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.