ACTIVE
A Health Economic Analysis of ACTIVE-A
Andre Lamy
Wesley Tong
Peggy Gao
Susan Chrolavicius
Salim Yusuf
Stuart J Connolly
ACTIVE
Role of the Sponsor
 The ACTIVE A trial and this economic analysis were
funded by grants from sanofi-aventis and BristolMyers Squibb.
 The authors had free access to the complete study data
and performed all of the analyses independently.
ACTIVE
The ACTIVE A trial
 The Atrial Fibrillation Clopidogrel Trial with Irbesartan
for Prevention of Vascular Events – Aspirin trial
 Clopidogrel with aspirin (C+A) vs aspirin alone
 For patients with atrial fibrillation unsuitable for vitamin
K antagonist
 7554 patients in 33 countries
 AF patients at high risk of stroke
 N Eng J Med 2009; 360:2066-78
ACTIVE
0.10
HR= 0.72 (0.62-0.83) p= 0.00002
0.05
Placebo+ Aspirin
Clopidogrel+ Aspirin
0.0
Cumulative Hazard Rates
0.15
Stroke
0
No. at Risk
C+A 3772
A S A 3782
1
2
3
4
3491
3458
3229
3155
2570
2517
1203
1186
Years
Graph courtesy of the ACTIVE group
ACTIVE
Stroke Types and Severity
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
Summary of Clinical Findings
 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 Infarctions
 Result in 20 major bleeds (3 fatal)
ACTIVE
ACTIVE-A Economic Analysis
 Clopidogrel + 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
Design
 In-trial analysis
 Study time horizon used (average follow-up: 3.6 years)
 Only direct medical costs
 Based on utilization data from CRFs
 Canadian healthcare perspective
 All costs in 2008 CAD
 Discounted at 3% per year
 Hypothesis: Clopidogrel + aspirin is cost neutral
compared to aspirin alone.
ACTIVE
Cost Components
Average Cost
Per Patient
Study drug
Events
Non-study
drugs
Procedures
List Price
ODB Formulary
Drugs
Treatments
Length of Stay
Investigations
HHS
OCCP
ACTIVE
Cost of Stroke
Cost (2008 CAD)
Ischemic Stroke
$58,277
Hemorrhagic Stroke
$61,537
TIA
$8,104
 Stroke costs include:
 Hospital
 Assistive devices
 Ambulatory care
 Allied health
 Physician fees
professionals
 Home modifications
 Caregiver expenses
 Tests and procedures
 All medications
Goeree R, Blackhouse G, Petrovic R, Salama S. J Med Econ 2005;8:147-67
ACTIVE
Unit Costs
Cost
Cost
Myocardial Infarction
$9,405
PCI with Stent
$19,002
CHF
$11,262
Catheter/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 Analysis
 Bootstrap method (5000 samples) for SE and 95% CI.
 Bias corrected and accelerated method for confidence
intervals
Sensitivity Analyses
 Clopidogrel cost ($2.52/day 2008 CAD)
 50% of base
 200% of base
ACTIVE
Results
Placebo + Aspirin
Mean Cost (CI)
Events
Clopidogrel + Aspirin
Mean Cost (CI)
Incremental Cost
Mean Cost (CI)
$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
$13,756 ($13,032, $14,544)
$14,132 ($13,445, $14,842)
$376 (−$645, $1,397)
$12,961 ($12,274, $13,697)
$13,308 ($12,664, $13,978)
$347 (−$613, $1,307)
Total
Total,
discounted
ACTIVE
Results
Average Cost per Category
Average Cost (2008 CAD)
$16,000
$14,000
$14,132
$13,756
$2,114
$1,450
$729
$1,478
$815
$12,000
$10,000
$8,000
$6,000
$11,464
$9,839
$4,000
$2,000
$Placebo + Aspirin
Events
Procedures
Clopidogrel + Aspirin
Non-study Medications
Study Medication
ACTIVE
Sensitivity Analysis - Clopidogrel Cost
$16,289
$18,000
$13,756
Average Cost (2008 CAD)
$16,000
$14,000
$1,478
$815
$12,000
$10,000
$14,132
$2,114
$13,054
$4,228
$1,450
$729
$1,057
$1,428
$729
$1,492
$729
$9,891
$9,839
$9,839
Clopidogrel +
Aspirin
Clopidogrel
50% of base
Clopidogrel
200% of base
$8,000
$6,000
$11,464
$4,000
$2,000
$-
Placebo + Aspirin
Events
Procedures
Non-study Medications
Study Medication
ACTIVE
Limitations
 Only direct health care costs (mostly hospitalizations)
 Indirect costs for C+A vs A alone presumably lower due
to fewer strokes
 Wide Confidence Intervals (CI)
 Due to large standard error in event cost
 Bootstrapping and jackknife showed similar results
 Absolute difference in cost is within predefined margins
for cost neutrality (+/- 5%)
ACTIVE
Applicable to the United States?
 Resource Utilization
 No likely significant difference as treatments of AF
patients are similar.
 Unit costs
 Canadian costs are comparable to Medicare costs.
 Cost of clopidogrel will be the determinant factor
between cost-saving, cost-neutral or cost-effective
ACTIVE
Conclusion
 Cost 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 CIs
Base Case
Events
-$1,625 (-$2,614 -$637)
Clopidogrel Cost 50%
of Base
-$1,625 (-$2,614 -$637)
Procedures
-$86 (-$28 - $109)
-$86 (-$28 - $109)
-$86 (-$28 - $109)
Non-study
-$28 (-$80 - $24)
medications
-$27 (-$77 - $23)
-$31 (-$88 - $26)
Study
$2,114 ($2,073 medications $2,155)
$1,057 ($1,036 - $1,078) $4,228 ($4,146 – $4,311)
Total
$376 (-$645 - $1,397) -$680 (-$1,702 - $342)
Clopidogrel Cost 200%
of Base
-$1,625 (-$2,613 - -$637)
$2,488 ($1,467 – $3,509)
ACTIVE
Sensitvity Analysis – Drug Cost
Base Case
Events
Clopidogrel Cost 50% Clopidogrel Cost 200%
of Base
of Base
-$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
-$28 (-$281, $109)
-$27 (-$77, $23)
medications
Study
$2,114 ($2,073, $2,155) $1,057 ($1,036, $1,078)
medications
Total
$376 (-$645, $1,397)
-$680 (-$1,702, $342)
-$31 (-$88, $26)
Total,
discounted
$2,332 ($1,372, $3,292)
$347 (-$613, $1,307)
-$645 (-$1,606, $312)
$4,228 ($4,146, $4,310)
$2,488 ($1,467, $3,509)
ACTIVE
Bleeding
Outcome
Clopidogrel
+ Aspirin
Aspirin
Clopidogrel + Aspirin versus
Aspirin
#
rate/
year
#
rate/
year
RR
95% CI
P
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
Major
Table courtesy of the ACTIVE group
ACTIVE
Benefits and Risks:
Compared to Warfarin
Warfarin
versus
Aspirin
Clopidogrel & Aspirin
versus
Aspirin
Meta-analysis*
ACTIVE A
(RRR)
(RRR)
Reduction in stroke
- 38%
-28%
Increase in intra-cranial bleed
+128%
+87%
Increase in extra-cranial bleed
+70%
+51%
Effects
*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