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†††† EXECUTIVE SUMMARY.. 4

1.1†††† Conclusions and Recommendations. 4

1.2†††† Brief Overview of Clinical Studies. 4

1.3†††† Statistical Issues and Findings. 5

2†††† INTRODUCTION.. 5

2.1†††† Overview... 5

2.1.1†††† History of Drug Development 5

2.1.2†††† Specific Studies Reviewed. 5

2.1.3†††† Major Statistical Issues. 6

2.2†††† Data Sources. 6

3†††† STATISTICAL EVALUATION.. 6

3.1†††† Evaluation of Efficacy.. 6

3.1.1†††† Study Design and Endpoint 6

3.1.2†††† Patient Disposition, Demographic and Baseline Characteristics. 7

3.1.3†††† Statistical Methodologies. 8

3.1.4†††† Results and Conclusion. 8

3.2†††† Evaluation of Safety.. 10

4†††† FINDINGS IN SPECIAL/SUBGROUP POPULATIONS. 13

4.1†††† Age, Gender and Ethnic group. 13

4.2†††† Other Subgroup Populations. 15

5†††† SUMMARY AND CONCLUSIONS. 15

5.1†††† Statistical Issues and Collective Evidence. 15

5.2†††† Conclusions and Recommendations. 16

 


 

List of Tables

 

 

Table 1. Patient Participation, Demographic and Baseline Characteristics. 7

Table 2. Analysis of the Priamry and Secondary Endpoints. 9

Table 3. Some Sugroup Analysis of the Primary Endpoint 10

Table 4. Most Commonly Reported AEs. 11

Table 5. Number of Patients with Most Commonly Reported AEs Leading to Death. 11

Table 6. Number of Patients with Most Commonly Reported SAEs Other Than Death. 12

Table 7. Subgroup Analysis of Time to the First CV Death or CHF hospitalization. 13

Table 8. Subgroup Analysis of Time to the All-cause Death or CHF hospitalization. 13

Table 9. Subgroup Analysis of Time to the CV Death or CHF hospitalization or Nonfatal MI 14

 

 

List of Figures

 

Figure 1. Kaplan-Meier Estimate of Time to 1st CV Death or CHF Hospitalization. 9

Figure 2. Plot ofTesting of the Proportional Hazards Assumption. 10


1       EXECUTIVE SUMMARY

1.1      Conclusions and Recommendations

Candesartan cilexetil (Candesartan) significantly reduced cardiovascular (CV) death or Chronic Heart Failure (CHF) hospitalization in patients with depressed left ventricular (LV) systolic function and ejection fraction (EF) < 40% treated with 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).

1.2      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.

 

 

1.3      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.

 

2       INTRODUCTION

2.1      Overview

 

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

 

2.1.1    History of Drug Development

 

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

 

2.1.2    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.

 

2.1.3    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.

 

2.2      Data Sources

 

This application was submitted electronically.All the materials are located at \\Cdsesub1\n20838\S_022\2004-06-30.The final reports for 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.

 

3       STATISTICAL EVALUATION

3.1      Evaluation of Efficacy

3.1.1    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.

 

3.1.2    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.

 

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

 

 

 

SexN (%)

 

 

 

††††††† Male

1000 (78.6)

1006 (78.8)

2006 (78.7)

††††††† Female

272 (21.4)

270 (21.2)

542 (21.3)

AgeMean (SD) Years

64.1 (11.3)

64.0 (10.7)

64.1 (11.0)

EthnicityN (%)

 

 

 

††††††† 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.

 

3.1.3    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.

 

3.1.4    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.

 

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 (0.75Ė0.96)

 

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 Sponsorís 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: Reviewerís analysis.

 

 

Figure 2. Plot ofTesting of the Proportional Hazards Assumption

Source: Reviewerís 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 Sponsorís 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.

 

3.2      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.

 

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 Sponsorís 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 Sponsorís 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 Sponsorís 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.

 

4       FINDINGS IN SPECIAL/SUBGROUP POPULATIONS

4.1      Age, Gender and Ethnic group

 

Subgroup analysis of the primary endpoint was performed by age, gender and ethnic group.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 Sponsorís 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 Sponsorís 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 Sponsorís 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.

 

4.2      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.

 

5       SUMMARY AND CONCLUSIONS

5.1      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).

5.2      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).†††