Evidence TablesBlack population

isosorbide + hydralazine in comparison to placebo

isosorbide + hydralazine in comparison to ACEI

Carson P, Ziesche S, Johnson G et al. Racial differences in response to therapy for heart failure: Analysis of the Vasodilator-Heart Failure Trials. Journal of Cardiac Failure. 1999; 5(3):178–187. Ref ID: 650

V-HeFT I and II
RCT
Randomised,
Double-blinded
VHEFT I:
N=642

VHEFT II:
N=804
Inclusion criteria: male patients with a history of heart failure or documentation of left ventricular enlargement or dysfunction by chest radiography, echocardiography, or radionuclide ventriculography. One of the following was required (i) a radiographic cardiothoracic ratio (CTR) >0.55, an echocardiographic left ventricular end-diastolic diameter >2.7 cm/m2 of body surface area, or radionuclide left ventricular ejection fraction (EF) <0.45. Patients also had to have reduced maximal exercise tolerance, defined as a measured peak oxygen consumption (VO2) <25 mL/kg/min during a progressive bicycle ergometer exercise test.
Exclusion criteria: not mentioned
Patient Characteristics:
Nearly all patients were receiving background therapy with diuretics and/or digoxin.
VHEFT I:
642 male patients (NYHA classes I+II)
Black/white: 180/450
Age:
  • White: 59.2 ± 6.9
  • Black: 56.3 ± 9.0
  • p<0.01
Coronary artery disease (CAD)(%):
  • White: 53.2
  • Black: 20.8
  • p<0.01
History of hypertension (%)
  • White: 37.3
  • Black: 46.6
  • NS
VHEFT II:
804 male patients (NYHA classes I+II)
Black/white: 215/574
Age:
  • White: 61.1 ± 8.0
  • Black: 58.8 ± 9.0
  • NS
Coronary artery disease (CAD)(%):
  • White: 61.6
  • Black: 28.4
  • p<0.01
History of hypertension (%)
  • White: 41.5
  • Black: 64.9
  • p<0.01
VHEFT I:
-

prazosin 5mg 4×day

OR

-

combination of hydralazine 75mg + isosorbide dinitrate 40mg 4× day.

VHEFT II:
-

combination of hydralazine 75mg + isosorbide dinitrate 40mg 4× day

VHEFT I:
-

placebo

VHEFT II:
-

enalapril 10mg 2×day

Minimum 6 months or until deathMortality, hospitalizations,
EF, exercise tolerance
Veterans Affairs Cooperative Studies Program
Effect Size
Outcomes
  1. Mortality (end period reported 66 months-5.5yrs)
    VHEFT I
    • Black patients:
      • HI group: deaths 15/49 (annual mortality rate (AMR) 9.7%)
      • Placebo: deaths 35/79 (AMR 17.3%)
      • p=0.04
    • White patients:
      • HI group: deaths 56/132 (AMR 16.9%)
      • Placebo: deaths 85/192 (AMR 18.8%)
    VHEFT II
    • Black patients:
      • HI group: deaths 39/109 (AMR 12.9%)
      • Enalapril: deaths 39/106 (AMR 12.8%)
      • p=NS
    • White patients:
      • HI group: deaths 112/282 (AMR 14.9%)
      • Enalapril: deaths 90/292 (AMR 11.0%)
      • P=0.09
    • A trend for a significant interaction between race and treatment was shown, p=0.09
  2. Hospitalization for CHF
    VHEFT I
    • White
    • Black
      • Placebo 16 (20.3)
      • HI 11 (22.4)
      • p=0.77
    • White vs. black p=0.18
    VHEFT II
    • White
    • Black
    • White vs. black p=0.20
    • No difference in hospitalization for HF between black vs. white patients
  3. Hospitalization for any reason
    VHEFT I
    • White
    • Black
    • White vs. black p=0.10
    VHEFT II
    • White
    • Black
    • White vs. black p=0.51
    • No difference in all cause hospitalization between black vs. white patients
  4. Exercise tolerance-change in Maximal VO2 (figures taken from graph)
    VHEFT II
Authors’ Conclusion: ‘the H-I combination appears to be particularly effective in prolonging survival in black patients and is as effective as enalapril in this subgroup. In contrast, enalapril shows its more favourable effect on survival, particularly in the white population.’
Taylor AL, Ziesche S, Yancy C et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. New England Journal of Medicine. 2004; 351(20):2049–2057. Ref ID: 61

A-HeFT
RCT
Mult-centre
Double blind
Randomisation – stratified by use or nonuse of beta blockers as background therapy. Blocks of 4 per stratum were used, with each site allowed to randomise upto 6 blocks of patients (24 patients) in the non-beta block group and up to 10 blocks (40 patients) in the beta blocker groups

Treatment allocation – performed centrally
Power analysis (N=400 per group)
Full ITT analysis
N=1050
No. of centres
N=161
Screening criteria: Patients 18 yrs or older, self-identified as black (defined as of African descent), who had NYHA class III or IV heart failure for at least three months

Inclusion criteria: On standard therapy for heart failure, as deemed appropriate by their physicians; such therapy included angiotensin-converting-enzyme inhibitors (ACEIs), beta blockers for at least three months before randomisation, digoxin, spronolactone and diurectics

Evidence of left ventricular ejection fraction (LVEF) within the six months preceding randomisation in the form of resting LVEF of no more than 35% or a resting LVEF of less than 45% with a left ventricular internal end-diastolic diameter of more than 2.9 cm per square meter of body-surface area, or more than 6.5 cm on the basis of echocardiography (Echo)

Exclusion criteria: acute myocardial infarction, acute coronary syndrome, or stroke within the preceding three months; cardiac surgery or percutaneous coronary intervention within the preceding three months or the likelihood of a requirement for such procedures during the study period; clinically significant valvular heart disease, hypertrophic or restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension; a history of cardiac arrest or life threatening arrhythmias within the preceding three months (unless treated with an implantable defibrillator); treatment with parental inotropic agents within the one month before randomisation, a potential need for cardiac transplantation; the presence of symptomatic hypotension; the presence of an illness other than heart failure that was likely to result in death within the study period
Fixed-dose combination of isosorbide dinitrate plus hydralazine

N=518

37.5 mg hydralazine hydrochloride + 20 mg isosorbide dinitrate three times daily

Dose increased to two tables three time daily, total dose 225 mg hydralazine and 120 mg isosorbide

Increase in dose was dependent on the absence of drug-induced side effects
Placebo

N=532
Upto 18 mths (mean 10 mths)Primary: Composite score made up of weighted values for death from any cause, a first hospitalisation for heart failure during the 18-month follow-up period, and a change in quality of life at 6 months

Quality of life – Minnesota Living with Heart Failure questionnaire, 21 items (self-administered). Higher score = poorer quality of life

Composite score
Death (any time during trial) −3
Survival to end of trial 0
First hospitalisation for heart failure −1
No hospitalisation 0
Change if quality of life at 6 mths (or last measurement):
Improvement by ≥ 10 units, +2, improvement by 5 to 9 units +1, change by < 5 units 0. worsening by 5 to 9 units −1, worsening by ≤ 10 units −2 (score −6 to +2)

Secondary endpoints: individual components of the composite score, the total number of hospitalisations for heart failure, total number of hospitalisations for any reason, overall quality of life throughout the trial, the number of unscheduled emergency room and office or clinic visits
Nitromed
Patient population
Isosorbide plus hydralazinePlacebo
Age yrs56.7 (12.7)56.9 (13.3)
Male sex (%)58.8*63.9
Weight (kg)92.5 (21.4)94.2 (25.5)
Primary cause of heart failure (%)
Ischemic heart disease23.422.7
Hypertension40.037.4
Idiopathic24.527.6
Valvular cause2.53.2
Other9.79.0
NYHA class (%)
I022.7
II0.20
III96.70
IV3.194.7
5.3
Diabetes (%)44.8**37.0
Renal insufficiency (%)16.218.2
Atrial fibrillation (%)15.018.0
Cardiac resynchronisation therapy (%)2.02.1
Implantable cardiac defibrillator (%)16.617.3
Ejection fraction (%)23.9 (7.3)24.2 (7.5)
LVIDD (cm)6.5 (0.9)6.5 (1.0)
Blood pressure
Systolic127.2 (17.4)125.3 (18.1)
Diastolic77.6 (10.3)***75.6 (10.5)
Minnesota Living with Heart Failure Questionnaire score (0 to 105)50.9 (24.9)***50.7 (25.5)
Medications for heart failure (%)
Diurectic88.091.5
ACEI69.469.5
ARB17.216.5
Beta blocker74.173.5
Carvedilol55.255.8
Digoxin58.560.7
Spironolactone40.237.6
*p=0.008 vs placebo; ** p=0.01 vs placebo; *** p=0.002 vs placebo
Effect
The trial was halted early due to the significantly higher mortality in patients given placebo compared to isosorbide plus hydralazine (planned recruitment N=1100, actual N=1050)

Isosorbide plus hydralazine (N=518) vs placebo (N=532)
Primary composite score (range6 to 2) mean (SD), mean duration of follow-up 10 months (range 0 to 18)
Isosorbide plus hydralazine vs placebo
−0.1 (1.9) vs 0.5 (2.0); p=0.01

Mortality (any cause), mean duration of follow-up 10 months (range 0 to 18)
Isosorbide plus hydralazine vs placebo
At the time the trial was halted 32/518 (6.2%) vs 54/532 (10.2%)

Change in quality of life score at six months mean (SD) (n=742 completed and for rest earlier assessment used or worst possible score used)
Isosorbide plus hydralazine vs placebo
−5.6 (20.6) vs −2.7 (21.1); p=0.02

Adverse events, mean duration of follow-up 10 months (range 0 to 18)
Isosorbide plus hydralazine vs placebo
Headache 47.5 vs 19.2; p<0.001
Dizziness 29.3 vs 12.3; p<0.001

TAKEN FROM Taylor AL, Ziesche S, Yancy CW et al. Early and sustained benefit on event-free survival and heart failure hospitalization from fixed-dose combination of isosorbide dinitrate/hydralazine: consistency across subgroups in the African-American Heart Failure Trial. Circulation. 2007; 115(13):1747–1753. Ref ID: 14

Mortality (cardiovascular death), mean duration of follow-up 10 months (range 0 to 18)
Isosorbide plus hydralazine vs placebo
26/518 (5.0%) vs 45/532 (8.5%); p=0.027

TAKEN FROM: Angus DC, Linde ZW, Tam SW et al. Cost-effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure. Circulation. 2005; 112(24):3745–3753. Ref ID: 423

Mean follow-up 12.8 months

Total number of hospitalisations for heart failure (by total no. of patients)
Iso/Hyd vs placebo
173/518 vs 251/532

Total number of ER and unscheduled office visits (by total no. of patients)
Iso/hyd vs placebo
32/518 vs 43/532

From: Appendix E, Clinical Evidence Tables

Cover of Chronic Heart Failure
Chronic Heart Failure: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care: Partial Update [Internet].
NICE Clinical Guidelines, No. 108.
National Clinical Guideline Centre (UK).
Copyright © 2010, National Clinical Guideline Centre.

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