AHeFTSlideDeck

Slide1: 

A Placebo-Controlled Trial of Fixed-Dose I/H Added to Standard Therapy in African American Patients With Heart Failure Anne L. Taylor, MD Jay N. Cohn, MD University of Minnesota Medical School A-HeFT African American Heart Failure Trial

Slide2: 

Cohn JN. Vasodilator therapy for heart failure. The influence of impedance on left ventricular performance. Circulation. 1973;48:5-8.

Slide3: 

Guiha NH, Cohn JN, Mikulic E, Franciosa JA, Limas CJ. Treatment of refractory heart failure with infusion of nitroprusside. N Engl J Med. 1974;291:587-592. From the New England Journal of Medicine, September 15, 1974 Volume 291, Number 12

Slide4: 

Pierpont GL, Cohn JN, Franciosa JA. Combined oral hydralazine-nitrate therapy in left ventricular failure. Hemodynamic equivalency to sodium nitroprusside. Chest. 1978;73:8-13.

V-HeFT I : Survival in All Patients: 

273 201 (53) 132 (94) 82 (128) 186 147 (23) 108 (48) 70 (67) Time (Months) Placebo vs I/H: P=.046 0 6 12 18 24 30 36 42 40 50 60 70 80 90 100 Placebo Prazosin I/H Percent Survival (%) á36% Placebo: N (cumulative death) I/H: N (cumulative death) V-HeFT I : Survival in All Patients

V-HeFT I : Survival Benefit in Subgroups: 

V-HeFT I : Survival Benefit in Subgroups I/H Placebo Cumulative Mortality Months 0% 10% 20% 30% 40% 50% 60% 70% 80% 42 54 66 6 18 30 0 Non-African Americans African Americans Months 42 54 66 6 18 30 0 0% 10% 20% 30% 40% 50% 60% 70% 80% Cumulative Mortality Risk Ratio=0.53 P=.04 n=480 n=180

Mechanism of Drug Effects: 

Mechanism of Drug Effects Isosorbide dinitrate Nitric oxide donor Large and small artery dilator Venous dilator Hydralazine Antioxidant (Inhibits destruction of NO) Arteriolar dilator BiDil Fixed-dose I/H Nitric oxide enhancer

Normal: 

Normal Growth/Remodeling Suppression Neurohormone Stimulation Nitric Oxide

Heart Failure: 

Heart Failure Growth/Remodeling Suppression

Heart Failure, Untreated: 

Heart Failure, Untreated Growth/Remodeling Suppression

Heart Failure, Treated with Neurohormonal Antagonists: 

Heart Failure, Treated with Neurohormonal Antagonists Growth/Remodeling Suppression Neurohormone Stimulation Neurohormone Inhibitors

Heart Failure: 

Heart Failure Growth/Remodeling Suppression

Heart Failure: 

Heart Failure Growth/Remodeling Suppression Neurohormone Stimulation Neurohormone Inhibitors Nitric Oxide Deficiency Nitric Oxide Enhancer

Heart Failure in AA: 

Heart Failure in AA Growth/Remodeling Suppression NH Stimulation NH Inhibitors Nitric Oxide Deficiency Nitric Oxide Enhancer

Slide15: 

A-HeFT Results A-HeFT African American Heart Failure Trial

A-HeFT: Hypothesis: 

A-HeFT: Hypothesis Nitric Oxide Enhancing Medication Fixed-dose I/H (NO donor + antioxidant) will improve outcomes in African American patients with moderate-to-severe symptomatic HF

A-HeFT: Trial Summary: 

A-HeFT: Trial Summary 169 sites 1050 randomized patients (518 fixed-dose I/H, 532 placebo) Up to 18 months of follow-up No patient lost to follow-up Study initiated 5/01, terminated 7/19/04 for significant survival benefit in the fixed-dose I/H group

A-HeFT: 43% Relative Risk Reduction for Mortality: 

A-HeFT: 43% Relative Risk Reduction for Mortality Days Since Baseline Visit Date Fixed-dose I/H 518 463 407 359 313 251 13 Placebo 532 466 401 340 285 232 24 0 100 200 300 400 500 600 85 90 95 100 Survival (%) P=.01 Fixed-dose I/H Placebo Hazard ratio=0.57

A-HeFT: Design: 

A-HeFT: Design Inclusion Criteria Self-identified African American, symptomatically stable NYHA class III-IV on standard HF treatment; b-blockers for at least 3 months LVEF 35% or LVEF <45% and a resting LVIDD >2.9 cm/m2 or >6.5 cm (by Echo) Exclusion Criteria Women of childbearing age who were pregnant, nursing, or not using contraception MI, ACS, CVA, cardiac surgery, PCI within 3 months Valvular disease, HOCM, restrictive CMY, myocarditis Ventricular arrhythmias unless ICD Requirement for inotropes or OHTx

A-HeFT: Statistical Analysis: 

A-HeFT: Statistical Analysis Intention-to-treat analysis Worst case score for missing data Analysis of death: Kaplan-Meier, log-rank test Comparison of rates of death and first hospitalization for HF: Fisher’s exact test Comparison of change in QOL score: two sample t test for the difference in scores

A-HeFT: Baseline Characteristics: 

A-HeFT: Baseline Characteristics *P<.05 64% 56% Male Gender * 9% 10% Other 3% 3% Valvular HD 28% 25% Idiopathic 37% 40% Hypertension 23% 23% Ischemic Heart Disease Primary Cause of Heart Failure 5% 3% Class IV 95% 97% NYHA Class III 94 93 Weight (kg) 57 57 Age (y) Placebo (N=532) Fixed-dose I/H (N=518)

A-HeFT: Primary End Point Score: 

A-HeFT: Primary End Point Score Composite Score of Death, Hospitalization, & QOL Death (at any time during the trial) = -3 Alive at end of trial = 0 Hospitalization for heart failure (adjudicated) = -1 No hospitalization = 0 Change in QOL at 6 months (or last measurement, if earlier than 6 months) Improvement 10 units = +2 Improvement 5 and <10 units = +1 Change less than 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 is a self-administered, 21-question tool assessing emotional and physical parameters which measure how an individual with heart failure lives compared to how they would like to live Scores range from 0 to 5 for each question (0-105 total possible score) Lower scores indicate better QOL

A-HeFT: Baseline Characteristics: 

*P<.05. 17% 17% Implantable Cardiac Defibrillator 2% 2% Cardiac Resynchronization Therapy 18% 15% Atrial Fibrillation 18% 16% Renal Insufficiency 37% 45% Diabetes * 51 +/-26 51 +/-25 QOL Score 6.5 +/-1.0 6.5 +/-0.9 LVIDD (cm) 24% +/-8 24% +/-7 Ejection Fraction Placebo (N=532) Fixed-dose I/H (N=518) 125 +/-18 127 +/-17 Systolic BP (mmHg) 76 +/-10 78 +/-10 Diastolic BP (mmHg) A-HeFT: Baseline Characteristics

A-HeFT: Baseline Heart Failure Medications: 

A-HeFT: Baseline Heart Failure Medications 38 40 Spironolactone 61 59 Digoxin 74 74 b-Blocker 17 17 ARB 70 69 ACE Inhibitor 92 88 Diuretic % of Patients Placebo (N=532) Fixed-dose I/H (N=518)

Slide26: 

Trial Outcomes A-HeFT African American Heart Failure Trial

A-HeFT: Primary Endpoint (Composite Score): 

A-HeFT: Primary Endpoint (Composite Score) Placebo Fixed-dose I/H -0.5 0 P=0.01 -0.25

A-HeFT: Components of Composite Score: 

0 15 10 N=32 10.2% 6.2% Death P=0.02 Placebo Fixed-dose I/H First HF Hospitalization 10 30 20 24.4% 16.4% P=0.001 -6 0 -4 P=0.02 -2 Change in Quality of Life -2.7 -5.6 N=54 5 A-HeFT: Components of Composite Score N=130

A-HeFT: 43% Relative Risk Reduction for Mortality : 

A-HeFT: 43% Relative Risk Reduction for Mortality Days Since Baseline Visit Date Fixed-dose I/H 518 463 407 359 313 251 13 Placebo 532 466 401 340 285 232 24 0 100 200 300 400 500 600 85 90 95 100 Survival (%) P=.01 Fixed-dose I/H Placebo Hazard ratio=0.57

A-HeFT: Common Adverse Events: 

Placebo <.001 12.3 29.3 Dizziness 0.9 5.2 Severe <.001 19.2 47.5 Headache (all) .005 7.0 3.1 Severe exacerbation of HF .04 12.8 8.7 Exacerbation of HF P Value Fixed-dose I/H % of Patients A-HeFT: Common Adverse Events

A-HeFT: Conclusions: 

A-HeFT: Conclusions Fixed-dose I/H benefits African American HF patients treated with neurohormonal blockers: Increases survival by 43% Decreases first hospitalization for HF by 33% Improves QOL Nitric oxide enhancing therapy is a novel and highly effective heart failure treatment

Slide32: 

The A-HeFT Team A-HeFT African American Heart Failure Trial

The A-HeFT Team: 

The A-HeFT Team Steering Committee: Anne L. Taylor, MD, Chairperson Kirkwood F. Adams, MD Peter Carson, MD Jay N. Cohn, MD Keith Ferdinand, MD Elizabeth Ofili, MD Adeoye Olukotun, MD Malcolm Taylor, MD Clyde Yancy, MD Susan Ziesche, RN DSMB: David DeMets, PhD, Chairman Richard Grimm, MD, PhD Pamela Ouyang, MD Jackson T. Wright, Jr, MD, PhD ICAC: Peter Carson, MD, Chairman Allan B. Miller, MD Joann Lindenfeld, MD Christopher O’Connor, MD Felix Tristani, MD Jalal Ghali, MD Inderjit Anand, MD NitroMed: Manuel Worcel, MD Michael Sabolinski, MD Bill Tam, PhD Carol Gloff, PhD Ginny Braman Michael Lovell, PhD Dawn Spooner Judith Jaroncyk

Slide34: 

Mechanisms of Effective Therapy for Heart Failure RAS Blockade NO Enhancing Therapy/ Fixed-dose I/H b-Adrenergic Blockade Aldosterone Blockade