------+--------+--------+
| **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        | 418    | 333    | 450    | 398    |
| failure aggravated             | (32.9) | (26.1) | (35.4) | (31.2) |
+--------------------------------+--------+--------+--------+--------+
| Angina pectoris/angina         | 152    | 126    | 168    | 148    |
| pectoris aggravated            | (11.9) | (9.9)  | (13.2) | (11.6) |
+--------------------------------+--------+--------+--------+--------+
| Hypotension                    | 91     | 133    | 102    | 143    |
|                                | (7.2)  | (10.4) | (8.0)  | (11.2) |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia ventricular         | 106    | 78     | 120    | 88     |
|                                | (8.3)  | (6.1)  | (9.4)  | (6.9)  |
+--------------------------------+--------+--------+--------+--------+
| Pneumonia                      | 77     | 55     | 93     | 73     |
|                                | (6.1)  | (4.3)  | (7.3)  | (5.7)  |
+--------------------------------+--------+--------+--------+--------+
| Arrhythmia atrial              | 61     | 59     | 71     | 67     |
|                                | (4.8)  | (4.6)  | (5.6)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Fibrillation atrial            | 67     | 52     | 71     | 65     |
|                                | (5.3)  | (4.1)  | (5.6)  | (5.1)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia ventricular/       | 61     | 51     | 66     | 62     |
| arrhythmia/arrhythmia          | (4.8)  | (4.0)  | (5.2)  | (4.9)  |
| aggravated                     |        |        |        |        |
+--------------------------------+--------+--------+--------+--------+
| Myocardial infarction          | 61     | 47     | 70     | 52     |
|                                | (4.8)  | (3.7)  | (5.5)  | (4.1)  |
+--------------------------------+--------+--------+--------+--------+
| Chest pain                     | 62     | 45     | 68     | 53     |
|                                | (4.9)  | (3.5)  | (5.3)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Cerebrovascular disorder       | 43     | 51     | 53     | 63     |
|                                | (3.4)  | (4.0)  | (4.2)  | (4.9)  |
+--------------------------------+--------+--------+--------+--------+
| Coronary artery disorder       | 39     | 55     | 47     | 68     |
|                                | (3.1)  | (4.3)  | (3.7)  | (5.3)  |
+--------------------------------+--------+--------+--------+--------+
| Tachycardia supraventricular   | 46     | 47     | 50     | 54     |
|                                | (3.6)  | (3.7)  | (3.9)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Syncope                        | 44     | 44     | 48     | 55     |
|                                | (3.5)  | (3.4)  | (3.8)  | (4.3)  |
+--------------------------------+--------+--------+--------+--------+
| Cardiomyopathy                 | 34     | 32     | 42     | 47     |
|                                | (2.7)  | (2.5)  | (3.3)  | (3.7)  |
+--------------------------------+--------+--------+--------+--------+
| Renal function abnormal/renal  | 31     | 45     | 36     | 53     |
| dysfunction aggravated         | (2.4)  | (3.5)  | (2.8)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Pulmonary oedema               | 37     | 35     | 41     | 42     |
|                                | (2.9)  | (2.7)  | (3.2)  | (3.3)  |
+--------------------------------+--------+--------+--------+--------+
| Anaemia                        | 34     | 32     | 40     | 42     |
|                                | (2.7)  | (2.5)  | (3.1)  | (3.3)  |
+--------------------------------+--------+--------+--------+--------+
| Renal failure acute            | 24     | 42     | 32     | 50     |
|                                | (1.9)  | (3.3)  | (2.5)  | (3.9)  |
+--------------------------------+--------+--------+--------+--------+
| Accident and/or injury         | 30     | 31     | 39     | 39     |
|                                | (2.4)  | (2.4)  | (3.1)  | (3.1)  |
+--------------------------------+--------+--------+--------+--------+
| Dehydration                    | 18     | 39     | 22     | 54     |
|                                | (1.4)  | (3.1)  | (1.7)  | (4.2)  |
+--------------------------------+--------+--------+--------+--------+
| Diabetes mellitus/diabetes     | 39     | 29     | 40     | 36     |
| mellitus aggravated            | (3.1)  | (2.3)  | (3.1)  | (2.8)  |
+--------------------------------+--------+--------+--------+--------+

Source: Table 68 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.

# FINDINGS IN SPECIAL/SUBGROUP POPULATIONS

## Age, Gender and Ethnic group 

Subgroup analysis of the primary endpoint was performed by age, gender
and ethnic group. The results are presented in Table 7. The hazard
ratios were less than 1 (in favor of Candesartan) in all the subgroups
except for the oriental, South Asian, Malay subgroups. The sample sizes
were very small in the three groups. The results of the subgroup
analysis of the secondary endpoints are presented in Tables 8 and 9.
Since the secondary endpoints are highly correlated with the primary
endpoint, the results were similar.

[]{#__RefHeading___Toc86725488 .anchor}Table 7. Subgroup Analysis of
Time to the First CV Death or CHF hospitalization

+---------+-------------+----+---------+--------+----------------+----+
| **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 |
+---------+-------------+----+---------+--------+----------------+----+
| 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 with
treatment as the only independent variable.

[]{#__RefHeading___Toc86725489 .anchor}Table 8. Subgroup Analysis of
Time to the All-cause Death or CHF hospitalization

+---------+-------------+----+---------+--------+----------------+----+
| **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 | 204     | 223    | 0.883 (0.730,  | 0  |
| (Years) |             | 68 |         |        | 1.068)         | .2 |
|         |             |    |         |        |                | 00 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 65 -\<  | 8  | 205     | 208    | 0.844 (0.696,  | 0  |
|         | 75          | 23 |         |        | 1.023)         | .0 |
|         |             |    |         |        |                | 84 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 4  | 130     | 156    | 0.917 (0.727,  | 0  |
|         |             | 57 |         |        | 1.157)         | .4 |
|         |             |    |         |        |                | 66 |
+---------+-------------+----+---------+--------+----------------+----+
| Age     | \< 75       | 20 | 409     | 431    | 0.877 (0.766,  | 0  |
| (Years) |             | 91 |         |        | 1.004)         | .0 |
|         |             |    |         |        |                | 57 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 4  | 130     | 156    | 0.917 (0.727,  | 0  |
|         |             | 57 |         |        | 1.157)         | .4 |
|         |             |    |         |        |                | 66 |
+---------+-------------+----+---------+--------+----------------+----+
| Sex     | Male        | 20 | 433     | 468    | 0.880 (0.772,  | 0  |
|         |             | 06 |         |        | 1.003)         | .0 |
|         |             |    |         |        |                | 55 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Female      | 5  | 106     | 119    | 0.839 (0.646,  | 0  |
|         |             | 42 |         |        | 1.091)         | .1 |
|         |             |    |         |        |                | 90 |
+---------+-------------+----+---------+--------+----------------+----+
| Ethnic  | European    | 23 | 480     | 531    | 0.876 (0.774,  | 0  |
| Group   |             | 07 |         |        | 0.991)         | .0 |
|         |             |    |         |        |                | 36 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Black       | 1  | 25      | 35     | 0.564 (0.337,  | 0  |
|         |             | 27 |         |        | 0.943)         | .0 |
|         |             |    |         |        |                | 29 |
+---------+-------------+----+---------+--------+----------------+----+
|         | South Asian | 27 | 11      | 4      | 1.264 (0.400,  | 0  |
|         |             |    |         |        | 3.998)         | .6 |
|         |             |    |         |        |                | 90 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Arab/Middle | 12 | 3       | 0      |                |    |
|         | East        |    |         |        |                |    |
+---------+-------------+----+---------+--------+----------------+----+
|         | Oriental    | 35 | 12      | 5      | 1.729 (0.608,  | 0  |
|         |             |    |         |        | 4.917)         | .3 |
|         |             |    |         |        |                | 05 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Malay       | 18 | 5       | 4      | 0.828 (0.222,  | 0  |
|         |             |    |         |        | 3.091)         | .7 |
|         |             |    |         |        |                | 79 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 22 | 3       | 8      | 0.573 (0.152,  | 0  |
|         |             |    |         |        | 2.165)         | .4 |
|         |             |    |         |        |                | 12 |
+---------+-------------+----+---------+--------+----------------+----+
| Region  | Western     | 11 | 220     | 278    | 0.767 (0.643,  | 0  |
|         | Europe      | 93 |         |        | 0.916)         | .0 |
|         |             |    |         |        |                | 03 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Eastern     | 2  | 46      | 47     | 0.843 (0.562,  | 0  |
|         | Europe      | 19 |         |        | 1.267)         | .4 |
|         |             |    |         |        |                | 12 |
+---------+-------------+----+---------+--------+----------------+----+
|         | North       | 9  | 225     | 224    | 0.983 (0.817,  | 0  |
|         | America (US | 54 |         |        | 1.183)         | .8 |
|         | and Canada) |    |         |        |                | 58 |
+---------+-------------+----+---------+--------+----------------+----+
|         | USA         | 5  | 143     | 138    | 1.056 (0.836,  | 0  |
|         |             | 97 |         |        | 1.334)         | .6 |
|         |             |    |         |        |                | 48 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Asia        | 59 | 21      | 10     | 1.122 (0.528,  | 0  |
|         |             |    |         |        | 2.384)         | .7 |
|         |             |    |         |        |                | 65 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Russia      | 15 | 3       | 5      | 1.158 (0.276,  | 0  |
|         |             |    |         |        | 4.864)         | .8 |
|         |             |    |         |        |                | 41 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 1  | 24      | 23     | 0.870 (0.491,  | 0  |
|         |             | 08 |         |        | 1.541)         | .6 |
|         |             |    |         |        |                | 32 |
+---------+-------------+----+---------+--------+----------------+----+
| NYHA    | II          | 6  | 108     | 113    | 0.899 (0.690,  | 0  |
|         |             | 14 |         |        | 1.170)         | .4 |
|         |             |    |         |        |                | 27 |
+---------+-------------+----+---------+--------+----------------+----+
|         | III         | 18 | 407     | 437    | 0.878 (0.767,  | 0  |
|         |             | 56 |         |        | 1.005)         | .0 |
|         |             |    |         |        |                | 59 |
+---------+-------------+----+---------+--------+----------------+----+
|         | IV          | 78 | 24      | 37     | 0.841 (0.502,  | 0  |
|         |             |    |         |        | 1.408)         | .5 |
|         |             |    |         |        |                | 10 |
+---------+-------------+----+---------+--------+----------------+----+
| LVEF    | \< 0.25     | 7  | 202     | 218    | 0.860 (0.710,  | 0  |
|         |             | 70 |         |        | 1.042)         | .1 |
|         |             |    |         |        |                | 23 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 0.25    | 17 | 337     | 369    | 0.874 (0.754,  | 0  |
|         |             | 78 |         |        | 1.013)         | .0 |
|         |             |    |         |        |                | 73 |
+---------+-------------+----+---------+--------+----------------+----+

Source: Table 110 of the Sponsor's clinical study report of study
SH-AHS-0006. The nominal P-value, hazard ratio and CI were from Cox
regression model with treatment as the only independent variable.

[]{#__RefHeading___Toc86725490 .anchor}Table 9. Subgroup Analysis of
Time to the CV Death or CHF hospitalization or Nonfatal MI

+---------+-------------+----+---------+--------+----------------+----+
| **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 | 198     | 217    | 0.883 (0.728   | 0  |
| (Years) |             | 68 |         |        | 1.071)         | .2 |
|         |             |    |         |        |                | 05 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 65 -\<  | 8  | 180     | 197    | 0.777 (0.634,  | 0  |
|         | 75          | 23 |         |        | 0.951)         | .0 |
|         |             |    |         |        |                | 14 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 4  | 117     | 136    | 0.940 (0.734,  | 0  |
|         |             | 57 |         |        | 1.204)         | .6 |
|         |             |    |         |        |                | 25 |
+---------+-------------+----+---------+--------+----------------+----+
| Age     | \< 75       | 20 | 378     | 414    | 0.843 (0.733,  | 0  |
| (Years) |             | 91 |         |        | 0.969)         | .0 |
|         |             |    |         |        |                | 16 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 75      | 4  | 117     | 136    | 0.940 (0.734,  | 0  |
|         |             | 57 |         |        | 1.204)         | .6 |
|         |             |    |         |        |                | 25 |
+---------+-------------+----+---------+--------+----------------+----+
| Sex     | Male        | 20 | 395     | 436    | 0.860 (0.751,  | 0  |
|         |             | 06 |         |        | 0.986)         | .0 |
|         |             |    |         |        |                | 30 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Female      | 5  | 100     | 114    | 0.822 (0.629,  | 0  |
|         |             | 42 |         |        | 1.076)         | .1 |
|         |             |    |         |        |                | 54 |
+---------+-------------+----+---------+--------+----------------+----+
| Ethnic  | European    | 23 | 439     | 499    | 0.852 (0.750,  | 0  |
| Group   |             | 07 |         |        | 0.969)         | .0 |
|         |             |    |         |        |                | 14 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Black       | 1  | 24      | 31     | 0.598 (0.351,  | 0  |
|         |             | 27 |         |        | 1.020)         | .0 |
|         |             |    |         |        |                | 59 |
+---------+-------------+----+---------+--------+----------------+----+
|         | 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       | 4      | 0.761 (0.204,  | 0  |
|         |             |    |         |        | 2.847)         | .6 |
|         |             |    |         |        |                | 85 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 22 | 3       | 8      | 0.573 (0.152,  | 0  |
|         |             |    |         |        | 2.165)         | .4 |
|         |             |    |         |        |                | 12 |
+---------+-------------+----+---------+--------+----------------+----+
| Region  | Western     | 11 | 200     | 257    | 0.756 (0.629,  | 0  |
|         | Europe      | 93 |         |        | 0.910)         | .0 |
|         |             |    |         |        |                | 03 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Eastern     | 2  | 41      | 43     | 0.826 (0.538,  | 0  |
|         | Europe      | 19 |         |        | 1.267)         | .3 |
|         |             |    |         |        |                | 80 |
+---------+-------------+----+---------+--------+----------------+----+
|         | North       | 9  | 211     | 212    | 0.969 (0.801,  | 0  |
|         | America (US | 54 |         |        | 1.173)         | .7 |
|         | and Canada) |    |         |        |                | 47 |
+---------+-------------+----+---------+--------+----------------+----+
|         | USA         | 5  | 131     | 135    | 0.978 (0.769,  | 0  |
|         |             | 97 |         |        | 1.244)         | .8 |
|         |             |    |         |        |                | 56 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Asia        | 59 | 19      | 9      | 1.108 (0.501,  | 0  |
|         |             |    |         |        | 2.452)         | .8 |
|         |             |    |         |        |                | 00 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Russia      | 15 | 2       | 5      | 0.787 (0.152,  | 0  |
|         |             |    |         |        | 4.073)         | .7 |
|         |             |    |         |        |                | 75 |
+---------+-------------+----+---------+--------+----------------+----+
|         | Other       | 1  | 22      | 24     | 0.753 (0.422,  | 0  |
|         |             | 08 |         |        | 1.342)         | .3 |
|         |             |    |         |        |                | 36 |
+---------+-------------+----+---------+--------+----------------+----+
| NYHA    | II          | 6  | 98      | 107    | 0.863 (0.656,  | 0  |
|         |             | 14 |         |        | 1.136)         | .2 |
|         |             |    |         |        |                | 94 |
+---------+-------------+----+---------+--------+----------------+----+
|         | III         | 18 | 374     | 408    | 0.862 (0.749,  | 0  |
|         |             | 56 |         |        | 0.992)         | .0 |
|         |             |    |         |        |                | 38 |
+---------+-------------+----+---------+--------+----------------+----+
|         | IV          | 78 | 23      | 35     | 0.809 (0.477,  | 0  |
|         |             |    |         |        | 1.370)         | .4 |
|         |             |    |         |        |                | 30 |
+---------+-------------+----+---------+--------+----------------+----+
| LVEF    | \< 0.25     | 7  | 189     | 208    | 0.836 (0.686,  | 0  |
|         |             | 70 |         |        | 1.018)         | .0 |
|         |             |    |         |        |                | 74 |
+---------+-------------+----+---------+--------+----------------+----+
|         | \>= 0.25    | 17 | 306     | 342    | 0.857 (0.734,  | 0  |
|         |             | 78 |         |        | 1.000)         | .0 |
|         |             |    |         |        |                | 49 |
+---------+-------------+----+---------+--------+----------------+----+

Source: Table 112 of the Sponsor's clinical study report of study
SH-AHS-0006. The nominal P-value, hazard ratio and CI were from Cox
regression model with treatment as the only independent variable.

## Other Subgroup Populations

The results of subgroup analysis of the primary endpoint by region,
classification of NYHA and LVEF are presented in Table 7. The hazard
ratios were less than 1 (in favor of Candesartan) in all the subgroups
except for the USA and Asia subgroups. The sample size was too small in
Asia. The estimate of the hazard ratio was 1.02 in the USA subgroup,
which was very close to 1. It should be noted that the hazard ratios
were 0.74 (N = 1193) and 0.98 (N = 954) in the Western Europe and North
America with similar sample size, respectively. The results of the
subgroup analysis for the two secondary endpoints are similar to those
for the primary endpoint.

Some other subgroup analysis results of the primary endpoint are
presented in Table 3. In Table 3, the patients were divided into whether
they took recommended ACE inhibitor doses at baseline or during the
study. It seemed that Candesartan reduced the risk of the CV death or
CHF hospitalization in each of the subgroups.

# SUMMARY AND CONCLUSIONS

## Statistical Issues and Collective Evidence

The primary endpoint, time to the first CV death or CHF hospitalization,
achieved statistical significance (P = 0.011) with a relative risk
reduction of 15% over placebo. It seemed that both CV death and CHF
hospitalization contributed to the benefit. The benefits of Candesartan
seemed consistent among various subgroups except between North America
and Western Europe, where the hazard ratios were 0.98 (N = 954) and 0.74
(N = 1193), 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. However, since the
allocated Type I error rates were very small for the interim analyses,
the effect should be small if any.

In the pre-specified analysis of the two secondary endpoints,
statistical significance was also achieved for each of the two secondary
endpoints. Candesartan reduced the risk of all-cause death or CHF
hospitalization with a 13% relative risk reduction (nominal P = 0.021)
and the risk of CV death or CHF hospitalization or nonfatal MI with a
15% relative risk reduction (nominal P = 0.010).

## Conclusions and Recommendations

Candesartan significantly reduced CV death or CHF hospitalization in
patients with depressed LV systolic function treated with 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.

The benefits of Candesartan appeared to be very small in North America
when compared with Western Europe (Tables 7, 8 and 9).