1. The Cost of Clopidogrel Use in Atrial Fibrillation
A Health Economic Analysis of ACTIVE-A
Andre Lamy
Wesley Tong
Peggy Gao
Susan Chrolavicius
Salim Yusuf
Stuart J Connolly

2. Role of the Sponsor
The 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.

3. 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:

4. Stroke
Graph courtesy of the ACTIVE group

5. 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
<0.001
Hemorrhagic 30
0.2 22
1.37
0.27
Non-disabling
(mod. Rankin 0-2)
107
0.9
153
1.2
0.70
0.004
Disabling or fatal (mod. Rankin 3-6)
198
1.6
267
0.74
0.001
Table courtesy of the ACTIVE group

6. 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)

7. 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

8. 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.

9. Average Cost Per Patient
Cost Components
Average Cost Per Patient
Procedures
Non-study drugs
Events
Study drug
List Price
ODB Formulary
Treatments
Length of Stay
Investigations
Drugs
HHS
OCCP

10. Cost of Stroke Stroke costs include: Hospital Assistive devices
Cost (2008 CAD)
Ischemic Stroke
$58,277
Hemorrhagic Stroke
$61,537
TIA
$8,104
Stroke costs include:
Hospital
Assistive devices
Ambulatory care
Allied health professionals
Physician fees
Home modifications
Tests and procedures
Caregiver expenses
All medications
Goeree R, Blackhouse G, Petrovic R, Salama S. J Med Econ 2005;8:147-67

11. Unit Costs 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

12. Bootstrap method (5000 samples) for SE and 95% CI.
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

13. Results Placebo + Aspirin Mean Cost (CI) Clopidogrel + Aspirin
Incremental Cost
Events
$11,464
$9,839
−$1,625
Procedures
$815
$729
−$86
Non-study Medication
$1,478
$1,450
−$28
Study Medication $0
$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)

14. Results
$14,132
$13,756

15. $16,289
$13,756
$14,132
$13,054

16. 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%)

17. 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

18. 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

20. Results with CIs Base Case Clopidogrel Cost 50% of Base
Events
-$1,625 (-$2,614 - ‑$637)
-$1,625 (-$2,613 - ‑$637)
Procedures
-$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)

21. Sensitvity Analysis – Drug Cost
Base Case
Clopidogrel Cost 50% of Base
Clopidogrel Cost 200% of Base
Events
-$1,625 (-$2,613, -$637)
Procedures
-$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)

22. Clopidogrel + Aspirin versus Aspirin
Bleeding
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
<0.001
Severe
190
1.5
122
1.0
Fatal 42
0.3 27
0.2
1.56
0.07
Intra-cranial 54
0.4 29
1.87
0.006
Extra-cranial
200
1.6
134
1.1
1.51
Table courtesy of the ACTIVE group

23. Benefits and Risks: Compared to Warfarin
Effects
Warfarin versus Aspirin
Clopidogrel & Aspirin versus 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:
Table courtesy of the ACTIVE group