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

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.

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

Stroke Graph courtesy of the ACTIVE group

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 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 0.74 0.62-0.89 0.001 Table courtesy of the ACTIVE group

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-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

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.

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

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

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

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

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)

Results $14,132 $13,756

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

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%)

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

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

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)

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)

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 1.29-1.92 <0.001 Severe 190 1.5 122 1.0 1.25-1.98 Fatal 42 0.3 27 0.2 1.56 0.96-2.53 0.07 Intra-cranial 54 0.4 29 1.87 1.19-1.94 0.006 Extra-cranial 200 1.6 134 1.1 1.51 1.21-1.88 Table courtesy of the ACTIVE group

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: 857-67 Table courtesy of the ACTIVE group