Isosorbide/hydralazine combination

D. C. Angus, Zwirble WT Linde, S. W. Tam, J. K. Ghali, M. L. Sabolinski, V. G. Villagra, W. C. Winkelmayer, M. Worcel, and American Heart Failure Trial African. Cost- effectiveness of fixed-dose combination of isosorbide dinitrate and hydralazine therapy for blacks with heart failure. Circulation 112 (24):3745–3753, 2005.
Study detailsPopulation & interventionsHealth outcomesCostsCost effectiveness
Economic analysis:
Cost-effectiveness analysis

Study design:
Decision-analytic model (based on the A-HeFT study)

Perspective:
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US perspective

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Included direct healthcare costs and excluded indirect and non-healthcare costs

Time horizon:
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18 months (A-HeFT follow- up)

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Lifetime

Discounting:
Future costs and survival were discounted at 3% per annum.
Population:
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Black people with moderate to severe heart failure

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Mean age: 56.8 years

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100 % black people

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40% women

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94.9% NYHA class III heart failure

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93% were on ACEi or ARB

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87% were on BB

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Treatment N=518; control N=532

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Baseline characteristics were similar across arms

Intervention 1:
Standard therapy (BB, ACEi or ARB, aldosterone antagonist, digoxin and diuretics as appropriate)

Intervention 2:
Standard therapy + ISDN/HYD therapy (20mg/ 37.5mg); starting with 1 tablet 3 times daily and titrating to 2 tablets 3 times daily as tolerated.

Average dose: 4.2 tablets per day.

68% took full doses of 6 tablets per day at some time.

Failure of adherence (treatment vs placebo): 3.2% vs 10.2%; p=0.016.

Mean follow-up: 12.8 months.
Health outcomes incorporated:
Data from A-HeFT RCT (18- month follow-up):
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Mortality (treatment vs placebo): 6.2% vs 10.2%; p=0.016

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Survival time: 403 vs 380 days; p=0.01

Post trial survival:
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Use 5-year follow-up data for NYHA class III patients reported by Bardy 2005

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Assumed that survival curves of treatment and control arms decayed at the same rate.

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Zero survival at 10 years.

Cost components incorporated:
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Hospitalisation (including physician cost);

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ER visits;

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Unscheduled physician visits;

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Scheduled physician visits;

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ISDN/HYD therapy; Concomitant medication;

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Other cares.

Resource use as collected from the A-HeFT trial.

Currency & cost year:
2004 US dollars

Resource use results from A-HeFT:
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43% of hospitalisations were related to heart failure

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30% fewer heart failure-related hospitalisations for treatment group

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One-day reduction in the average LOS for each heart failure- related hospitalisations for the treatment group

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All-cause hospitalisations, unscheduled office visits, ER visits, and use of concomitant medications: not significantly different between groups

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All-cause hospitalisation LOS shorter for treatment group

ICER:
Reported cost per life-year gained.

Results reported using 2 total cost estimates:
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Heart failure-related cost;

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All healthcare-related cost

Cost-effectiveness within the A-HeFT study period (18 months):
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ISDN/HYD therapy is dominant (improved survival and saved cost) using both heart failure-related cost ($9144-$8611=$553) and all healthcare-related cost ($19728- $17998=$1730).

Bootstrap simulation sampling:
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Heart-failure related cost: 49% dominant; 66% better than $10 000/life-year gained

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All health costs: 71% dominant; 82% better than $10 000/life-year gained

Lifetime horizon:
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Using the assumption that there were no additional benefits of ISDN/HYD therapy beyond the trial period (survival and resource use – except drug cost for treatment arm); ICER = $41 800 per life-year gained (hearth failure-related costs); $44 400 (all medical costs)

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When considering that ISDN/HYD therapy had benefit beyond the trial, considering one additional year of effect, the lifetime ICER was estimated to be $22 900 per life-year gained (hearth failure-related cost); $32 900 (all medical costs).

Sensitivity analysis:
Were varied:
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Hospital cost and ISDN/HYD therapy cost ± 50%;

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Cost of concomitant medication, unscheduled office visits, ER visits, and other usual medical care from +100% to −50%.

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Other hospitalisation costs were used.

Sensitivity analysis results:
The incremental cost was most sensitive to hospital cost and treatment cost (ISDN/HYD therapy) variations.
Using an alternative hospitalisation cost (Medicare heart failure-related hospitalisation cost unadjusted for race, gender, and LOS [adjusted for the main analysis]):
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ISDN/HYD therapy no longer dominant

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Using hearth failure-related costs; ICER = $10 335 per life-year gained; 24% of simulations dominant; 49% of simulations less than $10 000/life-year gain

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Using all medical costs; ICER = $1546 per life- year gained; 46% of simulations dominant; 66% of simulations less than $10 000/life- year gained

Data sources
Health outcomes:
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First 18-month survival from the A-HeFT study.

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Survival curves post-trial: was used 5-year follow-up data for NYHA class III patients reported by Bardy 20051.

1 Gust H. Bardy, M.D., Kerry L. Lee, Ph.D., Daniel B. Mark, M.D., Jeanne E. Poole, M.D., Douglas L. Packer, M.D., Robin Boineau, M.D., Michael Domanski, M.D., Charles Troutman, R.N., Jill Anderson, R.N., George Johnson, B.S.E.E., Steven E. McNulty, M.S., Nancy Clapp-Channing, R.N., M.P.H., Linda D. Davidson-Ray, M.A., Elizabeth S. Fraulo, R.N., Daniel P. Fishbein, M.D., Richard M. Luceri, M.D., John H. Ip, M.D., for the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an Implantable Cardioverter Defibrillator for Congestive Heart Failure. N Engl J Med 2005;352:225–237.
Cost sources:
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Hospitalisation cost: 2003 Medicare Hospital Discharge Database. Washington, DC. Data adjusted to years 2004. Increased this cost by 17% to account for physician fees (published method).

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Cost for ER and unscheduled physician visits; cost for scheduled physician visits; and cost for other cares: Medicare Utilisation for Part B (supplementary Medical Insurance SMI). Baltimore, Md: Centres for Medicare and Medicaid Services; 2004.

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Concomitant medication: 2004 Red book.

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ISDN/HYD therapy: Manufacturer’s (NitroMed Inc) announced price.

Comments
Source of funding:
NitroMed Inc

Limitations:
This study did not use QALYs as health outcome (assessed in A-HeFT trial using the ‘Minnesota Living With Heart Failure’ survey, for which no validated approach to generate utility scores exist). To note that patients in the treatment arm reported better quality of life.
Overall quality*: Minor limitationsOverall applicability**: Partially applicable

Abbreviations: ICER = incremental cost-effectiveness ratio; NHS = National Health Service; A-HeFT = African-American Heart Failure Trial; ISDN/HYD = Fixed-dose combination of isosorbide dinitrate and hydralazine; BB = Beta-blockers; ACEi = Angiotensin-converting enzyme inhibitors; ARB = Angiotensin receptor blockers; RCT = Randomised controlled trial; LOS = Length of stay; NYHA = New York Heart Association.

*

Very serious limitations/Potentially serious limitations/Minor limitations;

**

Directly applicable/Partially applicable/Not applicable

From: Appendix G, Health Economics 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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