# Presentation: 913071

## A-HeFT―Design and Study Population

**Anne Taylor, MD**
**Professor of Medicine****University of Minnesota Medical School**

## A-HeFT Objective

**Demonstrate the safety and efficacy of BiDil****®**** compared with placebo in black patients with moderate to severe HF concurrently receiving standard HF treatment**

- DV A-HeFT CSR P 15

**6**

## A-HeFT Study Design

**Double-blind, randomized, parallel-group, placebo-controlled study of black patients ****with stable symptomatic HF while on ****standard HF therapy**

- DV A-HeFT CSR P. 15 CSR

**6**

## A-HeFT Dosing

**BiDil****®**** is an oral fixed-dose combination tablet**
**20 mg ISDN**
**37.5 mg HYD**
**Patients were randomized to BiDil or placebo**
**1 tablet tid, with forced titration to ****a target of 2 tablets tid **
**Target dose **
**120 mg/day ISDN**
**225 mg/day HYD**

**6**

- DV A-HeFT CSR P 37, 40

## A-HeFT Study Design

**6**

- DV A-HeFT CSR F 1

**QoL**
**Echo**

**QoL**

**QoL**

**QoL**

**QoL**

**Screening**

**Randomize****QoL****Echo**

**BiDil****®**

**Placebo**

**Visit no.**

**Day/wk/mo**

**–****2 wk**

**0**

**1**

**Baseline**

**Titration**

**3-5****days**

**2**

**1 tab tid**

**2 tabs tid**

**3****mo**

**3**

**QoL**

**6****mo**

**4**

**9****mo**

**5**

**12****mo**

**6**

**15****mo**

**7**

**18****mo**

**8 (final)**

**Randomization stratified by ****β****-blocker usage.**

**CD-**

## Inclusion Criteria

**Inclusion Criteria**

**Self-identified African American (black) patients**
**Symptomatically stable NYHA Class III-IV**
**On standard HF treatment**
**If on β-blockers, treated for at least 3 mo prior to study entry**
**Ejection fraction**
**LVEF ≤ 35% or **
**LVEF < 45% with resting LVIDD > 2.9 cm/m****2**** ****(or > 6.5 cm)**

- DV A-HeFT CSR pp 37-38

## Exclusion Criteria (1)

**Exclusion Criteria (1)**

**Unstable angina, myocardiaI infarction, acute coronary syndrome, cerebrovascular accident, cardiac surgery, percutaneous cardiac intervention within 3 mo**
**Valvular disease, hypertrophic obstructive cardiomyopathy, or myocarditis **
**Sustained VT unless implantable cardiac defibrillator**
**Requirement for inotropes**
**Women of childbearing age who were pregnant, nursing, or not using contraception**
**Rapidly deteriorating or uncompensated HF such that cardiac transplantation would be likely over the ensuing 1 year**

- DV A-HeFT CSR § 4.3.2

## Exclusion Criteria (2)

**Exclusion Criteria (2)**

**Symptomatic hypotension**
**Significant hepatic, renal, or other disease limiting survival over 1 year trial duration**
**Any condition that would jeopardize the evaluation of efficacy or safety**
**Any contraindications to the use of isosorbide dinitrate or hydralazine**
**Receipt of another investigational drug or device within 3 mo**
**Requirement for hydralazine, long-acting nitrates, or phosphodiesterase type 5 inhibitors**

- DV A-HeFT CSR § 4.3.2

## Primary Endpoint

**Composite score **
**All-cause mortality**
**First HF hospitalization**
**Change in QoL at 6 mo relative to baseline**

- DV A-HeFT CSR § 4.5.2

## 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-HeFT CSR 66, 67, T26, T24

## A-HeFT―Quality-of-Life Assessment

**The Minnesota Living With Heart Failure questionnaire (MLHFQ) is a self-administered, ****21-question tool measuring physical and emotional effects of HF**
**Scores range from 0 to 5 for each question****(0 to 105 total possible score)**
**Lower scores indicate better QoL**
**QoL was measured at baseline and every 3 mo during the trial**

## A-HeFT Design—Statistical Analysis for Primary Endpoint Composite Score

**Intention-to-treat analysis**
**Worst-case score for missing data**
**3 components**
**Mortality (score 0 or –3)**
**Hospitalization for HF (score 0 or –1)**
**Change in QoL at 6 mo (score –2 to 2)**
**Cui, Hung, and Wang (1999) group ****sequential method**

- DV A-HeFT CSR pp 36, 76

## Secondary Endpoints

**Death from any cause**
**Time to death**
**Cause-specific mortality**
**HF hospitalizations**
**Time to first hospitalization**
**Number of hospitalizations**
**Total days in hospital**
**Change from baseline in overall QoL MLHFQ score at each timepoint**

- DV A-HeFT CSR § 4.5.2

## A-HeFT Design—Statistical Analysis for Secondary Endpoints

**Analysis of death: Kaplan-Meier, log-rank test**
**Analysis of first hospitalization for HF: ****Kaplan-Meier, log-rank test**
**Comparison of event rates of death and hospitalization for HF: 2-sample *****t***** test or Wilcoxon test**
**Comparison of change in QoL: 2-sample *****t***** tests for the difference between groups in MLHFQ scores at each timepoint**

- DV A-HeFT CSR, NitroMed BB

## Sample Size Calculation and Interim Analyses

**Protocol specified 2 interim analyses plus a final analysis**
**Sample size re-estimation at the second interim analysis when 300 patients completed 6 mo**
**313 patients who reached 6 mo were included in this interim analysis (528 patients were randomized)**
**Cui, Hung, and Wang method for analysis **
**For an ****α**** ****= 0.05**
**900 patients were required for 80% power**
**Per advice of FDA used an ****α**** = 0.02 for sample size ****re-estimation but not for hypothesis testing**
**1100 patients were required for 80% power **

- DV NitroMed BB pp 68-70

## Trial Termination (1)

**No boundaries to terminate trial for mortality had been formulated at start of study (May 2001)**
**DSMB noted a disparity between treatment groups in deaths (March 2004)**
**O’Brien-Fleming type group sequential alpha spending function as described by Lan and DeMets to guide further decision making established at that time**
**Treatment difference in mortality in March 2004 fell just below the value specified by newly formulated boundaries**
**DSMB recommended 1 additional safety review to take place 3 mo to 5 mo later**

- DV NitroMed BB p 69-70

## Trial Termination (2)

**DSMB recommendation to stop trial at added safety review (July 2004)**
**Due to positive effect in mortality in BiDil group relative to placebo**
**Results discussed with Steering Committee, who also recommended study be stopped**
**NitroMed followed recommendations and stopped study on July 19, 2004**

- DV NitroMed BB pp 69-71

## Trial Overview

**180 sites (169 sites randomized at least ****1 patient)**
**1050 randomized patients ****(518 BiDil****®****, 532 placebo)**
**Up to 18 mo of follow-up**
**No patient lost to follow-up for vital status**
**First patient enrolled 5/29/01**
**Study terminated 7/19/04 for significant survival benefit in the BiDil group**

- DV A-HeFT CSR< NitroMed BB

## Baseline Characteristics (1)

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

|  |  | BiDil®n = 518 | Placebon = 532 |
| --- | --- | --- | --- |
| Age (mean), yr |  | 57 | 57 |
| Male sex* |  | 56% | 64% |
| NYHA class |  |  |  |
| 	III |  | 95% | 95% |
| 	IV |  |   3% |   5% |
| Primary cause of heart failure |  |  |  |
| Ischemic heart disease |  | 23% | 23% |
| Hypertension |  | 40% | 37% |
| Idiopathic |  | 25% | 28% |
| Valvular heart disease |  | 3% | 3% |
| Other |  | 10% | 9% |

- DV A-HeFT CSR T 14, 15

## Baseline Characteristics (2)

|  |  | BiDil®n = 518 | Placebon = 532 |
| --- | --- | --- | --- |
| Systolic BP, mm Hg (mean ± SD) |  | 127 ± 18 | 125 ± 18 |
| Diastolic BP,* mm Hg (mean ± SD) |  | 78 ± 10 | 76 ± 11 |
| QoL score (mean ± SD) |  | 51 ± 25 | 51 ± 26 |
| LVIDD, cm (mean ± SD) |  | 6.5 ± 0.9 | 6.5 ± 1.0 |
| Ejection fraction, % (mean ± SD) |  | 24 ± 7 | 24 ± 8 |
| Diabetes,* % |  | 45 | 37 |
| Renal insufficiency, % |  | 16 | 18 |
| Atrial fibrillation, % |  | 15 | 18 |
| Implantable cardiac defibrillator, % |  | 17 | 17 |

- DV A-HeFT CSR T 14, 15, 16, PTT16.1

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

## Baseline Cardiovascular Medications 

|  |  | Patients, n (%) |  |
| --- | --- | --- | --- |
|  |  | BiDil®(n = 518) | Placebo(n = 532) |
| ACE inhibitor |  | 386 (74.5) | 400 (75.2) |
| ARB |  | 124 (23.9) | 112 (21.1) |
| ACE inhibitor or ARB |  | 478 (92.3) | 495 (93.0) |
| β-blocker |  | 434 (83.8) | 437 (82.1) |
| Aldosterone antagonist |  | 208 (40.2) | 201 (37.8) |
| Digitalis glycoside |  | 304 (58.7) | 324 (60.9) |
| Diuretic |  | 473 (91.3) | 494 (92.9) |
| Calcium channel blocker |  | 109 (21.0) | 104 (19.5) |

- DV A-HeFT CSR T22

## Patient Disposition

|  | Patients, n (%) |  |
| --- | --- | --- |
|  | BiDil® | Placebo |
| Total randomized patients | 518 (100.0) | 532 (100.0) |
| Completed study | 469 (90.5) | 457 (85.9) |
| Discontinued from study prematurely | 49 (9.5) | 75 (14.1) |
| 	Death | 30 (5.8) | 54 (10.2) |
| 	Investigator decision | 9 (1.7) | 13 (2.4) |
| 	Patient withdrew consent | 5 (1.0) | 3 (0.6) |
| 	Patients lost to follow-up (non-vital     status follow-up) | 2 (0.4) | 0 |
| 	Cardiac transplantation | 3 (0.6) | 3 (0.6) |
| 	Not reported | 0 | 2 (0.4) |

**6**

- DV A-HeFT CSR P. 83

## Study Drug Prescribed as Assessed by Total Tablets/Day at Various Time PointsA-HeFT

|  | Mean ± SD |  |
| --- | --- | --- |
| Timepoint | BiDil®n = 517 | Placebon = 527 |
| 3 mo | 4.4 ± 2.1 | 5.0 ± 1.9 |
| 6 mo | 4.5 ± 2.0 | 5.1 ± 1.8 |
| 9 mo | 4.8 ± 1.9 | 5.2 ± 1.7 |
| 12 mo 	 | 4.8 ± 1.9 | 5.3 ± 1.6 |
| 15 mo | 4.9 ± 1.7 | 5.3 ± 1.7 |
| Endpoint | 4.1 ± 2.0 | 5.2 ± 1.5 |

**17-DV**

- CSR T20

## Mean Daily Prescribed Dose of BiDil®

|  |        ISDN | HYD |
| --- | --- | --- |
|   3 mo (n = 368) |        88 (42) | 188 (71) |
|   6 mo (n = 317) |        90 (40) | 191 (68) |
|   9 mo (n = 260) |        96 (38) | 195 (64) |
| 12 mo (n = 220) |        96 (38) | 199 (60) |
| 15 mo (n = 169) |        98 (34) | 199 (64) |

**Dose, mg/day (SD)**

- DV A-HeFT CSR T 20