Time to First CHF Hospitalization for All Patients V-HeFT I, V-HeFT II

1
Time to First CHF Hospitalization for All
PatientsV-HeFT I, V-HeFT II
DV
V-HeFT I
V-HeFT II
100
100
90
90
Without hospitalization,
80
80
70
ISDN/HYDPlacebo
70
ISDN/HYDEnalapril
60
60
0
365
730
0
365
730
Time, days since randomization
Patients, n ISDN/HYD 186 138 94 401 316 223 Placeb
o 273 173 112 Enalapril 403 321 236
2
Time to First CHF Hospitalization for Black
Patients and White PatientsV-HeFT I
26
DV Final NDA20-727_Brief_Document.pdf F 6
Black patients
White patients
100
100
90
80
80
70
Percent without HF hospitalization
60
60
ISDN/HYDPlacebo
50
40
40
0
365
730
0
365
730
Time, days since randomization
Patients, n ISDN/HYD 49 41 30 132 94 62 Placebo 79
50 36 192 122 76
3
Time to First CHF Hospitalization for Black
Patients and White PatientsV-HeFT II
26
Black patients
White patients
100
90
80
70
Without HF hospitalization,
60
ISDN/HYDEnalapril
50
40
0
365
730
Time, days since randomization
Patients, n ISDN/HYD 109 88 60 282 220 159 Enalapr
il 106 82 60 292 236 175
4
Patients With Unscheduled Emergency Room
VisitsA-HeFT
16
DV A-HeFT CSR T38
Patients, Patients,
Unscheduled visits BiDiln 518 Placebon 532 P value
Any reason 0 73.2 72.4 0.782
1 17.0 16.4
2 5.2 5.5
3 1.9 3.2
4 2.7 2.3
HF 0 96.5 94.4 0.105
1 2.7 4.5
2 0.6 0.4
3 0.2 0.8
Cardiac cause 0 93.8 94.9 0.503
1 5.2 4.5
2 0.6 0.4
3 0.4 0.2
Non-cardiac cause 0 77.4 78.2 0.767
1 15.4 14.5
2 4.4 3.9
3 1.4 1.1
4 1.4 2.3
5
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6
Percent of Patients With QoL Data at Each
VisitA-HeFT
DV A-HeFT final rpt, pub 1.19
BiDil BiDil Placebo Placebo
Timepoint N n () N n ()
Baseline 518 512 (99) 532 528 (99)
Mo 3 438 423 (97) 471 441 (94)
Mo 6 388 369 (95) 382 371 (97)
Mo 9 319 307 (96) 315 305 (97)
Mo 12 278 269 (97) 264 250 (95)
Mo 15 226 226 (100) 218 218 (100)
Mo 18 198 198 (100) 184 184 (100)
7
MLHF Questionnaire-Change in Score at 6 mo and
at Endpoint Using LOCFA-HeFT
A-HeFT final rpt, T16.1
Change in score at 6 mo in all patients Change in score at 6 mo in all patients Change in score at 6 mo in all patients
BiDil Placebo P value
N 369 371 0.0105
Mean 7.1 3.1
SD 20.61 21.27
Change in score at endpoint using LOCF Change in score at endpoint using LOCF Change in score at endpoint using LOCF
N 512 528 0.0030
Mean 7.6 3.4
SD 22.57 22.74
2-sample t test.
8
Sensitivity Analyses Results for Primary
Endpoint A-HeFT
16
DV A-HeFT CSR T27
BiDil Placebo P value
No HF hospitalization imputation 1 No HF hospitalization imputation 1
N 518 532 0.014
Mean SD 0.14 1.91 0.45 2.03
Range 6 to 2 6 to 2
Last known QOL 2
N 518 532 0.005
Mean SD 0.03 1.79 0.36 2.03
Range 6 to 2 6 to 2
Patients randomized on or prior to April 19, 2004 3 Patients randomized on or prior to April 19, 2004 3 Patients randomized on or prior to April 19, 2004 3 Patients randomized on or prior to April 19, 2004 3
N 475 477 0.015
Mean SD 0.18 1.95 0.52 2.07
Range 6 to 2 6 to 2

1. Primary analysis population using last known QoL
   assessment 6 months last known HF
   hospitalization and survival no imputation for
   missing HF hospitalization or survival.
2. Primary analysis population using last known QoL
   assessment during the trial, with imputation of
   worst score for QoL for those patients without
   any QoL post-baseline HF hospitalization and
   survival imputation using Worst-Case scenario.
3. Patients with the opportunity to have at least 3
   months of follow-up and, therefore, a 3-month QoL
   assessment, with imputation of worst score for
   QoL for those patients without any 3-month QoL
   HF hospitalization and survival imputation using
   Worst-Case scenario.

9
AE Incidence by RaceBlack Patients and White
PatientsV-HeFT I, V-HeFT II
27
DV ISS-T14, 15
Patients, Patients, Patients, Patients, Patients, Patients,
Black Black Black White White White
ISDN/HYDn 158 Placebon 79 Enalapriln 106 ISDN/HYDn 414 Placebon 192 Enalapriln 292
Headache 72 54 64 78 49 59
Dizziness 67 53 67 68 63 67
Arthralgias 65 61 72 67 57 72
Other 52 44 59 65 52 68
Palpitation 53 37 49 58 47 56
Nausea or vomiting 47 41 57 55 47 60
Ischemic chest pain 37 37 42 49 44 48
Diarrhea 40 38 43 43 39 45
Flushing 32 28 22 38 31 36
Rash 32 29 35 42 42 41
Fever 33 22 29 35 28 33
Syncope 23 20 15 18 26 12
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Arthritis-Related AEs in Safety Population
6
DV A-HeFT CSR T56
Patients, n () Patients, n ()
BiDiln 517 Placebon 527
Arthralgia 8 (1.5) 2 (0.4)
Arthritis 8 (1.5) 7 (1.3)
Arthritis rheum 1 (0.2) 1 (0.2)
Arthrosis 1 (0.2) 3 (0.6)
Joint disorder 6 (1.2) 7 (1.3)
Synovitis 0 1 (0.2)