ACTIVE A Health Economic Analysis of ACTIVE-A Andre Lamy Wesley Tong Peggy Gao Susan Chrolavicius Salim Yusuf Stuart J Connolly.

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

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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.

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Cost ComponentsAverage Cost Per Patient

Procedures

Non-study drugs

EventsStudy drug

TreatmentsLength of

StayInvestigation

s

Drugs

HHS OCCP

List Price ODB Formulary

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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

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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)

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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

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$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

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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

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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