A-HeFT? Results and Conclusions

1
A-HeFT?Results and Conclusions

• Clyde Yancy, MD
• Professor of MedicineUniversity of Texas
  SouthwesternMedical Center at Dallas

2
A-HeFT Efficacy
3
Primary Endpoint Composite Score
DV A Hef\FT CSR pg 66-67 Taylor_ACC-5
Score Death (at any time during the
trial) 3 Alive at end of trial
0 First HF hospitalization (adjudicated) 1 No
HF hospitalization 0 Change in QoL at 6
mo(or last measurement, if earlier than 6
mo) Improvement 10 units 2 Improvement
5 and lt 10 units 1 Change lt 5 units
0 Worsening 5 and lt 10 units
1 Worsening 10 units 2 Possible score
6 to 2
4
Primary EndpointComposite Score
DV A-HeFT CSR T 24
0.16
Mean SEM
0.47
P 0.016
Composite score range, 6 to 2.
5
Components of Primary Composite EndpointA-HeFT
37
DV A-HeFT CSR T26
Patients, n () Patients, n ()
BiDil(n 518) Placebo(n 532)
Death 32 (6.2) 54 (10.2)
First hospitalization for HF 85 (16.4) 130 (24.4)
Change in QoL at 6 mo relative to baseline Marked improvement Marked worsening 180 (38.1) 80 (16.9) 166 (33.4) 117 (23.5)
6
All Cause MortalityEvent Rate
DV A-HeFT CSR pg 114 and pg 149
Log-rank P 0.012
n 54
n 32
7
43 Decrease in Relative Risk of Mortality
DV A-HeFT CSR pg 18
100
BiDil
95
Placebo
Survival,
90
HR 0.57 (0.37, 0.89) P 0.012
85
0
100
200
300
400
500
Time since baseline visit date, days
Patients at risk, n
BiDil 518 463 407 360 314 253 Placebo 532 466 40
1 340 285 233
8
Cause-Specific MortalityA-HeFT
16
DV A-HeFT CSR T31
Patients, n () Patients, n ()
Deaths BiDiln 518 Placebon 532 Fishers Exact P value
Total 32 (6.2) 54 (10.2) 0.012
Cardiac due to LV dysfunction 21 (4.1) 42 (7.9) 0.009
Sudden cardiac 17 (3.3) 24 (4.5) 0.343
Pump failure 4 (0.8) 16 (3.0) 0.012
MI-related 0 (0.0) 2 (0.4)
Non-cardiac 5 (1.0) 3 (0.6) 0.501
Cerebrovascular accident 4 (0.8) 3 (0.6)
Vascular-related 1 (0.2) 0 (0.0)
Non-cardiovascular 6 (1.2) 9 (1.7) 0.605
Non-cardiovascular cause 3 (0.6) 5 (0.9)
Unknown cause 3 (0.6) 4 (0.8)
Log-rank P value.
9
First Hospitalization for HFEvent Rate
DV A-HeFT CSR T26, T34
Log-rankP lt 0.001
n 85
n 130
10
BiDil Decreases Relative Risk of First HF
Hospitalization by 39
DV A-HeFT CSR F 5 and Table 32
BiDil
Without hospitalization,
Placebo
HR 0.61 (0.46, 0.80) P lt 0.001
Time since baseline visit date, days
Patients at risk, n
BiDil 518 430 357 305 253 197 6 Placebo 532 407 3
29 264 203 160 12
11
First HF Hospitalization Event Rates and Total
Days in Hospital for HF
A-HeFT CSR T32
BiDiln 518 Placebon 532 HR (95 CI) P value
Event rate for first HF hospitalization 85 (16.4) 130 (24.4) 0.61 (0.46, 0.80) lt 0.001
Days in hospital for HF per patient with HF hospitalization
n 85 130
Mean SD 13.7 (16.6) 15.3 (20.2) 0.539
Median 9 9
Range 2 - 122 2 - 164
Log-rank test. Two-sample t test.
12
HF Hospitalizations
25
CE-12
DV NitroMed BB T26
BiDiln 518 Placebon 532 P value
Total number of HF hospitalizations 173 251
Mean number of HF hospitalizations per patient 0.3 0.5 0.002
Hospitalizations by frequency 0.008
0 433 402
1 44 69
2 20 38
3 10 7
4 11 16
Total number of hospital days for HF 1167 1995
Mean number of days in the hospital for HF per patient 2.3 3.8 0.001
Mean (SD) days per hospitalization 6.7 (9.8) 7.9 (9.0)
Percent days hospitalized for HF 0.6 1.1 0.001
Wilcoxon rank-sum test.
13
BiDil Decreases Relative Risk of Mortality or
First HF Hospitalization by 37
DV A-HeFT Fig 6 Pg 119
BiDil
Placebo
HR 0.63 (0.49, 0.81) P lt 0.001
Time since baseline visit date, days
Patients at risk, n
BiDil 518 433 363 312 261 203 13 Placebo 532 411
337 270 208 164 15
14
MLHF QuestionnaireChange in QoL Score at 6 Mo
DV TQoL_LHF ptt 16.1
P 0.011
15
MLHF QuestionnaireChange in QoL From Baseline

DV A-HeFT CSR PTT 16.1
423
441
369
371
198
184
n
307
305
269
250
226
218
512
528
Improvement
P 0.014
P 0.13
P 0.053
P 0.011
P 0.039
P 0.024
P 0.003
Month
Minnesota Living With HF questionnaire. Lower
QoL score indicates better QoL. Mean SEM.
16
Subgroup Analyses for the Primary Endpoint
Composite Score (1)
DVA-HeFT CSR F 2
Favors BiDil
Favors placebo
N
All 1050
Sex Female 420
Male 630
Age, yr lt 65 742
65 308
Ischemic etiology Yes 242
No 808
History of hypertension Yes 940
No 110
Systolic BP gt 125 mm Hg Yes 537
No 513
Diabetes mellitus Yes 429
No 621
Chronic renal insufficiency Yes 181
No 869
-1.5
-1
-0.5
0
0.5
1
1.5
Mean difference in composite score
17
Subgroup Analyses for the Primary Endpoint
Composite Score (2)
DV A-HeFT CSR F 2
Favors BiDil
Favors placebo
N
ACE inhibitors Yes 786
No 264
ARBs Yes 236
No 814
ß-Blockers Yes 871
No 179
Aldosterone agonists Yes 409
No 641
Digitalis glycosides Yes 628
No 422
Diuretics non-aldosteroneantagonists Yes 967
Diuretics non-aldosteroneantagonists No 83
CCBs Yes 213
No 837
-1.5
-1
-0.5
0
0.5
1
1.5
Mean difference in composite score
18
Subgroup Analyses of Hazard Ratio for All-Cause
Mortality (1)
DV A-HeFT Fig 4
N
Favors BiDil
Favors placebo
All 1050
Sex Female 420
Male 630
Age, yr lt 65 742
65 308
Ischemic etiology Yes 242
No 808
Hypertensive etiology Yes 406
No 644
History of hypertension Yes 940
No 110
Systolic BP gt 125 mm Hg Yes 537
No 513
Diabetes mellitus Yes 429
No 621
Chronic renal insufficiency Yes 181
No 869
0
0.5
1
1.5
2
4
Relative risk (95 CI)
19
Subgroup Analyses of Hazard Ratio for All-Cause
Mortality (2)
DV Taylor_ACC-17 A-HeFT CSR T 30
N
Favors BiDil
Favors placebo
ACE inhibitors Yes 786
No 264
ARBs Yes 236
No 814
ACE inhibitors or ARBs Yes 973
No 77
ß-Blockers Yes 871
No 179
Aldosterone agonists Yes 409
No 641
Digitalis glycosides Yes 628
No 422
Diuretics non-aldosteroneantagonists Yes 967
Diuretics non-aldosteroneantagonists No 83
CCBs Yes 213
No 837
0
0.5
1
1.5
2
7
Relative risk (95 CI)
20
Subgroup Analyses of HR for First HF
Hospitalization (1)
DV A-HeFT CSR Fig 4 ptt f7
N
Favors BiDil
Favors placebo
All 1050
Sex Female 420
Male 630
Age, yr lt 65 742
65 308
Ischemic etiology Yes 242
No 808
Hypertensive etiology Yes 406
No 644
History of hypertension Yes 940
No 110
Systolic BP gt 125 mm Hg Yes 537
No 513
Diabetes mellitus Yes 429
No 621
Chronic renal insufficiency Yes 181
No 869
0
0.5
1
1.5
2
Relative risk (95 CI)
21
Subgroup Analyses of HR for First HF
Hospitalization (2)
DV Taylor_ A- A-HeFT ptt f7
N
Favors BiDil
Favors placebo
ACE inhibitors Yes 786
No 264
ARBs Yes 236
No 814
ACE inhibitors or ARBs Yes 973
No 77
ß-Blockers Yes 871
No 179
Aldosterone agonists Yes 409
No 641
Digitalis glycosides Yes 628
No 422
Diuretics non-aldosteroneantagonists Yes 967
Diuretics non-aldosteroneantagonists No 83
CCBs Yes 213
No 837
0
0.5
1
1.5
2
6
Relative risk (95 CI)
22
Change in Blood Pressure From Baseline
DV Data from client A-HeFT PTT 20
Systolic BP
BiDil
Placebo
4
2
0
-2

-4




-6

-8
Change from baseline, mm Hg mean SEM
0
3
6
9
12
15
18
Diastolic BP






P lt 0.05
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Effect of BP Lowering on BiDil Treatment Effects
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DV
Mortality Mortality Mortality First HF hospitalization First HF hospitalization First HF hospitalization
Variables Riskratio 95 CI P value Riskratio 95 CI P value
Unadjusted 0.57 0.37 0.89 0.012 0.61 0.46 0.80 0.0004
Adjusted for baseline variables and average systolic BP 0.49 0.29 0.83 0.008 0.59 0.45 0.79 0.0003
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Summary of BiDil Efficacy
DV

• BiDil is efficacious in the treatment of
  symptomatic heart failure in black patients
• Decreases the risk of mortality
• Decreases hospitalization for HF
• Risk for first hospitalization
• Number of hospitalization
• Days in the hospital
• Improves quality of life

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A-HeFTClinical Safety
DV
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Adverse Events
A-HeFT CSR T 43, 46 5-11-05 BD P 85
Patients, Patients,
BiDil Placebo P value
Headache (all) 49.5 21.1 lt 0.0001
Severe 5.2 0.9 lt 0.001
Dizziness 31.9 13.7 lt 0.0001
Dyspnea 12.6 17.5 0.030
Exacerbation of HF 9.5 15.2 0.006
Hypotension 7.9 4.4 lt 0.05
Increased cough 5.2 7.8 NS
Peripheral edema 4.8 7.0 NS
Sinusitis 4.3 1.7 lt 0.05
Ventricular tachycardia 4.1 2.7 NS
Palpitations 3.9 2.7 NS
Severe exacerbation of HF 1.5 2.5
Tachycardia 2.1 1.1 NS
Favors BiDil.
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AEs of Special Interest
DV Pg 143 CSR Table 54/PTT 21.5 by severity
Patients, Patients, Patients, Patients,
BiDiln 517 BiDiln 517 Placebon 527 Placebon 527
AE Discontinued AE Discontinued
Headache 49.5 7.4 21.1 0.8
Dizziness 31.9 3.7 13.7 0.8
Hypotension 7.9 1.4 4.4 0.6
Discontinued study medication due to AEs.
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Most Frequent 1 Serious AEsSafety Population
16
DV A-HeFT CSR T49
Patients, Patients,
BiDiln 517 Placebon 527
At least 1 serious AE 35.0 34.7
Chest pain 6.4 5.5
Heart failure (exacerbation) 3.1 7.8
Ventricular tachycardia 2.7 1.5
Pneumonia 2.3 1.5
Syncope 2.1 1.5
Dyspnea 1.9 2.3
Arrhythmia 1.7 1.3
Hypotension 1.5 0.6
Cerebrovascular accident 1.4 2.5
Heart arrest 1.4 1.7
Dizziness 1.4 0.0
Diabetes mellitus 1.2 0.9
Cellulitis 1.2 0.4
P 0.001
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Patients in the Analysis Populations
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DV A-HeFT CSR T13, p 88
Patients, Patients,
BiDiln 518 Placebon 532
ITT population 100.0 100.0
Safety population 99.8 99.1
Per-protocol population 41.7 40.4
Excluded from per-protocol population, total 58.3 59.6
Permanent premature discontinuation of study drug 38.8 33.1
Permanent study drug discontinuation
Due to AEs 21.0 (109) 11.8 (63)
Up to 30 days before event 5.6 (29) 8.8 (47)
Of the 301 events in the ITT populations (first
HF hospitalization or death) only 40 events
remained in the per-protocol population(1 death,
39 hospitalizations)
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Conclusion
31
Summary of BiDil Efficacy and Safety
DV NitroMed BB p 120

• A-HeFT confirms the hypothesis generated from
  V-HeFT I and V-HeFT II
• BiDil is efficacious in the treatment of HF in
  black patients
• Increases survival by 43
• Decreases hospitalization for HF
• Risk for first hospitalization by 39
• Number of hospitalizations by 31
• Days in the hospital by 42
• Improves quality of life
• BiDil has a favorable safety profile for the
  proposed use

32
Summary of BiDil Efficacy and Safety
DV NitroMed BB p 120

• A-HeFT confirms the hypothesis generated from
  V-HeFT I and V-HeFT II
• BiDil is efficacious in the treatment of HF in
  black patients
• Increases survival by 43
• Decreases hospitalization for HF
• Risk for first hospitalization by 39
• Number of hospitalizations by 31
• Days in the hospital by 42
• Improves quality of life
• BiDil has a favorable safety profile for the
  proposed use