# Presentation: 736535

## A-HeFT―Results and Conclusions

**Clyde Yancy, MD**
**Professor of Medicine****University of Texas Southwestern****Medical Center at Dallas**

## A-HeFT Efficacy

## Primary Endpoint Composite Score 

**	****	****	****	****     ****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 < 10 units ****	****	****+1**
**	****	****Change****	****< 5 units ****	****  ****	****  0**
**	****	****Worsening****	****≥ 5 and < 10 units****	**** ****	****–1**
**	****	****Worsening****	****≥ 10 units****	****  ****	****–2**
**Possible score = ****	****	****   –6 to +2**

- DV A Hef\FT CSR pg 66-67 Taylor_ACC-5

## Primary Endpoint—Composite Score†

***P *****= 0.016**

- DV A-HeFT CSR T 24

**† ****Composite score range, –6 to +2.**

**–****0.16**

**–****0.47**

**Mean ± SEM**

## Components of Primary Composite EndpointA-HeFT

|  | 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) |

**37**

- DV A-HeFT CSR T26

## All Cause Mortality—Event Rate

**Log-rank *****P *****= 0.012**

**n = 54**

**n = 32**

- DV A-HeFT CSR pg 114 and pg 149

## 43% Decrease in Relative Risk of Mortality

**Placebo****	****532****	****466****	****401****	****340****	****285****	****233****	**

**43% Decrease in Relative Risk of Mortality**

**BiDil****®**

**Placebo**

**HR = 0.57 (0.37, 0.89)**
***P = *****0.012**

- DV  A-HeFT CSR pg 18

**Patients at risk, n**

**Time since baseline visit date, days**

**85**

**90**

**95**

**100**

**0**

**100**

**200**

**300**

**400**

**500**

**Survival, %**

## Cause-Specific MortalityA-HeFT

|  | Patients, n (%) |  |  |
| --- | --- | --- | --- |
| Deaths | BiDil®n = 518 | Placebon = 532 | Fisher’s 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) |  |

- DV A-HeFT CSR T31

- 16

**† ****Log-rank *****P***** value.**

## First Hospitalization for HF—Event Rate

**Log-rank*****P *****< 0.001**

**n = 85**

**n = 130**

- DV A-HeFT CSR T26, T34

## BiDil® Decreases Relative Risk of First HF Hospitalization by 39%

- DV A-HeFT CSR F 5 and Table 32

**Placebo**

**BiDil****®**

**HR = 0.61 (0.46, 0.80)**
***P***** < 0.001**

**BiDil ****	****518****	****430****	****357****	****305****	****253****	****197****	****6**
**Placebo****	****532****	****407****	****329****	****264****	****203****	****160****	****12**

**Patients at risk, n**

**Without ****hospitalization, %**

**Time since baseline visit date, days**

## First HF Hospitalization Event Rates and Total Days in Hospital for HF

|  | BiDil®n = 518 | Placebon = 532 | HR (95% CI) | P value |
| --- | --- | --- | --- | --- |
| Event rate for first HF hospitalization | 85 (16.4) | 130 (24.4) | 0.61 (0.46, 0.80) | < 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.**

- A-HeFT CSR T32

## HF Hospitalizations

**25**

- DV NitroMed BB T26

|  | BiDil®n = 518 | Placebon = 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.**

**CE-**

## BiDil® Decreases Relative Risk of Mortality or First HF Hospitalization by 37%

**BiDil****®**** Decreases Relative Risk of Mortality **_***or***_** First HF Hospitalization by 37%**

- DV A-HeFT Fig 6 Pg 119

**BiDil ****	****518****	****433****	****363****	****312****	****261****	****203****	****13**
**Placebo****	****532****	****411****	****337****	****270****	****208****	****164****	****15**

**Patients at risk, n**

**HR = 0.63 (0.49, 0.81)**
***P***** < 0.001**

**Placebo**

**BiDil**

## MLHF QuestionnaireChange in QoL Score at 6 Mo

***P***** = 0.011**

- DV TQoL_LHF ptt 16.1

## MLHF QuestionnaireChange in QoL From Baseline†

**† ****Minnesota Living With HF questionnaire.**
**Lower QoL score indicates better QoL. M****ean ****± SEM.**

**MLHF Questionnaire****Change in QoL From Baseline****†**

- DV A-HeFT CSR PTT 16.1

**Improvement**

***P***** = 0.014**

**Month**

***P***** = 0.13**

***P***** = 0.053**

***P***** = 0.011**

***P***** = 0.039**

***P***** = 0.024**

***P***** = 0.003**

**423**

**441**

**369**

**371**

**198**

**184**

**n = **

**307**

**305**

**269**

**250**

**226**

**218**

**512**

**528**

## Subgroup Analyses for the Primary Endpoint Composite Score (1)

**N**

**Favors BiDil****®**

**Favors placebo**

**Mean difference in composite score**

-  DVA-HeFT CSR F 2

| All |  | 1050 |
| --- | --- | --- |
| Sex | Female | 420 |
|  | Male | 630 |
| Age, yr | < 65 | 742 |
|  | ≥ 65 | 308 |
| Ischemic etiology | Yes | 242 |
|  | No | 808 |
| History of hypertension | Yes | 940 |
|  | No | 110 |
| Systolic BP > 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**

## Subgroup Analyses for the Primary Endpoint Composite Score (2)

- DV  A-HeFT CSR F 2

| ACE inhibitors | Yes | 786 |
| --- | --- | --- |
|  | No | 264 |
| ARBs | Yes | 236 |
|  | No | 814 |
| β-Blockers | Yes | 871 |
|  | No | 179 |
| Aldosterone agonists | Yes | 409 |
|  | No | 641 |
| Digitalis glycosides | Yes | 628 |
|  | No | 422 |
| Diuretics: non-aldosteroneantagonists | Yes | 967 |
|  | No | 83 |
| CCBs | Yes | 213 |
|  | No | 837 |

**Mean difference in composite score**

**N**

**-1.5**

**-1**

**-0.5**

**0**

**0.5**

**1**

**1.5**

**Favors BiDil****®**

**Favors placebo**

## Subgroup Analyses of Hazard Ratio for All-Cause Mortality (1)

**Subgroup Analyses of Hazard Ratio for ****All-Cause Mortality (1)**

**N**

**Relative risk (95% CI)**

| All |  | 1050 |
| --- | --- | --- |
| Sex | Female | 420 |
|  | Male | 630 |
| Age, yr | < 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 > 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**

- DV A-HeFT Fig 4

**Favors  BiDil****®**

**Favors placebo**

**4**

## Subgroup Analyses of Hazard Ratio for All-Cause Mortality (2)

**Subgroup Analyses of Hazard Ratio for ****All-Cause Mortality (2)**

- DV Taylor_ACC-17 A-HeFT CSR T 30

| ACE inhibitors | Yes | 786 |
| --- | --- | --- |
|  | No | 264 |
| ARBs | Yes | 236 |
|  | No | 814 |
| ACE inhibitors or ARBs | Yes | 973 |
|  | No | 77 |
| β-Blockers | Yes | 871 |
|  | No | 179 |
| Aldosterone agonists | Yes | 409 |
|  | No | 641 |
| Digitalis glycosides | Yes | 628 |
|  | No | 422 |
| Diuretics: non-aldosteroneantagonists | Yes | 967 |
|  | No | 83 |
| CCBs | Yes | 213 |
|  | No | 837 |

**N**

**Favors  BiDil****®**

**Favors placebo**

**Relative risk (95% CI)**

**0**

**0.5**

**1**

**1.5**

**2**

**7**

## Subgroup Analyses of HR for First HF Hospitalization (1)

**0**

**0.5**

**1**

**1.5**

**2**

**N**

**Favors  BiDil****®**

**Favors placebo**

**Relative risk (95% CI)**

| All |  | 1050 |
| --- | --- | --- |
| Sex | Female | 420 |
|  | Male | 630 |
| Age, yr | < 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 > 125 mm Hg | Yes | 537 |
|  | No | 513 |
| Diabetes mellitus | Yes | 429 |
|  | No | 621 |
| Chronic renal insufficiency | Yes | 181 |
|  | No | 869 |

- DV A-HeFT CSR Fig 4 ptt f7

## Subgroup Analyses of HR for First HF Hospitalization (2)

| ACE inhibitors | Yes | 786 |
| --- | --- | --- |
|  | No | 264 |
| ARBs | Yes | 236 |
|  | No | 814 |
| ACE inhibitors or ARBs | Yes | 973 |
|  | No | 77 |
| β-Blockers | Yes | 871 |
|  | No | 179 |
| Aldosterone agonists | Yes | 409 |
|  | No | 641 |
| Digitalis glycosides | Yes | 628 |
|  | No | 422 |
| Diuretics: non-aldosteroneantagonists | Yes | 967 |
|  | No | 83 |
| CCBs | Yes | 213 |
|  | No | 837 |

**N**

**Favors  BiDil****®**

**Favors placebo**

**Relative risk (95% CI)**

**0**

**0.5**

**1**

**1.5**

**2**

**6**

- DV Taylor_ A- A-HeFT ptt f7

## Change in Blood Pressure From Baseline

- DV Data from client; A-HeFT PTT 20

**Systolic BP**

**Change from baseline, mm Hg**
**mean ± SEM**

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

*****

**Diastolic BP**

*** *****P *****< 0.05**

**-8**

**-6**

**-4**

**-2**

**0**

**2**

**4**

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**BiDil****®**

**Placebo**

*****

## Effect of BP Lowering on BiDil® Treatment Effects

|  | Mortality |  |  | First HF hospitalization |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Variables | Riskratio | 95% CI | P value | Riskratio | 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 |

**23**

- DV

## Summary of BiDil® Efficacy 

**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**

- DV

## A-HeFTClinical Safety

- DV

## Adverse Events

|  | Patients, % |  |  |
| --- | --- | --- | --- |
|  | BiDil® | Placebo | P value |
| Headache (all) | 49.5 | 21.1 | < 0.0001 |
| 	Severe | 5.2 | 0.9 | < 0.001 |
| Dizziness | 31.9 | 13.7 | < 0.0001 |
| Dyspnea | 12.6† | 17.5 | 0.030 |
| Exacerbation of HF | 9.5† | 15.2 | 0.006 |
| Hypotension | 7.9 | 4.4 | < 0.05 |
| Increased cough | 5.2† | 7.8 | NS |
| Peripheral edema | 4.8† | 7.0 | NS |
| Sinusitis | 4.3 | 1.7 | < 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****.**

- A-HeFT CSR T 43, 46; 5-11-05 BD P 85

## AEs of Special Interest

|  | Patients, % |  |  |  |
| --- | --- | --- | --- | --- |
|  | BiDil®n = 517 |  | Placebon = 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 |

- DV Pg 143 CSR Table 54/PTT 21.5 by severity

**† ****Discontinued study medication due to AEs.**

## Most Frequent ≥ 1% Serious AEsSafety Population

|  | Patients, % |  |
| --- | --- | --- |
|  | BiDil®n = 517 | Placebon = 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 |

- DV A-HeFT CSR T49

**†***** ******P***** ≤ 0.001**

- 16

## Patients in the Analysis Populations

- DV A-HeFT CSR T13, p 88

|  | Patients, % |  |
| --- | --- | --- |
|  | BiDil®n = 518 | Placebon = 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) |

- 16

**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)**

## Conclusion

## Summary of BiDil® Efficacy and Safety

**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**

- DV NitroMed BB p 120

## Summary of BiDil® Efficacy and Safety

**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**

- DV NitroMed BB p 120