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A-HeFT ― Design and Study Population. Anne Taylor, MD Professor of Medicine University of Minnesota Medical School. 6. A-HeFT Objective. DV A-HeFT CSR P 15.

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a heft design and study population

A-HeFT―Design and Study Population

Anne Taylor, MD

Professor of MedicineUniversity of Minnesota Medical School

a heft objective

6

A-HeFT Objective

DV A-HeFT CSR P 15

  • Demonstrate the safety and efficacy of BiDil® compared with placebo in black patients with moderate to severe HF concurrently receiving standard HF treatment
a heft study design

6

A-HeFT Study Design

DV A-HeFT CSR P. 15 CSR

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

6

A-HeFT Dosing

DV A-HeFT CSR P 37, 40

  • 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
a heft study design5

6

CD-5

A-HeFT Study Design

DV A-HeFT CSR F 1

RandomizeQoLEcho

QoL

Echo

QoL

QoL

QoL

QoL

QoL

BiDil®

Placebo

Screening

Titration

Baseline

1 tab tid

2 tabs tid

4

Visit no.

1

2

3

5

6

7

8 (final)

6mo

Day/wk/mo

–2 wk

0

3-5days

3mo

9mo

12mo

15mo

18mo

Randomization stratified by β-blocker usage.

inclusion criteria
Inclusion Criteria

DV A-HeFT CSR pp 37-38

  • 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)
exclusion criteria 1
Exclusion Criteria (1)

DV A-HeFT CSR § 4.3.2

  • 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
exclusion criteria 2
Exclusion Criteria (2)

DV A-HeFT CSR § 4.3.2

  • 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
primary endpoint

DV A-HeFT CSR § 4.5.2

Primary Endpoint
  • Composite score
    • All-cause mortality
    • First HF hospitalization
    • Change in QoL at 6 mo relative to baseline
primary endpoint composite score
Primary Endpoint Composite Score

DV A-HeFT CSR 66, 67, T26, T24

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

a heft quality of life assessment
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
A-HeFT Design—Statistical Analysis for Primary Endpoint Composite Score

DV A-HeFT CSR pp 36, 76

  • 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
secondary endpoints
Secondary Endpoints

DV A-HeFT CSR § 4.5.2

  • 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
a heft design statistical analysis for secondary endpoints
A-HeFT Design—Statistical Analysis for Secondary Endpoints

DV A-HeFT CSR, NitroMed BB

  • 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
sample size calculation and interim analyses
Sample Size Calculation and Interim Analyses

DV NitroMed BB pp 68-70

  • 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
trial termination 1
Trial Termination (1)

DV NitroMed BB p 69-70

  • 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
trial termination 2
Trial Termination (2)

DV NitroMed BB pp 69-71

  • 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
trial overview
Trial Overview

DV A-HeFT CSR< NitroMed BB

  • 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
baseline characteristics 1
Baseline Characteristics (1)

DV A-HeFT CSR T 14, 15

*P < 0.05

baseline characteristics 2
Baseline Characteristics (2)

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

*P < 0.05

patient disposition

6

Patient Disposition

DV A-HeFT CSR P. 83

mean daily prescribed dose of bidil
Mean Daily Prescribed Dose of BiDil®

DV A-HeFT CSR T 20

Dose, mg/day (SD)

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