Transcript Document

Combination of Isosorbide Dinitrate and
Hydralazine in Blacks with Heart Failure
Anne L. Taylor, M.D., Susan Ziesche, R.N., Clyde Yancy, M.D.,
Peter Carson, M.D., Ralph D'Agostino, Jr., Ph.D., Keith Ferdinand,
M.D., Malcolm Taylor, M.D., Kirkwood Adams, M.D., Michael
Sabolinski, M.D., Manuel Worcel, M.D., Jay N. Cohn, M.D., for the
African-American Heart Failure Trial Investigators
Volume 351:2049-2057
November 11, 2004
Number 20
Pharm Background
• Hydralazine
Peripheral arterial vasodilator
Protection against degradation of NO induced by
oxidative stress
Unclear mechanism of action
• Isosorbide Dinitrate
Nitrate
Vasodilates arteries and veins
• Enalapril
ACE Inhibitor
Background
V-HeFT I (Vasodilator-Heart Failure Trial I)
Mortality of black patients receiving hydralazine plus
isosorbide dinitrate (H-I) was reduced (P = .04),
whereas white patients showed no difference from
placebo.
V-HeFT II (Vasodilator-Heart Failure Trial II)
Only white patients showed a mortality reduction from
enalapril therapy compared with H-I therapy (P = .02).
Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure:
analysis of the vasodilator-heart failure trials. J Card Fail 1999;5:178-187
V-HeFT I : Survival Benefit in Subgroups
African Americans
80%
80%
70%
70%
Cumulative Mortality
Cumulative Mortality
Non-African Americans
60%
50%
40%
30%
20%
10%
Risk Ratio=0.53
P=.04
60%
50%
40%
30%
20%
10%
n=480
n=180
0%
0%
0 6
18
30
42
54
66
0 6
Months
18
30
42
54
66
Months
I/H
Placebo
http://www.a-heft.org/AHeFTSlideDeck.ppt
Background
Conclusion: Whites and blacks showed differences in
cause, neurohormonal stimulation, and pharmacological
response in heart failure. This retrospective analysis
suggests angiotensin converting enzyme inhibitors are
particularly effective in whites, and the H-I combination can
be equally effective in blacks. Prospective trials involving
large numbers of black patients are needed to further
clarify their response to therapy.
Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for
heart failure: analysis of the vasodilator-heart failure trials. J Card Fail 1999;5:178-187
Background
• The Slavery Hypothesis, 1983
– Debunked by major historians
– Accepted without proof among many
scientists today
Background
• Hypertension is most prevalent in African
Americans
• 1 in 3 African Americans has hypertension
• 1 in 5 Americans has hypertension
• In 2002 the death rates per 100,000
population from (complications of) high blood
pressure were 14.4% for white males, 49.6%
for black males, 13.7% for white females and
40.5% for black females.
Background
• Blacks are affected by heart failure at a rate almost
twice the rate of whites and are more likely to die
from it at a younger age
• The mortality rate and the hospitalization rate for
African Americans with heart failure is significantly
higher than for non-African Americans, even after
adjustment for factors including access to medical
care, management of heart failure and
socioeconomic factors
http://www.nitromed.com/BiDil.asp
Study Design
• Randomized
• Placebo-controlled
• Double blind
• 161 centers
• 1050 patients
• No patients lost to follow-up
Inclusion Crieria
•
•
•
•
•
18+ years of age
Self-identified as black
NYHA class III or IV heart failure for 3+ months
Receiving “standard therapy” for heart failure
Evidence of left ventricular dysfunction
Exclusion Criteria
(selected)
• Severe cardiovascular event (acute MI, cardiac
arrest) or stroke in preceding 3 months
• Cardiac surgery or PCI in preceding 3 months
• Preexisting valvular disease, myocarditis, or
hypertrophic cardiomyopathy
• Inability to complete quality of life questionnaire
• Contraindications to nitrates or hydralazine
Evaluation and Follow-Up
• Initial evaluation: echocardiography, metabolic profile,
BNP, hemoglobin, quality of life questionnaire
• Every three months: quality of life questionnaire
• Every six months: EF, LV diastolic dimension, LV wall
thickness, BNP
• Telephone interview every month, follow-up visit every six
months
• Follow-up period: 18 months
Randomization
• Stratified by use or nonuse of beta blockers
• Randomized to:
– Fixed dose isosorbide dinitrate + hydralazine
– Placebo
Outcome Measure
• Composite Score:
– Death from any cause
– First hospitalization for heart failure during
18 month follow-up period
– Change in quality of life at 6 months
Scoring System
Statistical Analysis
• Intention-to-treat analysis
• Worst case score used for missing data
• Secondary analyses examined individual
components of composite end point
A-HeFT: Primary Endpoint
(Composite Score)
Placebo
Fixed-dose I/H
0
-0.25
-0.5
P=0.01
http://www.a-heft.org/AHeFTSlideDeck.ppt
A-HeFT: Components of Composite Score
Death
Change in
Quality of Life
First HF Hospitalization
(lower score is better)
-2.7
30
15
0
24.4%
10.2%
10
-2
6.2%
5
-5.6
20
N=54
16.4%
-4
N=130
N=32
0
N=85
10
P=0.02
-6
P=0.001
P=0.02
Placebo
Fixed-dose I/H
http://www.a-heft.org/AHeFTSlideDeck.ppt