CD-1

A-HeFT―Design and Study Population

Anne Taylor, MD

Professor of MedicineUniversity of Minnesota Medical School

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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

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A-HeFT Study Design

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

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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

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A-HeFT Study Design

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QoLEcho QoL QoL QoL QoL

Screening

RandomizeQoLEcho

BiDil®

Placebo

Visit no.

Day/wk/mo –2 wk 0

1

Baseline

Titration3-5

days

2

1 tab tid 2 tabs tid

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QoL

6mo

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9mo

5

12mo

6

15mo

7

18mo

8 (final)

Randomization stratified by β-blocker usage.

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CD-6

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/m2 (or > 6.5 cm)

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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

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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

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CD-9

Primary Endpoint

Composite score

– All-cause mortality

– First HF hospitalization

– Change in QoL at 6 mo relative to baseline

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CD-10

Primary Endpoint Composite Score Score

Death (at any time during the trial) –3 Alive at end of trial 0

First HF hospitalization (adjudicated) –1No HF hospitalization 0

Change in QoL at 6 mo(or last measurement, if earlier than 6 mo)

Improvement ≥ 10 units +2Improvement ≥ 5 and < 10 units +1Change < 5 units 0Worsening ≥ 5 and < 10 units –1Worsening ≥ 10 units –2

Possible score = –6 to +2

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CD-11

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

CD-12

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

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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

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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

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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

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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

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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

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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

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Baseline Characteristics (1)

* P < 0.05

BiDil®

n = 518Placebon = 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%

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Baseline Characteristics (2)

BiDil®

n = 518Placebon = 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

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* P < 0.05

CD-21

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)

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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)

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CD-23Study Drug Prescribed as Assessed by Total Tablets/Day at Various Time PointsA-HeFT

Mean ± SD

TimepointBiDil®

n = 517Placebon = 527

3 mo 4.4 ± 2.1 5.0 ± 1.96 mo 4.5 ± 2.0 5.1 ± 1.89 mo 4.8 ± 1.9 5.2 ± 1.712 mo 4.8 ± 1.9 5.3 ± 1.615 mo 4.9 ± 1.7 5.3 ± 1.7Endpoint 4.1 ± 2.0 5.2 ± 1.5

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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)

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