V-HeFT and the Road to A-HeFT · left ventricular internal diameter in diastole >2.7 cm per square...
Transcript of V-HeFT and the Road to A-HeFT · left ventricular internal diameter in diastole >2.7 cm per square...
Measuring Quality and Performance in Treatment of Heart Failure in African-American Patients:
V-HeFT and the Road to A-HeFT Peter Carson M.D.
Chronology of ISDN/Hydralazine
ISDN/HYD V-HeFT I
FDA
(Paper NDA)
BIDIL
Sub-group
Analyses A-HeFT
1980 1985 1995 2000
FDA
(BIDIL) FDA
(Sub-group)
1990
Heart Failure Therapy – the beginning
Vasodilator Therapy
5 NITRO0010 — AHeFT Slides — v11
Chest. 1978;73:8-13.
V-HeFT Inclusions/Exclusions
• Men between the ages of 18 and 75. Veterans Hospitals
• Cardiac dilatation (cardiothoracic ratio >0.55 on chest x-ray film or a left ventricular internal diameter in diastole >2.7 cm per square meter on echocardiography) or radionuclide LVEF <45 percent
• reduced exercise tolerance (peak <25 ml per kg of body weight per minute) -excluded if exercise tolerance was limited by chest pain rather than by breathlessness and fatigue.
• Exclusions - a myocardial infarction within the previous 3 months, obstructive valvular disease or considerable CAD, COPD, or other disease likely to limit five-year survival.
• No concomitant CV meds- BB, RAS inhibitors, vasodilators
Survival in All Patients V-HeFT I
9
ISDN/HYD n = 186 148 109 71 37 16
Placebo n = 276 202 135 84 41 10
Prazosin n = 183 135 94 58 27 7
25
50
75
100
0 365 730 1095 1460 1825
Su
rviv
al, %
P = 0.093
ISDN/HYD vs placebo
Days since randomization date
Cohn JN et al. N Engl J Med. 1986;314:1547-1552.
ISDN/HYD
Placebo
Prazosin
ISDN/HYD = isosorbide dinitrate plus hydralazine
2
6
Survival in All Patients V-HeFT II
ISDN/HYD n = 401 332 242 157 86 3
Enalapril n = 403 346 265 169 89 1
Enalapril
lSDN/HYD
40
50
60
70
80
90
100
0 365 730 1095 1460 1825
Su
rviv
al,
%
Time, days since randomization
HR = 1.23 (0.97, 1.55)
Log-rank P = 0.083
Cohn JN et al. N Engl J Med. 1991;325:303-310.
Effect of Captopril on BP
100
80
60
40
20
0 Placebo Captopril
12.5 mg Captopril 25.0 mg
Captopril 37.5 mg
Captopril 50.0 mg
43 33 36 42 38 40 50 34 46 35
Whites
Blacks
Perc
en
t P
ati
en
ts A
ch
ievin
g B
loo
d
Pre
ssu
re G
oal
(< 9
1 m
mH
g)
V-HeFT II: Baseline Variables
Black (n = 215)
White (n = 574)
Ejection fraction (%)
MVO (ml / Kg / min)
SBP sitting (mmHg)
PNE (pg / ml)
PRA (ng / mL / hr)
Cardiothoracic ratio
CAD (%)
Hx HTN (%)
29.2 ± 11.5
13.4 ± 3.4
126.0 ± 16.6
449 (330 - 602)
6.55 ( 3.4 - 12.7 )
54.3 ± 6
28.4
64.9
29.0 ± 11.1
13.9 ± 3.5 *
126.4 ± 17.3
504 (368 - 693) **
7.3 ( 3.9 - 17.7 )
52.2 ± 6 *
61.6 **
41.5 **
PNE = plasma norepinephrine; PRA = plasma renin activity
* = p < 0.05; ** = p < 0.01
2
Survival in Black Patients and White Patients V-HeFT II
Carson P et al. J Card Fail. 1999;5:178-187.
Black patients White patients
ISDN/HYD
Enalapril
Time, days since randomization Patients, n
ISDN/HYD 109 92 67 49 29 1 282 231 171 105 55 1
Enalapril 106 93 69 47 24 2 292 251 194 123 66 1
40
50
60
70
80
90
100
0 365 730 1095 1460 1825
Su
rviv
al, %
40
50
60
70
80
90
100
0 365 730 1095 1460 1825
Su
rviv
al, %
HR = 1.01 (0.65, 1.58)
P = 0.96
HR = 1.39 (1.05, 1.83)
P = 0.02
V - HeFT II: Mortality by Race and Hypertensive
History
Months 0 6 12 18 24 30 36 42 48 54 60 66
p < 0.47
Hyd - Iso Enalapril
0 0.1
0.2
0.3 0.4
0.5
0.6
0.7
0.8
Cu
mu
lative
Mo
rta
lity
Black Patients w / o Hypertensive History (n = 72)
p < 0.24
0 0.1
0.2
0.3 0.4
0.5
0.6
0.7
0.8
Cum
ula
tive M
ort
alit
y
Months 0 6 12 18 24 30 36 42 48 54 60 66
White Patients w / o Hypertensive History (n = 318)
Black Patients with Hypertensive History (n = 132)
p < 0.65
0 0.1
0.2
0.3 0.4
0.5
0.6
0.7
0.8 C
um
ula
tive
Mo
rta
lity
Months 0 6 12 18 24 30 36 42 48 54 60 66
p < 0.026
0 0.1
0.2
0.3 0.4
0.5
0.6
0.7
0.8
Cu
mu
lative
Mo
rta
lity
Months 0 6 12 18 24 30 36 42 48 54 60 66
White Patients with Hypertensive History (n = 218)
V-HeFT ll Remodeling
V-HeFT ll Data
Survival in All Patients V-HeFT I
9
ISDN/HYD n = 186 148 109 71 37 16
Placebo n = 276 202 135 84 41 10
Prazosin n = 183 135 94 58 27 7
25
50
75
100
0 365 730 1095 1460 1825
Su
rviv
al, %
P = 0.093
ISDN/HYD vs placebo
Days since randomization date
Cohn JN et al. N Engl J Med. 1986;314:1547-1552.
ISDN/HYD
Placebo
Prazosin
ISDN/HYD = isosorbide dinitrate plus hydralazine
V-HeFT I: Baseline Variables
Black (n = 180)
White (n = 480)
Ejection fraction (%)
SBP sitting (mmHg)
Age (years)
Cardiothoracic ratio
CAD (%)
Hx HTN (%)
31.3 ± 14.1
118.0 ± 16.4
56.3 ± 9.0
55.0 ± 6.3
20.8
46.6
29.3 ± 12.4
119.7 ±19.6
59.2 ± 6.9 **
52.7 ± 6.3 **
50.2 **
37.3 *
* = p < 0.05; ** = p < 0.01 Black vs White CAD = coronary artery disease
hx HTN = history of hypertension
Survival in Black Patients and White Patients V-HeFT I
Patients, n
ISDN/HYD 49 43 36 28 16 8 132 102 71 42 22 9
Placebo 79 61 44 29 14 3 192 140 91 55 27 8
Time, days since randomization
ISDN/HYD
Placebo
Black patients
HR = 0.53 (0.29, 0.98)
P = 0.04
White patients
HR = 0.88 (0.63, 1.24)
P = 0.47
30
40
50
60
70
80
90
100
0 365 730 1095 1460 1825 S
urv
ival
, %
30
40
50
60
70
80
90
100
0 365 730 1095 1460 1825
Su
rviv
al, %
Carson P et al. J Card Fail. 1999;5:178-187
CHF Hospitalization
V - HeFT I
Race Subgroup
Total
Hospitalized
CHF
V - HeFT II
White Black
Total
Hospitalized
CHF
HYD - ISO Enalapril Total HYD - ISO Total Enalapril
Placebo HYD - ISO Prazosin Total Placebo HYD - ISO Prazosin Total
49 (25.5 %)
40 (31.5 %)
32 (24.2 %)
121 16 (25.5 %)
12 (25.5 %)
12 (25.5 %)
39
51 (18.1 %)
51 (17.5 %)
102 24 (22.6 %)
23 (21.1 %)
47
V-HeFT and the Road to A-HeFT
• The V-HeFT retrospective analysis
indicated mortality benefit in African-
American patients.
• There was a physiologic rationale
developing related to NO
• Like all post-hoc analyses, this needed to
be prospectively tested for validity.
• IT WAS!
Taylor AL et al. N Engl J Med. 2004;351:2049-2057.
A-HeFT: All-Cause Mortality 43% Decrease
Fixed-dose H/I 518 463 407 359 313 251 13
Placebo 532 466 401 340 285 232 24
Days Since Baseline Visit Date
0 100 200 300 400 500 600 85
90
95
100
Sur
viva
l (%
)
P=0.01
ISDN/HYD FDC
Placebo Hazard ratio=0.57
Racial Differences in the Outcome of Left Ventricular Dysfunction Dries et al, NEJM 1999; 340:609-616
Exner DV et al. N Engl J Med 2001;344:1351-1357.
Outcomes among Black Patients as Compared with Matched White Patients.
Exner DV et al. N Engl J Med 2001;344:1351-1357.
Outcomes among Black and Matched White Patients Assigned to Enalapril Therapy as Compared with
Placebo.
Exner DV et al. N Engl J Med 2001;344:1351-1357.
Rates of Death from Any Cause (Top Panel) and of Hospitalization for Heart Failure (Bottom Panel) among Black Patients and Matched
White Patients Randomly Assigned to Enalapril or Placebo.