ACTIVEACTIVE
A Health Economic Analysis of ACTIVE-A
Andre LamyWesley Tong
Peggy GaoSusan Chrolavicius
Salim YusufStuart J Connolly
ACTIVE
Role of the SponsorThe ACTIVE A trial and this economic
analysis were funded by grants from sanofi-aventis and Bristol-Myers Squibb.
The authors had free access to the complete study data and performed all of the analyses independently.
ACTIVE
The ACTIVE A trialThe Atrial Fibrillation Clopidogrel Trial with
Irbesartan for Prevention of Vascular Events – Aspirin trial
Clopidogrel with aspirin (C+A) vs aspirin aloneFor patients with atrial fibrillation unsuitable
for vitamin K antagonist7554 patients in 33 countries
AF patients at high risk of strokeN Eng J Med 2009; 360:2066-78
ACTIVE
Graph courtesy of the ACTIVE group
ACTIVE
Outcome
Clopidogrel + Aspirin
Aspirin Clopidogrel + Aspirin versus Aspirin
# rate/
year
# rate/ year
RR 95% CI P
Ischemic/Uncertain 268 2.1 388 3.2 0.68 0.59-0.80 <0.001
Hemorrhagic 30 0.2 22 0.2 1.37 0.79-2.37 0.27
Non-disabling(mod. Rankin 0-2)
107 0.9 153 1.2 0.70 0.54-0.89 0.004
Disabling or fatal (mod. Rankin 3-6)
198 1.6 267 2.1 0.74 0.62-0.89 0.001
Table courtesy of the ACTIVE group
ACTIVE
The risk of stroke was reduced by 28%However the risk of major bleeding increased by 57%
Most common site was the GI tract.In 1000 patients treated for 3 years, clopidogrel with
aspirin will:Prevent 28 strokes (17 fatal/disabling)Prevent 6 Myocardial InfarctionsResult in 20 major bleeds (3 fatal)
ACTIVE
ACTIVE-A Economic AnalysisClopidogrel + aspirin shown to reduce stroke
risk but increase risk of bleeding
Objective:To determine the economic impact of adding
clopidogrel to aspirin in the ACTIVE-A population
ACTIVE
DesignIn-trial analysisStudy time horizon used (average follow-up: 3.6 years)Only direct medical costs
Based on utilization data from CRFsCanadian healthcare perspectiveAll costs in 2008 CAD
Discounted at 3% per yearHypothesis: Clopidogrel + aspirin is cost neutral
compared to aspirin alone.
ACTIVE
Cost ComponentsAverage Cost Per Patient
Procedures
Non-study drugs
EventsStudy drug
TreatmentsLength of
StayInvestigation
s
Drugs
HHS OCCP
List Price ODB Formulary
ACTIVE
Cost of StrokeCost (2008
CAD)Ischemic Stroke $58,277
Hemorrhagic Stroke $61,537
TIA $8,104
Goeree R, Blackhouse G, Petrovic R, Salama S. J Med Econ 2005;8:147-67
ACTIVE
Unit CostsCost Cost
Myocardial Infarction $9,405 PCI with Stent $19,002
CHF $11,262Catheter/coronary
angiography$5,544
non-CNS systemic embolism
$10,162 CABG $17,951
Unstable angina $4,814 Pulmonary embolism $7,006
Minor bleed requiring at least 1 unit of blood
$7,235 Atrial fibrillation $5,526
GI bleeding with transfusion
$7,235
ACTIVE
Statistical AnalysisBootstrap method (5000 samples) for SE and
95% CI.Bias corrected and accelerated method for
confidence intervals
Sensitivity AnalysesClopidogrel cost ($2.52/day 2008 CAD)
50% of base200% of base
ACTIVE
ResultsPlacebo + AspirinMean Cost (CI)
Clopidogrel + AspirinMean Cost (CI)
Incremental CostMean Cost (CI)
Events$11,464 $9,839 −$1,625
Procedures $815 $729 −$86
Non-study Medication $1,478 $1,450 −$28
Study Medication $0 $2,114 $2,114
Total$13,756 ($13,032, $14,544) $14,132 ($13,445, $14,842) $376 (−$645, $1,397)
Total, discounted $12,961 ($12,274, $13,697) $13,308 ($12,664, $13,978) $347 (−$613, $1,307)
ACTIVE
Results
$11,464 $9,839
$815 $729
$1,478 $1,450 $2,114
$-$2,000 $4,000 $6,000 $8,000
$10,000 $12,000 $14,000 $16,000
Placebo + Aspirin Clopidogrel + Aspirin
Aver
age
Cost
(20
08 C
AD)
Average Cost per Category
Events Procedures Non-study Medications Study Medication
$13,756 $14,132
ACTIVE
$11,464 $9,891 $9,839 $9,839
$815 $729 $729 $729
$1,478
$1,450 $1,428 $1,492
$2,114 $1,057
$4,228
$-
$2,000
$4,000
$6,000
$8,000
$10,000
$12,000
$14,000
$16,000
$18,000
Placebo + Aspirin Clopidogrel + Aspirin
Clopidogrel 50% of base
Clopidogrel 200% of base
Aver
age
Cost
(20
08 C
AD
)
Sensitivity Analysis - Clopidogrel Cost
Events Procedures Non-study Medications Study Medication
$13,756 $14,132 $16,289
$13,054
ACTIVE
LimitationsOnly direct health care costs (mostly
hospitalizations)Indirect costs for C+A vs A alone presumably
lower due to fewer strokesWide Confidence Intervals (CI)
Due to large standard error in event costBootstrapping and jackknife showed similar
resultsAbsolute difference in cost is within predefined
margins for cost neutrality (+/- 5%)
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Applicable to the United States?Resource Utilization
No likely significant difference as treatments of AF patients are similar.
Unit costsCanadian costs are comparable to Medicare
costs.Cost of clopidogrel will be the determinant
factor between cost-saving, cost-neutral or cost-effective
ACTIVE
ConclusionCost of clopidogrel + aspirin not significantly
different from aspirin alone
Supports the use of clopidogrel + aspirin in patients unsuitable for Vitamin K antagonist therapy in the ACTIVE-A trial
ACTIVE
ACTIVE
Results with CIsBase Case Clopidogrel Cost 50%
of BaseClopidogrel Cost 200% of Base
Events -$1,625 (-$2,614 - ‑$637)
-$1,625 (-$2,614 - ‑$637)
-$1,625 (-$2,613 - ‑$637)
Procedures -$86 (-$28 - $109) -$86 (-$28 - $109) -$86 (-$28 - $109)
Non-study medications
-$28 (-$80 - $24) -$27 (-$77 - $23) -$31 (-$88 - $26)
Study medications
$2,114 ($2,073 - $2,155)
$1,057 ($1,036 - $1,078) $4,228 ($4,146 – $4,311)
Total $376 (-$645 - $1,397) -$680 (-$1,702 - $342) $2,488 ($1,467 – $3,509)
ACTIVE
Sensitvity Analysis – Drug CostBase Case Clopidogrel Cost 50%
of BaseClopidogrel Cost 200% of Base
Events -$1,625 (-$2,613, -$637) -$1,625 (-$2,613, -$637) -$1,625 (-$2,613, -$637)
Procedures -$86 (-$281, $109) -$86 (-$281, $109) -$86 (-$281, $109)
Non-study medications
-$28 (-$281, $109) -$27 (-$77, $23) -$31 (-$88, $26)
Study medications
$2,114 ($2,073, $2,155) $1,057 ($1,036, $1,078) $4,228 ($4,146, $4,310)
Total $376 (-$645, $1,397) -$680 (-$1,702, $342) $2,488 ($1,467, $3,509)
Total, discounted
$347 (-$613, $1,307) -$645 (-$1,606, $312) $2,332 ($1,372, $3,292)
ACTIVE
Outcome
Clopidogrel + Aspirin
Aspirin Clopidogrel + Aspirin versus Aspirin
# rate/
year
# rate/ year
RR 95% CI P
Major 251 2.0 162 1.3 1.57 1.29-1.92 <0.001
Severe 190 1.5 122 1.0 1.57 1.25-1.98 <0.001
Fatal 42 0.3 27 0.2 1.56 0.96-2.53 0.07
Intra-cranial 54 0.4 29 0.2 1.87 1.19-1.94 0.006
Extra-cranial 200 1.6 134 1.1 1.51 1.21-1.88 <0.001
Bleeding
Table courtesy of the ACTIVE group
ACTIVEACTIVE
Benefits and Risks: Compared to Warfarin
Effects
Warfarinversus
Aspirin
Clopidogrel & Aspirinversus
Aspirin
Meta-analysis*(RRR)
ACTIVE A(RRR)
Reduction in stroke - 38% -28%
Increase in intra-cranial bleed +128% +87%
Increase in extra-cranial bleed +70% +51%
*Hart RC et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have non-valvular AF . Ann Intern Med 2007: 146: 857-67
Table courtesy of the ACTIVE group