Transcript ACTIVE-A
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.
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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