Candesartan cilexetil (Candesartan)
significantly reduced cardiovascular (CV) death or Chronic Heart Failure (CHF)
hospitalization in patients with depressed left ventricular (LV) systolic
function and ejection fraction (EF) <= 40% treated with or without an
angiotensin converting enzyme (ACE) inhibitor.
In the confirmatory analysis, Candesartan also significantly reduced the
risk of all-cause death or CHF hospitalization, and the risk of CV death or CHF
hospitalization or non-fatal MI.
In patients with preserved LV
systolic function and EF > 40%, Candesartan failed to show that it
significantly reduce the risk of CV death or CHF hospitalization. It did not show that Candesartan
significantly reduced the risk of all-cause death or CHF hospitalization, and
the risk of CV death or CHF hospitalization or non-fatal MI.
It was not clear whether
Candesartan reduced the risk of CV death or CHF hospitalization in patients
with depressed or preserved LV
systolic function in the oriental subgroup.
Candesartan probably significantly
reduced the risk of CV death in patients with depressed LV
systolic function and EF <= 40% treated with or without an ACE inhibitor. It failed to show that it significantly
reduced the risk of CV death in patients with preserved LV
systolic function and EF > 40%.
The CHARM (Candesartan in Heart Failure Assessment of
Reduction in Mortality and mobility) program consists of 3 pivotal studies
(SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007) with the same primary endpoint and
different patient populations. The
common primary endpoint was time to the first CV death or CHF hospitalization. Study SH-AHS-0003 treated patients with heart
failure who were ACE inhibitor intolerant and had depressed LV function and EF
<= 40%, Study SH-AHS-0006 studied patients with heart failure who were
treated with ACE inhibitors and had depressed LV systolic function and EF <=
40%, and Study SH-AHS-0007 had patients with heart failure and preserved LV
systolic function and EF > 40%. The
Sponsor is seeking indication that Candesartan reduces the risk of CV death or
CHF hospitalization in the three patient populations based on each of the three
studies. The Sponsor is also seeking the
indication that Candesartan reduces the risk of all-cause mortality based on
the data combining all three studies and the data combining the two studies
(SH-AHS-0003 and SH-AHS-0006).
The indication for the patients treated with an ACE
inhibitor (SH-AHS-0006) was granted with priority review status and the review
was completed in another review. This
review considers all the other indications.
Study SH-AHS-0003 (Alternative) was a randomized,
double-blind, placebo controlled, parallel group, multicenter study to evaluate
the influence of Candesartan cilexetil with a target dose of 32 mg once daily
on mortality and morbidity in patients with depressed LV
systolic function and EF <= 40% and an intolerance to ACE inhibitors. Male or female patients, over or equal to 18
years old, with symptomatic CHF corresponding to NYHA class II-IV were enrolled
in the study. A total of 2028 patients
were randomized in a 1:1 ratio into Candesartan group (n = 1013) and placebo
group (n = 1015). The median follow-up
time was 34 months, and individual follow-up time could last from 25 to 48
months. The design for Studies
SH-AHS-0006 (Added) and SH-AHS-0007 (Preserved) was similar to Study
SH-AHS-0003 except the patient population.
Study SH-AHS-0006 enrolled patients with EF <= 40% and treated with
an ACE inhibitor. In this study, a total
of 2548 patients were randomized in a 1:1 ratio into Candesartan group (n =
1276) and placebo group (n = 1272). Patient
follow-up time ranged from 41 to 48 months, with the median follow-up time of
41 months. Study SH-AHS-0007 had
patients with EF > 40% treated with or without ACE inhibitors. The number of randomized patients was 3023,
with 1514 patients in the Candesartan group and 1509 patients in the placebo
group. The patients were followed from
32 to 48 months, with a median follow-up time of 37 months. All patients remained in the study until the
last randomized patient had been in the CHARM program for two years.
In Study SH-AHS-0003 (Alternative), the primary endpoint,
time to the first CV death or CHF hospitalization, achieved statistical
significance (P < 0.001) with a relative risk reduction of 23% over
placebo. The two secondary endpoints,
time to the all-cause mortality or CHF hospitalization and time to CV death or
CHF hospitalization or non-fatal MI, also achieved statistical significance
with 20% (P = 0.001) and 22% (P < 0.001) relative risk reductions,
respectively.
In Study SH-AHS-0006 (Added), the primary endpoint achieved
statistical significance with a relative risk reduction of 15% (P =
0.011). The two secondary endpoints also
achieved statistical significance. A separate review was completed earlier for
Study SH-AHS-0006 since it was granted with priority review status.
In Study SH-AHS-0007 (Preserved), the primary endpoint did
not achieve statistical significance, with a p-value = 0.12 and a relative risk
reduction of 11%. The two secondary
endpoints did not achieve statistical significance either, with both p-values
larger than 0.12.
For the combined studies, the primary endpoint was the time
to all-cause mortality for the three studies combined, and the secondary
endpoint was time to all-cause mortality for the two studies combined
(SH-AHS-0003 and SH-AHS-0006). The
primary endpoint did not, but was close to, achieve statistical significance with
a p-value = 0.055 and a 9% relative risk reduction. This p-value should be compared with 0.049 to
account for the alpha adjustment due to the six interim analyses. The secondary endpoint had a 12% relative
risk reduction with a nominal p-value = 0.018.
The results for the primary and secondary endpoint were primarily driven
by the CV deaths in Studies SH-AHS-0003 and SH-AHS-0006. Strictly speaking, it can’t be declared that
the secondary endpoint achieved statistical significance based on the pre-specified
hierarchical test sequence. However,
Candesartan probably significantly reduced the risk of CV mortality in the
patient populations in Studies SH-AHS-0003 and SH-AHS-0006 based on the
following reasons. Candesartan had no
effect in the risk reduction of CV deaths or non-CV deaths in the patient population
of Study SH-AHS-0007, but it had relative risk reductions of 15% (P = 0.072)
and 16% (P = 0.029) in CV deaths in Studies SH-AHS-0003 and SH-AHS-0006,
respectively, and no effect on non-CV deaths in either studies. For CV mortality, the relative risk
reductions were quite consistent in the two studies, and the nominal p-value
was less than 0.05 in Study SH-AHS-0006.
The nominal p-value was bigger than 0.05 in Study SH-AHS-003 for CV
deaths, the reason might be that the number of events was much smaller in this
study. When the two studies were
combined, the relative risk reduction in CV mortality was 16% with a nominal
p-value = 0.005.
Six interim analyses were conducted on all-cause mortality
and it is not clear how these analyses would affect the Type I error rate for
the primary endpoint of each individual study (time to CV death or CHF
hospitalization). However, since the allocated
Type I error rates were very small for the interim analyses, the effect should
be small if any.
In the subgroup analysis of time to CV death or CHF
hospitalization, the hazard ratio was 3.73 with a nominal p-value = 0.026 in
the oriental subgroup of Study SH-AHS-0007, and the hazard ratios were bigger
than 1 in the other two studies in the oriental subgroup. The hazard ratio was 2.14 with a nominal
p-value = 0.012 in the oriental subgroup when the three studies were combined (Table
17). Since the sample size was small (n
= 133 for three studies combined), further study would be needed for efficacy
in this subgroup.
Candesartan is indicated for the treatment of hypertension
and it is available for oral use as tablets containing either 4 mg, 8 mg, 16
mg, or 32 mg of Candesartan cilexetil. In
this efficacy supplement application, the Sponsor is seeking indications that Candesartan
reduces the combined endpoint of CV mortality or hospitalization for the
management of chronic heart failure. Results
from the CHARM program are submitted in this application. CHARM was an international (26 countries
including the US)
program comprised of 3 independent concurrent double-blind, placebo-controlled
trials (SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007) in which a total of 7601
patients (7599 with data) with NYHA class II-IV heart failure. The patients in Study SH-AHS-0003
(CHARM-Alternative) were ACE inhibitor intolerant with depressed LV
systolic function and EF <= 40%. Study
SH-AHS-0006 (CHARM-Added) studied the patients with depressed LV
systolic function and EF <= 40% treated with an ACE inhibitor. Study SH-AHS-0007 (CHARM-Preserved) enrolled
patients with heart failure and preserved LV
systolic function and EF > 40%.
The Sponsor was seeking priority review for all 3 pivotal
studies. After negotiation with the
Sponsor, the Division granted the priority review status for the review of
Study SH-AHS-0006. The other two studies
are under standard review. The priority
review is completed.
Studies
SH-AHS-0003 and SH-AHS-0007 were fully reviewed. Study SH-AHS-0003 enrolled patients with
depressed LV systolic function (EF <=
40%) and intolerance to ACE inhibitors. It
is also called CHARM-alternative trial. Study SH-AHS-0007 enrolled patients with
preserved LV systolic function (EF
> 40%) treated or not treated with an ACE inhibitor. It is called CHARM-preserved trial.
The primary endpoint for each
of the three studies is the composite of CV mortality and CV hospitalization
for the management of CHF, and each study is intended for the indication that Candesartan
reduces the risk of the composite endpoint when compared with placebo for its
patient population. The data from the
two studies, together with Study SH-AHS-0006 in the CHARM program, are also
used for the indication that Candesartan reduces the risk of all-cause
mortality for the pooled patient population.
Six interim analyses were conducted on all-cause mortality at intervals
of approximately 6 months over a total of recruitment and follow-up period of around
48 months. In order to stop for
efficacy, one required a p-value < 0.0001 for any interim analysis within 18
months, or a p-value < 0.001 for any subsequent interim analysis.
The hypothesis for the
primary endpoint is tested at alpha = 0.05 in each study, and the analysis for
all-cause mortality is also performed at alpha = 0.05 level based on the pooled
data. This is a typical situation for a
clinical program consisting of several independent studies, each study has a
primary endpoint for an indication and the primary endpoint is tested at alpha
= 0.05. There is another primary
endpoint for the data combining all the studies, and this primary endpoint is different
from the primary endpoint in each study, and it is tested at alpha = 0.05 as
well. Strictly speaking, the total alpha
is not controlled for the whole program.
The data from each study are used twice for the primary analysis, once
for the analysis of the primary endpoint in each individual study and once for
the analysis of the primary endpoint of the studies combined. It is a complicated issue how to control the
total alpha for the whole program.
Since six interim analyses
were conducted, some adjustment of the p-value should be made for the all-cause
mortality for the pooled data of the 3 studies.
After adjusting for the interim analyses, the Type I error rate for the
final analysis of all-cause mortality is 0.0492. It is not clear how the interim analyses
would affect the alpha level for the analysis of the primary endpoint for each
individual study, since the interim analyses were conducted on all-cause
mortality which was not the primary endpoint for each individual study. However, the effect should be small since the
alpha error rates allocated for the interim analyses were very small.
This application was submitted electronically. All the materials are located at \\Cdsesub1\n20838\S_022\2004-06-30. The final reports for the three studies and
the summary of clinical efficacy for all the 3 studies were fully
reviewed. They are located at \\Cdsesub1\n20838\S_022\2004-06-30\clinstat\indication\controlled. The main analyses were independently
performed by this reviewer. SAS data
sets are located at \\Cdsesub1\n20838\S_022\2004-06-30\crt\datasets
.
The three studies
(SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007) were randomized, double-blind,
placebo controlled, parallel group, multicenter studies to evaluate the
influence of Candesartan with a target dose of 32 mg once daily on mortality
and morbidity in patients with symptomatic CHF corresponding to NYHA class
II-IV. The patient population was male
and female patients, over or equal to 18 years of age. Study SH-AHS-0003 enrolled patients with
depressed LV systolic function and EF <= 40% and an intolerance to ACE
inhibitors, Study SH-AHS-0006 enrolled patients with depressed LV systolic
function and EF <= 40% and treated with ACE inhibitors, and Study SH-AHS-007
had patients with preserved LV systolic function and EF > 40%. The patients were randomized in a 1-1 ratio
into one of the two treatment groups in each study. In Study SH-AHS-0003, a total of 2028
patients were randomized with n = 1013 in the Candesartan group and n = 1015 in
the placebo group. Study SH-AHS-006
randomized 2548 patients with n = 1276 in the Candesartan group and n = 1272 in
the placebo group. Study SH-AHS-0007 had
3023 patients with n = 1514 in the Candesartan group and n = 1509 in the
placebo group. All patients remained in
the study until the last randomized patient had been in the CHARM program for
two years. For Study SH-AHS-0003, the
patients were followed from 25 to 48 months, with a median follow-up time of 34
months. The study was conducted in 25
countries at a total of 484 sites, including 131 sites in the United States. For
Study SH-AHS-0006, the patients were followed from 41 to 48 months, with a
median follow-up time of 41 months. The
study was conducted in 25 countries at a total of 473 sites, including 123
sites in the United States. In
Study SH-AHS-0007, the patients were followed from 32 to 48 months, with a
median follow-up time of 37 months. The
study was conducted in 26 countries at a total of 514 sites, including 143
sites in the United States. The
first patient was randomized on March 22, 1999 and the last patient was completed on March
31, 2003 for each of
the three studies.
For each study, the
primary endpoint was time to the first CV death or hospitalization due to
symptomatic chronic heart failure. Secondary
endpoints were time to the first all-cause mortality or hospitalization due to
chronic heart failure, time to the first CV death or hospitalization due to chronic
heart failure or nonfatal MI.
For the combined
studies, the primary endpoint was time to all-cause mortality for the three
studies combined. The secondary endpoint
was the time to all-cause mortality for the combined studies of SH-AHS-0003 and
SH-AHS-0006.
Tables 1, 2, 3 and 4
are the summaries of the patient participation, demographic and baseline
characteristics for Studies of SH-AHS-0003, SH-AHS-0006, SH-AHS-0007 and three
studies combined, respectively. Almost
everybody completed the study in each group of the studies. The demographic and baseline characteristics
seem to be comparable between the two treatment groups for the variables listed
in the tables in each of the three studies.
Table 1. Patient Participation, Demographic
and Baseline Characteristics (SH-AHS-0003)
|
|
Placebo
N = 1015
|
Cand. Cil.
N = 1013
|
Total
N = 2028
|
|
Disposition N (%)
|
|
|
|
|
Completed
|
1014 (99.9)
|
1011 (99.8)
|
2025 (99.9)
|
|
Lost to Follow-up
|
1 (0.1)
|
2 (0.2)
|
3 (0.1)
|
|
Demographic Characteristics
|
|
|
|
|
Sex N (%)
|
|
|
|
|
Male
|
691 (68.1)
|
691 (68.2)
|
1382 (68.1)
|
|
Female
|
324 (31.9)
|
322 (31.8)
|
646 (31.9)
|
|
Age Mean (SD)
Years
|
66.8 (10.5)
|
66.3 (11.0)
|
66.6 (10.7)
|
|
Ethnicity N
(%)
|
|
|
|
|
European Origin
|
901 (88.8)
|
895 (88.4)
|
1796 (88.6)
|
|
Black
|
45 (4.4)
|
28 (2.8)
|
73 (3.6)
|
|
South Asia
|
15 (1.5)
|
22 (2.2)
|
37 (1.8)
|
|
Arab/Middle East
|
6
(0.6)
|
9 (0.9)
|
15 (0.7)
|
|
Oriental
|
27
(2.7)
|
29 (2.9)
|
56 (2.8)
|
|
Malay
|
10 (1.0)
|
14 (1.4)
|
24 (1.2)
|
|
Other
|
11 (1.1)
|
16 (1.6)
|
27 (1.3)
|
|
Baseline Characteristics
|
|
|
|
|
Ejection Fraction, Mean (SD)
|
0.30 (0.07)
|
0.30 (0.08)
|
0.30 (0.07)
|
|
Diabetes Mellitus, N (%)
|
270
(26.6)
|
278
(27.4)
|
548
(27.0)
|
|
Hypertension, N (%)
|
515
(50.7)
|
500
(49.4)
|
1015 (50.0)
|
|
Atrial Fibrillation, N
(%)
|
261 (25.7)
|
254 (25.1)
|
515 (25.4)
|
|
Previous MI, N (%)
|
618 (60.9)
|
629 (62.1)
|
1247 (61.5)
|
|
Angina Pectoris, N (%)
|
592 (58.3)
|
593 (58.5)
|
1185 (58.4)
|
|
Stroke, N (%)
|
90 (8.9)
|
85 (8.4)
|
175 (8.6)
|
|
NYHA II, N (%)
|
479 (47.2)
|
487 (48.1)
|
966 (47.6)
|
|
NYHA III, N (%)
|
499 (49.2)
|
490 (48.4)
|
989 (48.8)
|
|
NYHA IV, N (%)
|
37 (3.6)
|
36 (3.6)
|
73 (3.6)
|
|
Current Smoker, N (%)
|
127 (12.5)
|
149 (14.7)
|
276 (13.8)
|
Source: Table S1 of the clinical study report of Study
SH-AHS-0003 by AstraZeneca.
Table 2. Patient Participation, Demographic
and Baseline Characteristics (SH-AHS-0006)
|
|
Placebo
N = 1272
|
Cand. Cil.
N = 1276
|
Total
N = 2548
|
|
Disposition N (%)
|
|
|
|
|
Completed
|
1271 (99.9)
|
1273 (99.8)
|
2544 (99.8)
|
|
Lost to Follow-up
|
1 (0.1)
|
3 (0.2)
|
4 (0.2)
|
|
Demographic Characteristics
|
|
|
|
|
Sex N (%)
|
|
|
|
|
Male
|
1000 (78.6)
|
1006 (78.8)
|
2006 (78.7)
|
|
Female
|
272 (21.4)
|
270 (21.2)
|
542 (21.3)
|
|
Age Mean (SD)
Years
|
64.1 (11.3)
|
64.0 (10.7)
|
64.1 (11.0)
|
|
Ethnicity N
(%)
|
|
|
|
|
European Origin
|
1164 (91.5)
|
1143 (89.6)
|
2307 (90.5)
|
|
Black
|
62 (4.9)
|
65 (5.1)
|
127 (5.0)
|
|
South Asia
|
8 (0.6)
|
19 (1.5)
|
27 (1.1)
|
|
Arab/Middle East
|
4 (0.3)
|
8 (0.6)
|
12 (0.5)
|
|
Oriental
|
13 (1.0)
|
22 (1.7)
|
35 (1.4)
|
|
Malay
|
7 (0.6)
|
11 (0.9)
|
18 (0.7)
|
|
Other
|
14 (1.1)
|
8 (0.6)
|
22 (0.9)
|
|
Baseline Characteristics
|
|
|
|
|
Ejection Fraction, Mean (SD)
|
0.28 (0.07)
|
0.28 (0.08)
|
0.28 (0.07)
|
|
Diabetes Mellitus, N (%)
|
382 (30.0)
|
376 (29.5)
|
758 (29.7)
|
|
Hypertension, N (%)
|
619 (48.7)
|
609 (47.7)
|
1228 (48.2)
|
|
Atrial Fibrillation, N (%)
|
341 (26.8)
|
346 (27.1)
|
687 (27.0)
|
|
Previous MI, N (%)
|
703 (55.3)
|
714 (56.0)
|
1417 (55.6)
|
|
Angina Pectoris, N (%)
|
684 (53.8)
|
666 (52.2)
|
1350 (53.0)
|
|
Stroke, N (%)
|
112 (8.8)
|
108 (8.5)
|
220 (8.6)
|
|
NYHA II, N (%)
|
302 (23.7)
|
312 (24.5)
|
614 (24.1)
|
|
NYHA III, N (%)
|
925 (72.7)
|
931 (73.0)
|
1856 (72.8)
|
|
NYHA IV, N (%)
|
45 (3.5)
|
33 (2.6)
|
78 (3.1)
|
|
Current Smoker, N (%)
|
235 (18.5)
|
194 (15.2)
|
429 (16.8)
|
Source: Table S1 of the clinical study report of Study
SH-AHS-0006 by AstraZeneca.
Table 3. Patient Participation, Demographic
and Baseline Characteristics (SH-AHS-0007)
|
|
Placebo
N = 1509
|
Cand. Cil.
N = 1514
|
Total
N = 3023
|
|
Disposition N (%)
|
|
|
|
|
Completed
|
1508 (99.9)
|
1512 (99.9)
|
3020 (99.9)
|
|
Lost to Follow-up
|
1 (0.01)
|
2 (0.01)
|
3 (0.01)
|
|
Demographic Characteristics
|
|
|
|
|
Sex N (%)
|
|
|
|
|
Male
|
891 (59.0)
|
920 (60.8)
|
1811 (59.9)
|
|
Female
|
618 (41.0)
|
594 (39.2)
|
1212 (40.1)
|
|
Age Mean (SD)
Years
|
67.1 (11.1)
|
67.2 (11.1)
|
67.2 (11.1)
|
|
Ethnicity N
(%)
|
|
|
|
|
European Origin
|
1393 (92.3)
|
1374 (90.8)
|
2767 (91.5)
|
|
Black
|
57 (3.8)
|
69 (4.7)
|
126 (4.2)
|
|
South Asia
|
11 (0.7)
|
18 (1.2)
|
29 (1.0)
|
|
Arab/Middle East
|
5 (0.3)
|
5 (0.3)
|
10 (0.3)
|
|
Oriental
|
22 (1.5)
|
20 (1.3)
|
42 (1.4)
|
|
Malay
|
8 (0.5)
|
14 (0.9)
|
22 (0.7)
|
|
Other
|
13 (0.9)
|
14 (0.9)
|
27 (0.9)
|
|
Baseline Characteristics
|
|
|
|
|
Ejection Fraction, Mean (SD)
|
0.54 (0.09)
|
0.54 (0.09)
|
0.54 (0.09)
|
|
Diabetes Mellitus, N (%)
|
423 (28.0)
|
434 (28.7)
|
857 (28.4)
|
|
Hypertension, N (%)
|
959 (63.6)
|
984 (65.0)
|
1943 (64.3)
|
|
Atrial Fibrillation, N (%)
|
442 (29.3)
|
439 (29.0)
|
881 (29.1)
|
|
Previous MI, N (%)
|
659 (43.7)
|
681 (45.0)
|
1340 (44.3)
|
|
Angina Pectoris, N (%)
|
902 (59.8)
|
915 (60.4)
|
1817 (60.1)
|
|
Stroke, N (%)
|
128 (8.5)
|
140 (9.2)
|
268 (8.9)
|
|
NYHA II, N (%)
|
905 (60.0)
|
931 (61.5)
|
1836 (60.7)
|
|
NYHA III, N (%)
|
584 (38.7)
|
556 (36.7)
|
1140 (37.7)
|
|
NYHA IV, N (%)
|
20 (1.3)
|
27 (1.8)
|
47 (1.6)
|
|
Current Smoker, N (%)
|
187 (12.4)
|
222 (14.7)
|
409 (13.5)
|
Source: Table S1 of the clinical study report of Study
SH-AHS-0007 by AstraZeneca.
Table 4. Patient Participation, Demographic
and Baseline Characteristics (Pooled)
|
|
Placebo
N = 3796
|
Cand. Cil.
N = 3803
|
Total
N = 7599
|
|
Disposition N (%)
|
|
|
|
|
Completed
|
3793 (99.9)
|
3796 (99.8)
|
7589 (99.8)
|
|
Lost to Follow-up
|
3 (0.01)
|
7 (0.02)
|
10 (0.02)
|
|
Demographic Characteristics
|
|
|
|
|
Sex N (%)
|
|
|
|
|
Male
|
2582 (68.0)
|
2617 (68.8)
|
5199 (68.4)
|
|
Female
|
1214 (32.0)
|
1186 (31.2)
|
2400 (31.6)
|
|
Age Mean (SD)
Years
|
66.0 (11.1)
|
65.9 (11.0)
|
66.0 (11.0)
|
|
Ethnicity N
(%)
|
|
|
|
|
European Origin
|
3458 (91.1)
|
3412 (89.7)
|
6870 (90.4)
|
|
Black
|
164 (4.3)
|
162 (4.3)
|
326 (4.3)
|
|
South Asia
|
34 (0.9)
|
59 (1.6)
|
93 (1.2)
|
|
Arab/Middle East
|
15 (0.4)
|
22 (0.6)
|
37 (0.5)
|
|
Oriental
|
62 (1.6)
|
71 (1.9)
|
133 (1.8)
|
|
Malay
|
25 (0.7)
|
39 (1.0)
|
64 (0.8)
|
|
Other
|
38 (1.0)
|
38 (1.0)
|
76 (1.0)
|
|
Baseline Characteristics
|
|
|
|
|
Ejection Fraction, Mean (SD)
|
0.39 (0.15)
|
0.39 (0.15)
|
0.39 (0.15)
|
|
Diabetes Mellitus, N (%)
|
1075 (28.3)
|
1088 (28.6)
|
2163 (28.5)
|
|
Hypertension, N (%)
|
2093 (55.1)
|
2093 (55.0)
|
4186 (55.1)
|
|
Atrial Fibrillation, N
(%)
|
1044 (27.5)
|
1039 (27.3)
|
2083 (27.4)
|
|
Previous MI, N (%)
|
1980 (52.2)
|
2024 (53.2)
|
4004 (52.7)
|
|
Angina Pectoris, N (%)
|
2178 (57.4)
|
2174 (57.2)
|
4352 (57.3)
|
|
Stroke, N (%)
|
330 (8.7)
|
333 (8.8)
|
663 (8.7)
|
|
NYHA II, N (%)
|
1686 (44.4)
|
1730 (45.5)
|
3416 (45.0)
|
|
NYHA III, N (%)
|
2008 (52.9)
|
1977 (52.0)
|
3985 (52.4)
|
|
NYHA IV, N (%)
|
102 (2.7)
|
96 (2.5)
|
198 (2.6)
|
|
Current Smoker, N (%)
|
549 (14.5)
|
565 (14.9)
|
1114 (14.7)
|
Source: Table S1 of the clinical study report of pooled
clinical study report by AstraZeneca.
For each individual
study, the primary endpoint, time to the first CV death or hospitalization due
to symptomatic chronic heart failure, was compared between the two treatment
groups using the log-rank test. The
hazard ratio and its 95% CI were obtained by a Cox proportional hazards
model. The survival distribution by
treatment group was plotted using the Kaplan-Meier product limit
estimator. The analyses were conducted
on the ITT population, which included all the
randomized patients. The two secondary
endpoints were analyzed similarly as the primary endpoint. The primary and two secondary endpoints were
analyzed based on the principle of closed tests. The analyses were conducted in a hierarchical
sequence. The primary endpoint was
tested first and the two secondary endpoints were tested sequentially,
conditional on a significant result of the preceding test. Changes in the NYHA classification were
tested using a Wilcoxon rank-sum test.
For continuous variables, the mean change from baseline to last observed
value was tested in an ANCOVA model.
The analysis of the combined studies is similar to the analysis
of each of the three studies. The
primary endpoint was tested first and the secondary endpoint was tested
conditional on the significant result of the primary test for the combined
studies.
Six interim analyses were conducted on all-cause mortality at
intervals of approximately 6 months over a total of recruitment and follow-up
period of around 48 months for each individual study and the combined data of
the three studies. In order to stop for
efficacy, one required a p-value < 0.0001 for any interim analysis within 18
months, or a p-value < 0.001 for any subsequent interim analysis. The hypothesis for the test of the primary
endpoint is tested at alpha = 0.05 in each study, and the analysis for
all-cause mortality is also performed at alpha = 0.05 level based on the pooled
data of the three studies. After
adjusting for the interim analyses, the Type I error rate for the final
analysis of all-cause mortality is 0.0492.
No adjustment was made for the final analysis of the primary endpoint in
each individual study.
Tables 5, 6 and 7 present
the results for the analysis of the primary endpoint and two secondary
endpoints in each individual study, including the analysis of the components of
the composite endpoints. The primary
endpoint and two secondary endpoints achieved statistical significance in
Studies SH-AHS-0003 and SH-AHS-0006 based on the pre-specified hierarchical test
sequence. For the primary endpoint, time
to the first CV death or CHF hospitalization, Candesartan had relative risk
reductions of 23% and 15% over placebo, with p-values < 0.001 and 0.011 for
Studies SH-AHS-0003 and SH-AHS-0006, respectively. In these two studies, Candesartan also significantly
reduced the risk of the two secondary endpoints. In Study SH-AHS-0003, the relative risk
reduction was 20% (P = 0.001) for all-cause death or CHF hospitalization and
22% (P < 0.001) for CV death or CHF hospitalization or nonfatal MI. In Study SH-AHS-0006, the relative risk
reduction was 13% (P = 0.021) for all-cause death or CHF hospitalization and 15%
(P = 0.010) for CV death or CHF hospitalization or nonfatal MI. The primary endpoint and the two secondary
endpoints did not achieve statistical significance in Study SH-AHS-0007. In this study, the relative risk reduction
was 11% for the time to the first CV death or CHF hospitalization, with a
p-value = 0.12. The nominal p-values
were more than 0.12 for both secondary endpoints as well.
Table 8 presents the
results for the analysis of the primary endpoint and secondary endpoint of the
combined studies. The primary endpoint
for the combined studies, the time to all-cause mortality combining the data
from the three studies, did not achieve statistical significance with a p-value
= 0.055 and 9% relative risk reduction.
This p-value should be compared with 0.0492 after adjusting for the
interim analyses. The secondary
endpoint, the time to all-cause mortality combining the data from Studies
SH-AHS-0003 and SH-AHS-0006, had a relative risk reduction of 12% with a
nominal p-value = 0.018. Based on the
pre-specified hierarchical test sequence, statistical significance can not be
declared for the secondary endpoint since the primary endpoint did not achieve
statistical significance. However, it
can still be argued that Candesartan significantly reduced the risk of CV mortality
in Studies SH-AHS-0003 and SH-AHS-0006. In
each of the two studies (SH-AHS-0003 and SH-AHS-0006), it had a clear trend in
favor of Candesartan with relative risk reductions of 15% (P = 0.072) and 16%
(P = 0.029) in CV mortality, respectively.
The relative risk reductions were very consistent in the two studies,
and the nominal p-value was 0.029 in Study SH-AHS-006. The nominal p-value was bigger than 0.05 in
Study SH-AHS-003, the reason might be that there was not enough power to detect
the difference since there was smaller number of events in that study. No effects were observed for non-CV deaths in
the two studies, with relative risks of 1.01 (P = 0.95) and 1.11 (P = 0.53) for
Studies SH-AHS-0003 and SH-AHS-0006, respectively. When the two studies (Study SH-AHS-0003 and
Study SH-AHS-0006) were combined, the relative risk reduction for CV mortality
was 16% with a nominal p-value = 0.005. In
Study SH-AHS-0007, it seemed that the drug had no effect on either CV deaths or
non-CV deaths, with relative risks of 0.99 (P = 0.92) and 1.10 (P = 0.59) for
CV deaths and non-CV deaths, respectively.
Therefore, in my view, Candesartan may have a benefit of reducing the
risk of CV mortality in the patient populations of Studies SH-AHS-0003 and
SH-AHS-0006, but not in the patient population of Study SH-AHS-0007.
Table 5. Analysis of the Primary and Secondary
Endpoints (SH-AHS-0003)
|
Endpoint
|
Patients with event
|
Hazard
Ratio (95%CI)
|
P-value
|
|
Candesartan
N = 1013
|
Placebo
N = 1015
|
|
Primary
CV death or CHF hospitalization
|
334
|
406
|
0.77
(0.67–0.89)
|
<0.001
|
|
Secondary
All-cause death or CHF hospitalization
|
371
|
433
|
0.80 (0.70-0.92)
|
0.001
|
|
CV death or CHF hospitalization or
non-fatal MI
|
353
|
420
|
0.78
(0.68-0.90)
|
<0.001
|
|
Components
of the composite endpoints
CV death
|
219
|
252
|
0.85
(0.71-1.02)
|
0.072
|
|
CHF hospitalization
|
207
|
286
|
0.68
(0.57-0.81)
|
<0.001
|
|
All-cause mortality
|
265
|
296
|
0.87
(0.74-1.03)
|
0.104
|
|
Nonfatal MI
|
41
|
36
|
1.11
(0.71-1.73)
|
0.66
|
Source: Table
8 of the Sponsor’s summary of clinical efficacy. The results were confirmed independently by
this reviewer, with minor difference for nonfatal MI. Nominal P-values were from log-rank test and
hazard ratios were from Cox regression model with treatment as the only
independent variable.
Table 6. Analysis of the Primary and Secondary
Endpoints (SH-AHS-0006)
|
Endpoint
|
Patients with event
|
Hazard
Ratio (95%CI)
|
P-value
|
|
Candesartan
N = 1276
|
Placebo
N = 1272
|
|
Primary
CV death or CHF hospitalization
|
483
|
538
|
0.85
(0.75–0.96)
|
0.011
|
|
Secondary
All-cause death or CHF hospitalization
|
539
|
587
|
0.87 (0.78-0.98)
|
0.021
|
|
CV death or CHF hospitalization or
non-fatal MI
|
495
|
550
|
0.85
(0.76-0.96)
|
0.010
|
|
Components
of the composite endpoints
CV death
|
302
|
347
|
0.84
(0.72-0.98)
|
0.029
|
|
CHF hospitalization
|
309
|
356
|
0.83 (0.71-0.96)
|
0.013
|
|
All-cause mortality
|
377
|
412
|
0.89
(0.77-1.02)
|
0.086
|
|
Nonfatal MI
|
26
|
49
|
0.51
(0.32-0.82)
|
0.005
|
Source: Table 8
of the Sponsor’s summary of clinical efficacy.
The results were confirmed independently by this reviewer, with minor
difference for nonfatal MI. Nominal P-values
were from log-rank test and hazard ratios were from Cox regression model with
treatment as the only independent variable.
Table 7. Analysis of the Primary and Secondary
Endpoints (SH-AHS-0007)
|
Endpoint
|
Patients with event
|
Hazard
Ratio (95%CI)
|
P-value
|
|
Candesartan
N = 1514
|
Placebo
N = 1509
|
|
Primary
CV death or CHF hospitalization
|
333
|
366
|
0.89 (0.77–1.03)
|
0.12
|
|
Secondary
All-cause death or CHF hospitalization
|
386
|
411
|
0.92
(0.80-1.05)
|
0.22
|
|
CV death or CHF hospitalization or
non-fatal MI
|
365
|
399
|
0.90
(0.78-1.03)
|
0.13
|
|
Components
of the composite endpoints
CV death
|
170
|
170
|
0.99
(0.80-1.22)
|
0.92
|
|
CHF hospitalization
|
241
|
276
|
0.85 (0.72-1.01)
|
0.07
|
|
All-cause mortality
|
244
|
237
|
1.02
(0.85-1.22)
|
0.84
|
|
Nonfatal MI
|
49
|
63
|
0.77
(0.53-1.12)
|
0.17
|
Source: Table
8 of the Sponsor’s summary of clinical efficacy. The results were confirmed independently by
this reviewer, with minor difference for nonfatal MI. Nominal P-values were from log-rank test and
hazard ratios were from Cox regression model with treatment as the only
independent variable.
Table 8. Analysis of the Primary and Secondary
Endpoints (Pooled)
|
Endpoint
|
Number of Patients
|
Hazard
Ratio (95%CI)
|
P-value
|
|
Candesartan
n (N)
|
Placebo
n (N)
|
|
Primary
All-cause death (SH-AHS-0003, -0006, -0007)
|
886 (3803)
|
945 (3796)
|
0.91 (0.83-1.00)
|
0.055
|
|
Secondary
All-cause death (SH-AHS-0003, -0006)
|
642 (2289)
|
708 (2287)
|
0.88 (0.79-0.98)
|
0.018
|
|
Components
|
|
|
|
|
|
CV death (SH-AHS-0003, -0006, -0007)
Non-CV death (SH-AHS-0003, -0006, -0007)
|
691 (3803)
195 (3803)
|
769 (3796)
176 (3796)
|
0.88
(0.79-0.97)
1.08 (0.88-1.33)
|
0.012*
0.452*
|
|
CV death (SH-AHS-0003, -0006)
Non-CV death (SH-AHS-0003, -0006)
|
521 (2289)
121 (2289)
|
599 (2287)
109 (2287)
|
0.84
(0.75-0.95)
1.07
(0.83-1.39)
|
0.005*
0.595*
|
|
CV death (SH-AHS-0003)
Non-CV death (SH-AHS-0003)
|
219 (1013)
46 (1013)
|
252 (1015)
44 (1015)
|
0.85
(0.71-1.02)
1.01
(0.67-1.53)
|
0.072*
0.948*
|
|
CV death (SH-AHS-0006)
Non-CV death (SH-AHS-0006)
|
302 (1276)
75 (1276)
|
347 (1272)
65 (1272)
|
0.84
(0.72-0.98)
1.11
(0.80-1.55)
|
0.029*
0.529*
|
|
CV death (SH-AHS-0007)
Non-CV death (SH-AHS-0007)
|
170 (1514)
74 (1514)
|
170 (1509)
67 (1509)
|
0.99
(0.80-1.22)
1.10
(0.79-1.52)
|
0.918*
0.589
|
Source: Tables
S2, 28, 30 of the Sponsor’s pooled clinical study report, Table 55 of the
Sponsor’s clinical study report of SH-AHS-0003, Table 54 of the Sponsor’s
clinical study report of SH-AHS-0006, and Table 88 of the Sponsor’s clinical
study report of SH-AHS-0007. The results
were confirmed independently by this reviewer.
Nominal P-values were from log-rank test and hazard ratios were from Cox
regression model with treatment as the only independent variable. * Nominal P-values were from Cox regression
model with treatment as the only independent variable.
Figures 1, 2 and 3 are
the Kaplan-Meier estimates for time to the first CV death or CHF
hospitalization for Studies SH-AHS-0003, SH-AHS-0006 and SH-AHS-0007,
respectively. Figures 4 and 5 are the
Kaplan-Meier estimates for time to all-cause mortality for three studies
combined and two studies combined (SH-AHS-0003 and SH-AHS-0006), respectively. Figures
6 and 7 are the Kaplan-Meier estimates for CV and non-CV mortality when the two
studies are combined (SH-AHS-0003 and SH-AHS-0006), respectively.
Figure 1. Survival Estimate of Time to 1st
CV Death or CHF Hospitalization (SH-AHS-0003)
Source:
Reviewer’s analysis.
Figure 2. Survival Estimate of Time to 1st
CV Death or CHF Hospitalization (SH-AHS-0006)
Source: Reviewer’s analysis.
Figure 3. Survival Estimate of Time to 1st
CV Death or CHF Hospitalization (SH-AHS-0007)
Source: Reviewer’s Analysis.
Figure 4. Survival Estimate of Time to All
Cause Death (Three Studies Combined)
Source: Reviewer’s Analysis.
Figure 5. Survival Estimate of Time to All
Cause Death (Studies 0003 and 0006 Combined)
Source: Reviewer’s Analysis.
Figure 6. Survival Estimate of Time to CV Death
(Studies 0003 and 0006 Combined)
Source: Reviewer’s Analysis.
Figure 7. Survival Estimate of Time to Non-CV
Death (Studies 0003 and 0006 Combined)
Source: Reviewer’s Analysis.
The most commonly reported adverse events (AE) are in Tables
9, 10, 11, 12 and 13 for Studies SH-AHS-0003, SH-AHS-0006, SH-AHS-0007, three
studies combined and two studies combined (SH-AHS-0003 and SH-AHS-0006),
respectively. The tables use a cut-off
of 3% AEs in the total population during the study. It seemed that most of reported AEs are comparable
among the two treatment groups. Among
the AEs that occurred more in the Candesartan group during the study,
Hypotension, Renal function abnormal/renal dysfunction aggravated occurred more
in Candesartan group than Placebo group in each of the three studies, and Hyperkalaemia
occurred more in Candesartan group than Placebo group in Studies SH-AHS-0003
and SH-AHS-0006.
Table 9. Most
Commonly Reported AEs (SH-AHS-0003)
|
Preferred Term
|
Placebo
on treatment
(N = 1015)
n %
|
Candesartan
on treatment
(N = 1013)
n %
|
Placebo
during study
(N = 1015)
n %
|
Candesartan
during study
(N = 1013)
n %
|
|
Cardiac failure/cardiac failure aggravated
|
317 (31.2)
|
234 (23.1)
|
359 (35.4)
|
280 (27.6)
|
|
Hypotension
|
76 (7.5)
|
190 (18.8)
|
90 (8.9)
|
193 (19.1)
|
|
Angina pectoris/angina pectoris aggravated
|
110 (10.8)
|
105 (10.4)
|
120 (11.8)
|
127 (12.5)
|
|
Renal function abnormal/renal
dysfunction aggravated
|
49 (4.8)
|
136 (13.4)
|
50 (4.9)
|
141 (13.9)
|
|
Sudden death
|
85 (8.4)
|
65 (6.4)
|
106 (10.4)
|
80 (7.9)
|
|
Pneumonia
|
64 (6.3)
|
65 (6.4)
|
75 (7.4)
|
83 (8.2)
|
|
Myocardial infarction
|
58 (5.7)
|
71 (7.0)
|
68 (6.7)
|
85 (8.4)
|
|
Arrhythmia ventricular
|
64 (6.3)
|
58 (5.7)
|
79 (7.8)
|
73 (7.2)
|
|
Cerebrovascular disorder
|
55 (5.4)
|
41 (4.0)
|
61 (6.0)
|
52 (5.1)
|
|
Arrhythmia atrial
|
41 (4.0)
|
44 (4.3)
|
44 (4.3)
|
56 (5.5)
|
|
Fibrillation atrial
|
46 (4.5)
|
34 (3.4)
|
57 (5.6)
|
43 (4.2)
|
|
Chest pain
|
42 (4.1)
|
37 (3.7)
|
50 (4.9)
|
47 (4.6)
|
|
Coronary artery disorder
|
39 (3.8)
|
38 (3.8)
|
48 (4.7)
|
49 (4.8)
|
|
Tachycardia ventricular/arrhythmia
|
31 (3.1)
|
28 (2.8)
|
44 (4.3)
|
39 (3.8)
|
|
Cardiomyopathy
|
29 (2.9)
|
25 (2.5)
|
40 (3.9)
|
37 (3.7)
|
|
Tachycardia supraventricular
|
30 (3.0)
|
27 (2.7)
|
39 (3.8)
|
34 (3.4)
|
|
Hyperkalaemia
|
16 (1.6)
|
54 (5.3)
|
18 (1.8)
|
54 (5.3)
|
|
Dizziness/vertigo
|
21 (2.1)
|
43 (4.2)
|
23 (2.3)
|
45 (4.4)
|
|
Dyspnoea/dyspnoea
(aggravated)
|
39 (3.8)
|
17 (1.7)
|
43 (4.2)
|
22 (2.2)
|
|
Syncope
|
28 (2.8)
|
26 (2.6)
|
35 (3.4)
|
30 (3.0)
|
Source: Table S4 of the
Sponsor’s clinical study report of study SH-AHS-0003.
On treatment = on treatment
with investigational product; During study = total study period, irrespective
of treatment with investigational product or not.
Table 10. Most
Commonly Reported AEs (SH-AHS-0006)
|
Preferred Term
|
Placebo
on treatment
(N = 1272)
n %
|
Candesartan
on treatment
(N = 1276)
n %
|
Placebo
during study
(N = 1272)
n %
|
Candesartan
during study
(N = 1276)
n %
|
|
Cardiac failure/cardiac failure aggravated
|
435 (34.2)
|
350 (27.4)
|
472 (37.1)
|
421 (33.0)
|
|
Hypotension
|
176 (13.8)
|
288 (22.6)
|
184 (14.5)
|
296 (23.2)
|
|
Angina pectoris/angina pectoris aggravated
|
153 (12.0)
|
127 (10.0)
|
169 (13.3)
|
150 (11.8)
|
|
Sudden death
|
140 (11.0)
|
114 (8.9)
|
174 (13.7)
|
143 (11.2)
|
|
Renal function abnormal/renal
dysfunction aggravated
|
115 (9.0)
|
192 (15.0)
|
119 (9.4)
|
196 (15.4)
|
|
Arrhythmia ventricular
|
107 (8.4)
|
78 (6.1)
|
121 (9.5)
|
88 (6.9)
|
|
Pneumonia
|
88 (6.9)
|
57 (4.5)
|
108 (8.5)
|
76 (6.0)
|
|
Hyperkalaemia
|
44 (3.5)
|
121 (9.5)
|
46 (3.6)
|
123 (9.6)
|
|
Myocardial infarction
|
73 (5.7)
|
60 (4.7)
|
88 (6.9)
|
70 (5.5)
|
|
Atrial fibrillation
|
69 (5.4)
|
52 (4.1)
|
73 (5.7)
|
66 (5.2)
|
|
Arrhythmia atrial
|
61 (4.8)
|
59 (4.6)
|
71 (5.6)
|
67 (5.3)
|
|
Tachycardia
ventricular/arrhythmia/ arrhythmia aggravated
|
63 (5.0)
|
52 (4.1)
|
68 (5.3)
|
65 (5.1)
|
|
Cerebrovascular disorder
|
48 (3.8)
|
55 (4.3)
|
58 (4.6)
|
69 (5.4)
|
|
Chest pain
|
64 (5.0)
|
45 (3.5)
|
71 (5.6)
|
54 (4.2)
|
|
Coronary artery disorder
|
42 (3.3)
|
58 (4.5)
|
50 (3.9)
|
73 (5.7)
|
|
Syncope
|
45 (3.5)
|
49 (3.8)
|
49 (3.9)
|
59 (4.6)
|
|
Tachycardia supraventricular
|
46 (3.6)
|
47 (3.7)
|
50 (3.9)
|
54 (4.2)
|
|
Cardiomyopathy
|
38 (3.0)
|
33 (2.6)
|
48 (3.8)
|
51 (4.0)
|
|
Dizziness/vertigo
|
35 (2.8)
|
49 (3.8)
|
40 (3.1)
|
57 (4.5)
|
|
Pulmonary oedema
|
41 (3.2)
|
39 (3.1)
|
47 (3.7)
|
48 (3.8)
|
|
Renal failure acute
|
29 (2.3)
|
45 (3.5)
|
38 (3.0)
|
54 (4.2)
|
|
Anaemia
|
36 (2.8)
|
35 (2.7)
|
43 (3.4)
|
46 (3.6)
|
|
Accident and/or injury
|
32 (2.5)
|
34 (2.7)
|
43 (3.4)
|
44 (3.4)
|
|
Diabetes
mellitus/diabetes mellitus aggravated
|
41 (3.2)
|
30 (2.4)
|
42 (3.3)
|
37 (2.9)
|
|
Dehydration
|
18 (1.4)
|
40 (3.1)
|
22 (1.7)
|
55 (4.3)
|
Source: Table S4 of the
Sponsor’s clinical study report of study SH-AHS-0006.
On treatment = on treatment
with investigational product; During study = total study period, irrespective
of treatment with investigational product or not.
Table 11. Most
Commonly Reported AEs (SH-AHS-0007)
|
Preferred Term
|
Placebo
on treatment
(N = 1509)
n %
|
Candesartan
on treatment
(N = 1514)
n %
|
Placebo
during study
(N = 1509)
n %
|
Candesartan
during study
(N = 1514)
n %
|
|
Cardiac failure/cardiac failure aggravated
|
321 (21.3)
|
247 (16.3)
|
356 (23.6)
|
300 (19.8)
|
|
Angina pectoris/angina pectoris aggravated
|
198 (13.1)
|
182 (12.0)
|
217 (14.4)
|
213 (14.1)
|
|
Hypotension
|
120 (8.0)
|
236 (15.6)
|
125 (8.3)
|
247 (16.3)
|
|
Renal function abnormal/renal
dysfunction aggravated
|
74 (4.9)
|
146 (9.6)
|
79 (5.2)
|
150 (9.9)
|
|
Pneumonia
|
91 (6.0)
|
78 (5.2)
|
116 (7.7)
|
102 (6.7)
|
|
Atrial fibrillation
|
103 (6.8)
|
79 (5.2)
|
119 (7.9)
|
93 (6.1)
|
|
Myocardial infarction
|
85 (5.6)
|
74 (4.9)
|
101 (6.7)
|
87 (5.7)
|
|
Coronary artery disorder
|
89 (5.9)
|
73 (4.8)
|
102 (6.8)
|
83 (5.5)
|
|
Cerebrovascular disorder
|
86 (5.7)
|
68 (4.5)
|
97 (6.4)
|
82 (5.4)
|
|
Chest pain
|
71 (4.7)
|
72 (4.8)
|
81 (5.4)
|
82 (5.4)
|
|
Tachycardia supraventricular
|
76 (5.0)
|
55 (3.6)
|
88 (5.8)
|
60 (4.0)
|
|
Arrhythmia atrial
|
73 (4.8)
|
53 (3.5)
|
82 (5.4)
|
64 (4.2)
|
|
Sudden death
|
57 (3.8)
|
55 (3.6)
|
68 (4.5)
|
68 (4.5)
|
|
Accident and/or injury
|
49 (3.2)
|
46 (3.0)
|
63 (4.2)
|
59 (3.9)
|
|
Dizziness/vertigo
|
51 (3.4)
|
62 (4.1)
|
52 (3.4)
|
66 (4.4)
|
|
Anaemia
|
35 (2.3)
|
46 (3.0)
|
47 (3.1)
|
63 (4.2)
|
|
Dyspnoea/dyspnoea
(aggravated)
|
48 (3.2)
|
39 (2.6)
|
51 (3.4)
|
46 (3.0)
|
Source: Table S4 of the
Sponsor’s clinical study report of study SH-AHS-0007.
On treatment = on treatment
with investigational product; During study = total study period, irrespective
of treatment with investigational product or not.
Table 12. Most
Commonly Reported AEs (Three Studies Pooled)
|
Preferred Term
|
Placebo
on treatment
(N = 3796)
n %
|
Candesartan
on treatment
(N = 3803)
n %
|
Placebo
during study
(N = 3796)
n %
|
Candesartan
during study
(N = 3803)
n %
|
|
Cardiac failure/cardiac failure aggravated
|
1073 (28.3)
|
831 (21.9)
|
1187 (31.3)
|
1001 (26.3)
|
|
Hypotension
|
372 (9.8)
|
714 (18.8)
|
399 (10.5)
|
736 (19.4)
|
|
Angina pectoris/angina pectoris aggravated
|
461 (12.1)
|
414 (10.9)
|
506 (13.3)
|
490 (12.9)
|
|
Renal function abnormal/renal
dysfunction aggravated
|
238 (6.3)
|
474 (12.5)
|
248 (6.5)
|
487 (12.8)
|
|
Sudden death
|
282 (7.4)
|
234 (6.2)
|
348 (9.2)
|
291 (7.7)
|
|
Pneumonia
|
243 (6.4)
|
200 (5.3)
|
299 (7.9)
|
261 (6.9)
|
|
Myocardial infarction
|
216 (5.7)
|
205 (5.4)
|
257 (6.8)
|
242 (6.4)
|
|
Atrial fibrillation
|
218 (5.7)
|
165 (4.3)
|
249 (6.6)
|
202 (5.3)
|
|
Arrhythmia ventricular
|
207 (5.5)
|
159 (4.2)
|
239 (6.3)
|
193 (5.1)
|
|
Cerebrovascular disorder
|
189 (5.0)
|
164 (4.3)
|
216 (5.7)
|
203 (5.3)
|
|
Coronary artery disorder
|
170 (4.5)
|
169 (4.4)
|
200 (5.3)
|
205 (5.4)
|
|
Chest pain
|
177 (4.7)
|
154 (4.0)
|
202 (5.3)
|
183 (4.8)
|
|
Arrhythmia atrial
|
175 (4.6)
|
156 (4.1)
|
197 (5.2)
|
187 (4.9)
|
|
Hyperkalaemia
|
78 (2.1)
|
238 (6.3)
|
84 (2.2)
|
242 (6.4)
|
|
Tachycardia supraventricular
|
152 (4.0)
|
129 (3.4)
|
177 (4.7)
|
148 (3.9)
|
|
Dizziness/vertigo
|
107 (2.8)
|
154 (4.0)
|
115 (3.0)
|
168 (4.4)
|
|
Accident and/or injury
|
112 (3.0)
|
99 (2.6)
|
143 (3.8)
|
125 (3.3)
|
|
Tachycardia
ventricular/arrhythmia/ arrhythmia aggravated
|
110 (2.9)
|
100 (2.6)
|
132 (3.5)
|
128 (3.4)
|
|
Syncope
|
105 (2.8)
|
121 (3.2)
|
119 (3.1)
|
139 (3.7)
|
|
Anaemia
|
87 (2.3)
|
110 (2.9)
|
110 (2.9)
|
145 (3.8)
|
Source: Table S4 of the
Sponsor’s clinical study report of pooled data.
On treatment = on treatment
with investigational product; During study = total study period, irrespective
of treatment with investigational product or not.
Table 13. Most
Commonly Reported AEs (Studies SH-AHS-0003 and SH-AHS-0006 Combined)
|
Preferred Term
|
Placebo
on treatment
(N = 2287)
n %
|
Candesartan
on treatment
(N = 2289)
n %
|
Placebo
during study
(N = 2287)
n %
|
Candesartan
during study
(N = 2289)
n %
|
|
Cardiac failure/cardiac failure aggravated
|
752 (32.9)
|
584 (25.5)
|
831 (36.3)
|
701 (30.6)
|
|
Hypotension
|
252 (11.0)
|
478 (20.9)
|
274 (12.0)
|
489 (21.4)
|
|
Angina pectoris/angina pectoris aggravated
|
263 (11.5)
|
232 (10.1)
|
289 (12.6)
|
277 (12.1)
|
|
Renal function abnormal/renal
dysfunction aggravated
|
164 (7.2)
|
328 (14.3)
|
169 (13.7)
|
143 (11.2)
|
|
Sudden death
|
225 (9.8)
|
179 (7.8)
|
280 (12.2)
|
223 (9.7)
|
|
Arrhythmia ventricular
|
171 (7.5)
|
136 (5.9)
|
200 (8.7)
|
161 (7.0)
|
|
Pneumonia
|
152 (6.6)
|
122 (5.3)
|
183 (8.0)
|
159 (6.9)
|
|
Myocardial infarction
|
131 (5.7)
|
131 (5.7)
|
156 (6.8)
|
155 (6.8)
|
|
Hyperkalaemia
|
60 (2.6)
|
175 (7.6)
|
64 (2.8)
|
177 (7.7)
|
|
Cerebrovascular disorder
|
103 (4.5)
|
96 (4.2)
|
119 (5.2)
|
121 (5.3)
|
|
Fibrillation atrial
|
115 (5.0)
|
86 (3.8)
|
130 (5.7)
|
109 (4.8)
|
|
Arrhythmia atrial
|
102 (4.5)
|
103 (4.5)
|
115 (5.0)
|
123 (5.4)
|
|
Chest pain
|
106 (4.6)
|
82 (3.6)
|
121 (5.3)
|
101 (4.4)
|
|
Coronary artery disorder
|
81 (3.5)
|
96 (4.2)
|
98 (4.3)
|
122 (5.3)
|
|
Tachycardia
ventricular/arrhythmia/ arrhythmia aggravated
|
94 (4.1)
|
80 (3.5)
|
112 (4.9)
|
104 (4.5)
|
|
Tachycardia supraventricular
|
76 (3.3)
|
74 (3.2)
|
89 (3.9)
|
88 (3.8)
|
|
Cardiomyopathy
|
67 (2.9)
|
58 (2.5)
|
88 (3.8)
|
88 (3.8)
|
|
Syncope
|
73 (3.2)
|
75 (3.3)
|
84 (3.7)
|
89 (3.9)
|
|
Dizziness/vertigo
|
56 (2.4)
|
92 (4.0)
|
63 (2.8)
|
102 (4.5)
|
|
Pulmonary oedema
|
67 (2.9)
|
59 (2.6)
|
77 (3.4)
|
75 (3.3)
|
|
Accident and/or injury
|
63 (2.8)
|
53 (2.3)
|
80 (3.5)
|
66 (2.9)
|
|
Anaemia
|
52 (2.3)
|
64 (2.8)
|
63 (2.8)
|
82 (3.6)
|
|
Renal failure acute
|
41 (1.8)
|
69 (3.0)
|
57 (2.5)
|
85 (3.7)
|
Source:
Table 146 of the Sponsor’s clinical study report of study SH-AHS-pooled.
On treatment = on treatment
with investigational product; During study = total study period, irrespective
of treatment with investigational product or not.
Subgroup analysis of the primary endpoint was performed by
age, gender and ethnic group. For the
analysis of time to CV death or CHF hospitalization, the results are presented
in Tables 14, 15, 16 and 17 for Studies SH-AHS-0003, SH-AHS-0006, SH-AHS-0007
and three studies combined, respectively. For the analysis of all-cause mortality, the
results are in Tables 18 and 19 for three studies combined and two studies
(SH-AHS-0003 and SH-AHS-0006) combined, respectively.
For the time to CV death or CHF hospitalization, the hazard
ratios were less than 1 (in favor of Candesartan) in all the subgroups except
for the oriental, South Asian, Arab/Middle East subgroups in each of the three
studies, and for blacks in Study SH-AHS-0007.
The sample sizes were small in these subgroups, and the nominal p-values
were larger than 0.05 except for the oriental group in Study SH-AHS-0007. The hazard ratio was 3.73 with a nominal
p-value = 0.026 in the oriental subgroup of Study SH-AHS-0007 (Table 16 and
Figure 8), and the hazard ratios were bigger than 1 in the oriental subgroup in
the other two studies with the nominal p-values larger than 0.05. The hazard ratio was 2.14 with a nominal
p-value = 0.012 in the oriental subgroup when the three studies were combined (Table
17).
For all-cause mortality, the hazard ratios were less than 1
(in favor of Candesartan) in all the subgroups except for the oriental,
Arab/Middle East subgroups in the three studies combined and two studies
combined (SH-AHS-0003 and SH-AHS-0006).
Again, the sample sizes were small in these subgroups and the nominal
p-values were larger than 0.05.
Table 14. Subgroup Analysis of Time to CV
Death or CHF Hospitalization (SH-AHS-0003)
|
Variable
|
Group
|
Total
N
|
Candesartan
# of events
|
Placebo
# of Events
|
Hazard Ratio (95% CI)
|
P-value
|
|
Age(Years)
|
< 65
|
804
|
120
|
116
|
0.973 (0.754, 1.256)
|
0.833
|
|
|
>= 65 -< 75
|
752
|
123
|
165
|
0.711 (0.563, 0.898)
|
0.004
|
|
|
>= 75
|
472
|
91
|
125
|
0.647 (0.494, 0.848)
|
0.002
|
|
Age (Years)
|
< 75
|
1556
|
|
