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).
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.
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.
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%.
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.
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.
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.
This application was submitted electronically. All the materials are located at \\Cdsesub1\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. 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.
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.
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.
Table 1. Patient Participation, Demographic and
Baseline Characteristics
|
|
Placebo
N = 1272
|
Cand. Cil.
N = 1276
|
Total
N = 2548
|
|
Disposition N (%)
|
|
|
|
|
Completed
|
1271 (99.9)
|
1273 (99.8)
|
2544 (99.8)
|
|
Lost to Follow-up
|
1 (0.1)
|
3 (0.2)
|
4 (0.2)
|
|
Demographic Characteristics
|
|
|
|
|
Sex N (%)
|
|
|
|
|
Male
|
1000 (78.6)
|
1006 (78.8)
|
2006 (78.7)
|
|
Female
|
272 (21.4)
|
270 (21.2)
|
542 (21.3)
|
|
Age Mean (SD)
Years
|
64.1 (11.3)
|
64.0 (10.7)
|
64.1 (11.0)
|
|
Ethnicity N
(%)
|
|
|
|
|
European Origin
|
1164 (91.5)
|
1143 (89.6)
|
2307 (90.5)
|
|
Black
|
62 (4.9)
|
65 (5.1)
|
127 (5.0)
|
|
South Asia
|
8 (0.6)
|
19 (1.5)
|
27 (1.1)
|
|
Arab/Middle East
|
4 (0.3)
|
8 (0.6)
|
12 (0.5)
|
|
Oriental
|
13 (1.0)
|
22 (1.7)
|
35 (1.4)
|
|
Malay
|
7 (0.6)
|
11 (0.9)
|
18 (0.7)
|
|
Other
|
14 (1.1)
|
8 (0.6)
|
22 (0.9)
|
|
Baseline Characteristics
|
|
|
|
|
Ejection Fraction, Mean (SD)
|
0.28 (0.07)
|
0.28 (0.08)
|
0.28 (0.07)
|
|
Diabetes Mellitus, N (%)
|
382 (30.0)
|
376 (29.5)
|
758 (29.7)
|
|
Hypertension, N (%)
|
619 (48.7)
|
609 (47.7)
|
1228 (48.2)
|
|
Atrial Fibrillation, N (%)
|
341 (26.8)
|
346 (27.1)
|
687 (27.0)
|
|
Previous MI, N (%)
|
703 (55.3)
|
714 (56.0)
|
1417 (55.6)
|
|
Angina Pectoris, N (%)
|
684 (53.8)
|
666 (52.2)
|
1350 (53.0)
|
|
Stroke, N (%)
|
112 (8.8)
|
108 (8.5)
|
220 (8.6)
|
|
NYHA II, N (%)
|
302 (23.7)
|
312 (24.5)
|
614 (24.1)
|
|
NYHA III, N (%)
|
925 (72.7)
|
931 (73.0)
|
1856 (72.8)
|
|
NYHA IV, N (%)
|
45 (3.5)
|
33 (2.6)
|
78 (3.1)
|
|
Current Smoker, N (%)
|
235 (18.5)
|
194 (15.2)
|
429 (16.8)
|
Source: Table S1 of the clinical study report of Study
SH-AHS-0006 by AstraZeneca.
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.
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.
Table 2. Analysis of the Priamry and Secondary
Endpoints
|
Endpoint
|
No. of Patients with event
|
Hazard
Ratio (95%CI)
|
P-value
|
|
Candesartan
N = 1276
|
Placebo
N = 1272
|
|
Primary
CV death or CHF hospitalization
|
483
|
538
|
0.85
(0.75–0.96)
|
0.011
|
|
Secondary
All-cause death or CHF hospitalization
|
539
|
587
|
0.87 (0.78-0.98)
|
0.021
|
|
CV death or CHF hospitalization or
non-fatal MI
|
495
|
550
|
0.85
(0.76-0.96)
|
0.010
|
|
Components
of the composite endpoints
CV death
|
302
|
347
|
0.84
(0.72-0.98)
|
0.029
|
|
CHF hospitalization
|
309
|
356
|
0.83 (0.71-0.96)
|
0.013
|
|
All-cause mortality
|
377
|
412
|
0.89
(0.77-1.02)
|
0.086
|
|
Nonfatal MI
|
26
|
49
|
0.51
(0.32-0.82)
|
0.005
|
Source: Table 8
of the Sponsor’s summary of clinical efficacy.
The results were confirmed independently by this reviewer, with minor
difference for nonfatal MI. Nominal P-values
were from log-rank test and hazard ratios were from Cox regression model with
treatment as the only independent variable.
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.
Figure 1. Kaplan-Meier Estimate of Time to 1st
CV Death or CHF Hospitalization
Source: Reviewer’s analysis.
Figure 2. Plot of Testing of the Proportional Hazards
Assumption
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.
Table 3. Some Sugroup Analysis of the Primary
Endpoint
|
Subgroup
|
Total N (n with events)
|
Hazard
Ratio (95%CI)
|
P-value
|
|
Candesartan
N (n)
|
Placebo
N (n)
|
|
Patients
with recommended ACE inhibitors at baseline
|
643 (232)
|
648 (275)
|
0.79
(0.67-0.95)
|
0.010
|
|
Patients
without recommended ACE inhibitors at baseline
|
633 (251)
|
624 (263)
|
0.92
(0.77-1.09)
|
0.314
|
|
Patients
with recommended ACE inhibitors during study
|
748 (270)
|
787 (330)
|
0.81
(0.69-0.95)
|
0.010
|
|
Patients
without recommended ACE inhibitor during study
|
528 (213)
|
485 (208)
|
0.91
(0.75-1.10)
|
0.345
|
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.
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.
Table 4. Most
Commonly Reported AEs
|
Preferred Term
|
Placebo
on treatment
(N = 1272)
n %
|
Candesartan
on treatment
(N = 1276)
n %
|
Placebo
during study
(N = 1272)
n %
|
Candesartan
during study
(N = 1276)
n %
|
|
Cardiac failure/cardiac failure aggravated
|
435 (34.2)
|
350 (27.4)
|
472 (37.1)
|
421 (33.0)
|
|
Hypotension
|
176(13.8)
|
288 (22.6)
|
184 (14.5)
|
296 (23.2)
|
|
Angina pectoris/angina pectoris aggravated
|
153 (12.0)
|
127 (10.0)
|
169 (13.3)
|
150 (11.8)
|
|
Sudden death
|
140 (11.0)
|
114 (8.9)
|
174 (13.7)
|
143 (11.2)
|
|
Renal function abnormal/renal
dysfunction aggravated
|
115 (9.0)
|
192 (15.0)
|
119 (9.4)
|
196 (15.4)
|
|
Arrhythmia ventricular
|
107 (8.4)
|
78 (6.1)
|
121 (9.5)
|
88 (6.9)
|
|
Pneumonia
|
88 (6.9)
|
57 (4.5)
|
108 (8.5)
|
76 (6.0)
|
|
Hyperkalaemia
|
44 (3.5)
|
121 (9.5)
|
46 (3.6)
|
123 (9.6)
|
|
Myocardial infarction
|
73 (5.7)
|
60 (4.7)
|
88 (6.9)
|
70 (5.5)
|
|
Atrial fibrillation
|
69 (5.4)
|
52 (4.1)
|
73 (5.7)
|
66 (5.2)
|
|
Arrhythmia atrial
|
61 (4.8)
|
59 (4.6)
|
71 (5.6)
|
67 (5.3)
|
|
Tachycardia
ventricular/arrhythmia/ arrhythmia aggravated
|
63 (5.0)
|
52 (4.1)
|
68 (5.3)
|
65 (5.1)
|
|
Cerebrovascular disorder
|
48 (3.8)
|
55 (4.3)
|
58 (4.6)
|
69 (5.4)
|
|
Chest pain
|
64 (5.0)
|
45 (3.5)
|
71 (5.6)
|
54 (4.2)
|
|
Coronary artery disorder
|
42 (3.3)
|
58 (4.5)
|
50 (3.9)
|
73 (5.7)
|
|
Syncope
|
45 (3.5)
|
49 (3.8)
|
49 (3.9)
|
59 (4.6)
|
|
Tachycardia supraventricular
|
46 (3.6)
|
47 (3.7)
|
50 (3.9)
|
54 (4.2)
|
|
Cardiomyopathy
|
38 (3.0)
|
33 (2.6)
|
48 (3.8)
|
51 (4.0)
|
|
Dizziness/vertigo
|
35 (2.8)
|
49 (3.8)
|
40 (3.1)
|
57 (4.5)
|
|
Pulmonary oedema
|
41 (3.2)
|
39 (3.1)
|
47 (3.7)
|
48 (3.8)
|
|
Renal failure acute
|
29 (2.3)
|
45 (3.5)
|
38 (3.0)
|
54 (4.2)
|
|
Anaemia
|
36 (2.8)
|
35 (2.7)
|
43 (3.4)
|
46 (3.6)
|
|
Accident and/or injury
|
32 (2.5)
|
34 (2.7)
|
43 (3.4)
|
44 (3.4)
|
|
Diabetes
mellitus/diabetes mellitus aggravated
|
41 (3.2)
|
30 (2.4)
|
42 (3.3)
|
37 (2.9)
|
|
Dehydration
|
18 (1.4)
|
40 (3.1)
|
22 (1.7)
|
55 (4.3)
|
Source:
Table S4 of the Sponsor’s clinical study report of study SH-AHS-0006.
On treatment = on treatment
with investigational product; During study = total study period, irrespective
of treatment with investigational product or not.
Table 5.
Number of Patients with Most Commonly Reported AEs Leading to Death
|
Preferred Term
|
Placebo
on treatment
(N = 1272)
n %
|
Candesartan
on treatment
(N = 1276)
n %
|
Placebo
during study
(N = 1272)
n %
|
Candesartan
during study
(N = 1276)
n %
|
|
Sudden death
|
139 (10.9)
|
113 (8.9)
|
174 (13.7)
|
143 (11.2)
|
|
Cardiac failure/cardiac
failure aggravated
|
61 (4.8)
|
28 (2.2)
|
112 (8.8)
|
74 (5.8)
|
|
Myocardial infarction
|
12 (0.9)
|
15 (1.2)
|
20 (1.6)
|
21 (1.6)
|
|
Death
|
5 (0.4)
|
7 (0.5)
|
13 (1.0)
|
19 (1.5)
|
|
Pneumonia
|
11 (0.9)
|
3 (0.2)
|
19 (1.5)
|
10 (0.8)
|
|
Cardiac arrest
|
8 (0.6)
|
8 (0.6)
|
13 (1.0)
|
13 (1.0)
|
|
Fibrillation ventricular
|
14 (1.1)
|
6 (0.5)
|
16 (1.3)
|
9 (0.7)
|
|
Cerebrovascular disorder
|
7 (0.6)
|
8 (0.6)
|
11 (0.9)
|
12 (0.9)
|
|
Sepsis
|
6 (0.5)
|
5 (0.4)
|
10 (0.8)
|
11 (0.9)
|
|
Cardiomyopathy
|
3 (0.2)
|
2 (0.2)
|
8 (0.6)
|
8 (0.6)
|
|
Pulmonary carcinoma
|
4 (0.3)
|
5 (0.4)
|
5 (0.4)
|
10 (0.8)
|
|
Pulmonary oedema
|
4 (0.3)
|
3 (0.2)
|
8 (0.6)
|
6 (0.5)
|
|
Renal failure nos
|
3 (0.2)
|
0 (0)
|
8 (0.6)
|
4 (0.3)
|
|
Accident and/or injury
|
3 (0.2)
|
3 (0.2)
|
5 (0.4)
|
5 (0.4)
|
|
Renal failure acute
|
3 (0.2)
|
2 (0.2)
|
5 (0.4)
|
5 (0.4)
|
|
Multiorgan failure
|
0 (0)
|
1 (0.1)
|
4 (0.3)
|
4 (0.3)
|
|
Colon carcinoma
|
0 (0)
|
1 (0.1)
|
0 (0)
|
7 (0.5)
|
|
Coronary artery disorder
|
2 (0.2)
|
1 (0.1)
|
2 (0.2)
|
5 (0.4)
|
|
Renal function abnormal
|
2 (0.2)
|
0 (0)
|
5 (0.4)
|
2 (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.
Table 6.
Number of Patients with Most Commonly Reported SAEs Other Than Death
|
Preferred Term
|
Placebo
on treatment
(N = 1272)
n %
|
Candesartan
on treatment
(N = 1276)
n %
|
Placebo
during study
(N = 1272)
n %
|
Candesartan
during study
(N = 1276)
n %
|
|
Cardiac failure/cardiac failure aggravated
|
418 (32.9)
|
333 (26.1)
|
450 (35.4)
|
398 (31.2)
|
|
Angina pectoris/angina
pectoris aggravated
|
152 (11.9)
|
126 (9.9)
|
168 (13.2)
|
148 (11.6)
|
|
Hypotension
|
91 (7.2)
|
133 (10.4)
|
102 (8.0)
|
143 (11.2)
|
|
Arrhythmia ventricular
|
106 (8.3)
|
78 (6.1)
|
120 (9.4)
|
88 (6.9)
|
|
Pneumonia
|
77 (6.1)
|
55 (4.3)
|
93 (7.3)
|
73 (5.7)
|
|
Arrhythmia atrial
|
61 (4.8)
|
59 (4.6)
|
71 (5.6)
|
67 (5.3)
|
|
Fibrillation atrial
|
67 (5.3)
|
52 (4.1)
|
71 (5.6)
|
65 (5.1)
|
|
Tachycardia ventricular/
arrhythmia/arrhythmia aggravated
|
61
(4.8)
|
51 (4.0)
|
66 (5.2)
|
62 (4.9)
|
|
Myocardial infarction
|
61 (4.8)
|
47 (3.7)
|
70 (5.5)
|
52 (4.1)
|
|
Chest pain
|
62 (4.9)
|
45 (3.5)
|
68 (5.3)
|
53 (4.2)
|
|
Cerebrovascular disorder
|
43 (3.4)
|
51 (4.0)
|
53 (4.2)
|
63 (4.9)
|
|
Coronary artery disorder
|
39 (3.1)
|
55 (4.3)
|
47 (3.7)
|
68 (5.3)
|
|
Tachycardia supraventricular
|
46 (3.6)
|
47 (3.7)
|
50 (3.9)
|
54 (4.2)
|
|
Syncope
|
44 (3.5)
|
44 (3.4)
|
48 (3.8)
|
55 (4.3)
|
|
Cardiomyopathy
|
34 (2.7)
|
32 (2.5)
|
42 (3.3)
|
47 (3.7)
|
|
Renal function abnormal/renal
dysfunction aggravated
|
31 (2.4)
|
45 (3.5)
|
36 (2.8)
|
53 (4.2)
|
|
Pulmonary oedema
|
37 (2.9)
|
35 (2.7)
|
41 (3.2)
|
42 (3.3)
|
|
Anaemia
|
34 (2.7)
|
32 (2.5)
|
40 (3.1)
|
42 (3.3)
|
|
Renal failure acute
|
24 (1.9)
|
42 (3.3)
|
32 (2.5)
|
50 (3.9)
|
|
Accident and/or injury
|
30 (2.4)
|
31 (2.4)
|
39 (3.1)
|
39 (3.1)
|
|
Dehydration
|
18 (1.4)
|
39 (3.1)
|
22 (1.7)
|
54 (4.2)
|
|
Diabetes
mellitus/diabetes mellitus aggravated
|
39 (3.1)
|
29 (2.3)
|
40 (3.1)
|
36 (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.
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.
Table 7.
Subgroup Analysis of Time to the First CV Death or CHF hospitalization
|
Variable
|
Group
|
Total
N
|
Candesartan
# of events
|
Placebo
# of Events
|
Hazard Ratio (95% CI)
|
P-value
|
|
Age(Years)
|
< 65
|
1268
|
192
|
211
|
0.879 (0.723, 1.069)
|
0.197
|
|
|
>= 65 -< 75
|
823
|
176
|
193
|
0.782 (0.637, 0.959)
|
0.018
|
|
|
>= 75
|
457
|
115
|
134
|
0.945 (0.736, 1.212)
|
0.654
|
|
Age (Years)
|
< 75
|
2091
|
368
|
404
|
0.842 (0.732, 0.970)
|
0.017
|
|
|
>= 75
|
457
|
115
|
134
|
0.945 (0.736, 1.212)
|
0.654
|
|
Sex
|
Male
|
2006
|
387
|
427
|
0.862 (0.752, 0.990)
|
0.035
|
|
|
Female
|
542
|
96
|
111
|
0.815 (0.620, 1.072)
|
0.143
|
|
Ethnic Group
|
European
|
2307
|
427
|
490
|
0.845 (0.742, 0.962)
|
0.011
|
|
|
Black
|
127
|
24
|
29
|
0.655 (0.381, 1.126)
|
0.126
|
|
|
South Asian
|
27
|
11
|
4
|
1.264 (0.400, 3.998)
|
0.690
|
|
|
Arab/Middle East
|
12
|
3
|
0
|
|
|
|
|
Oriental
|
35
|
10
|
4
|
1.804 (0.564, 5.768)
|
0.320
|
|
|
Malay
|
18
|
5
|
3
|
1.104 (0.263, 4.636)
|
0.892
|
|
|
Other
|
22
|
3
|
8
|
0.573 (0.152, 2.165)
|
0.412
|
|
Region
|
Western Europe
|
1193
|
194
|
255
|
0.739 (0.613, 0.891)
|
0.002
|
|
|
Eastern Europe
|
219
|
41
|
43
|
0.825 (0.538, 1.266)
|
0.378
|
|
|
North America (US and Canada)
|
954
|
205
|
204
|
0.984 (0.811, 1.194)
|
0.870
|
|
|
USA
|
597
|
128
|
128
|
1.019 (0.798, 1.303)
|
0.877
|
|
|
Asia
|
59
|
19
|
8
|
1.282 (0.561, 2.930)
|
0.556
|
|
|
Russia
|
15
|
2
|
5
|
0.787 (0.152, 4.073)
|
0.775
|
|
|
Other
|
108
|
22
|
23
|
0.800 (0.446, 1.435)
|
0.454
|
|
NYHA
|
II
|
614
|
93
|
104
|
0.841 (0.636, 1.112)
|
0.225
|
|
|
III
|
1856
|
367
|
399
|
0.868 (0.753, 1.000)
|
0.051
|
|
|
IV
|
78
|
23
|
35
|
0.847 (0.500, 1.435)
|
0.536
|
|
LVEF
|
< 0.25
|
770
|
186
|
203
|
0.851 (0.698, 1.039)
|
0.113
|
|
|
>= 0.25
|
1778
|
297
|
335
|
0.849 (0.726, 0.993)
|
0.040
|
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.
Table 8. Subgroup
Analysis of Time to the All-cause Death or CHF hospitalization
|
Variable
|
Group
|
Total
N
|
Candesartan
# of events
|
Placebo
# of Events
|
Hazard Ratio (95% CI)
|
P-value
|
|
Age(Years)
|
< 65
|
1268
|
204
|
223
|
0.883 (0.730, 1.068)
|
0.200
|
|
|
>= 65 -< 75
|
823
|
205
|
208
|
0.844 (0.696, 1.023)
|
0.084
|
|
|
>= 75
|
457
|
130
|
156
|
0.917 (0.727, 1.157)
|
0.466
|
|
Age (Years)
|
< 75
|
2091
|
409
|
431
|
0.877 (0.766, 1.004)
|
0.057
|
|
|
>= 75
|
457
|
130
|
156
|
0.917 (0.727, 1.157)
|
0.466
|
|
Sex
|
Male
|
2006
|
433
|
468
|
0.880 (0.772, 1.003)
|
0.055
|
|
|
Female
|
542
|
106
|
119
|
0.839 (0.646, 1.091)
|
0.190
|
|
Ethnic Group
|
European
|
2307
|
480
|
531
|
0.876 (0.774, 0.991)
|
0.036
|
|
|
Black
|
127
|
25
|
35
|
0.564 (0.337, 0.943)
|
0.029
|
|
|
South Asian
|
27
|
11
|
4
|
1.264 (0.400, 3.998)
|
0.690
|
|
|
Arab/Middle East
|
12
|
3
|
0
|
|
|
|
|
Oriental
|
35
|
12
|
5
|
1.729 (0.608, 4.917)
|
0.305
|
|
|
Malay
|
18
|
5
|
4
|
0.828 (0.222, 3.091)
|
0.779
|
|
|
Other
|
22
|
3
|
8
|
0.573 (0.152, 2.165)
|
0.412
|
|
Region
|
Western Europe
|
1193
|
220
|
278
|
0.767 (0.643, 0.916)
|
0.003
|
|
|
Eastern Europe
|
219
|
46
|
47
|
0.843 (0.562, 1.267)
|
0.412
|
|
|
North America (US and Canada)
|
954
|
225
|
224
|
0.983 (0.817, 1.183)
|
0.858
|
|
|
USA
|
597
|
143
|
138
|
1.056 (0.836, 1.334)
|
0.648
|
|
|
Asia
|
59
|
21
|
10
|
1.122 (0.528, 2.384)
|
0.765
|
|
|
Russia
|
15
|
3
|
5
|
1.158 (0.276, 4.864)
|
0.841
|
|
|
Other
|
108
|
24
|
23
|
0.870 (0.491, 1.541)
|
0.632
|
|
NYHA
|
II
|
614
|
108
|
113
|
0.899 (0.690, 1.170)
|
0.427
|
|
|
III
|
1856
|
407
|
437
|
0.878 (0.767, 1.005)
|
0.059
|
|
|
IV
|
78
|
24
|
37
|
0.841 (0.502, 1.408)
|
0.510
|
|
LVEF
|
< 0.25
|
770
|
202
|
218
|
0.860 (0.710, 1.042)
|
0.123
|
|
|
>= 0.25
|
1778
|
337
|
369
|
0.874 (0.754, 1.013)
|
0.073
|
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.
Table 9.
Subgroup Analysis of Time to the CV Death or CHF hospitalization or Nonfatal MI
|
Variable
|
Group
|
Total
N
|
Candesartan
# of events
|
Placebo
# of Events
|
Hazard Ratio (95% CI)
|
P-value
|
|
Age(Years)
|
< 65
|
1268
|
198
|
217
|
0.883 (0.728 1.071)
|
0.205
|
|
|
>= 65 -< 75
|
823
|
180
|
197
|
0.777 (0.634, 0.951)
|
0.014
|
|
|
>= 75
|
457
|
117
|
136
|
0.940 (0.734, 1.204)
|
0.625
|
|
Age (Years)
|
< 75
|
2091
|
378
|
414
|
0.843 (0.733, 0.969)
|
0.016
|
|
|
>= 75
|
457
|
117
|
136
|
0.940 (0.734, 1.204)
|
0.625
|
|
Sex
|
Male
|
2006
|
395
|
436
|
0.860 (0.751, 0.986)
|
0.030
|
|
|
Female
|
542
|
100
|
114
|
0.822 (0.629, 1.076)
|
0.154
|
|
Ethnic Group
|
European
|
2307
|
439
|
499
|
0.852 (0.750, 0.969)
|
0.014
|
|
|
Black
|
127
|
24
|
31
|
0.598 (0.351, 1.020)
|
0.059
|
|
|
South Asian
|
27
|
11
|
4
|
1.264 (0.400, 3.998)
|
0.690
|
|
|
Arab/Middle East
|
12
|
3
|
0
|
|
|
|
|
Oriental
|
35
|
10
|
4
|
1.804 (0.564, 5.768)
|
0.320
|
|
|
Malay
|
18
|
5
|
4
|
0.761 (0.204, 2.847)
|
0.685
|
|
|
Other
|
22
|
3
|
8
|
0.573 (0.152, 2.165)
|
0.412
|
|
Region
|
Western Europe
|
1193
|
200
|
257
|
0.756 (0.629, 0.910)
|
0.003
|
|
|
Eastern Europe
|
219
|
41
|
43
|
0.826 (0.538, 1.267)
|
0.380
|
|
|
North America (US and Canada)
|
954
|
211
|
212
|
0.969 (0.801, 1.173)
|
0.747
|
|
|
USA
|
597
|
131
|
135
|
0.978 (0.769, 1.244)
|
0.856
|
|
|
Asia
|
59
|
19
|
9
|
1.108 (0.501, 2.452)
|
0.800
|
|
|
Russia
|
15
|
2
|
5
|
0.787 (0.152, 4.073)
|
0.775
|
|
|
Other
|
108
|
22
|
24
|
0.753 (0.422, 1.342)
|
0.336
|
|
NYHA
|
II
|
614
|
98
|
107
|
0.863 (0.656, 1.136)
|
0.294
|
|
|
III
|
1856
|
374
|
408
|
0.862 (0.749, 0.992)
|
0.038
|
|
|
IV
|
78
|
23
|
35
|
0.809 (0.477, 1.370)
|
0.430
|
|
LVEF
|
< 0.25
|
770
|
189
|
208
|
0.836 (0.686, 1.018)
|
0.074
|
|
|
>= 0.25
|
1778
|
306
|
342
|
0.857 (0.734, 1.000)
|
0.049
|
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.
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.
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).
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).
