Cost-Effectiveness in Acute Coronary Syndromes The ACUITY Economic Study

1. Cost-Effectiveness in Acute Coronary SyndromesThe ACUITY Economic Study David J. Cohen, M.D., M.Sc. on behalf of the ACUITY Investigators Harvard Clinical Research Institute Beth Israel Deaconess Medical Center Boston, MA Mid America Heart Institute Kansas City, Missouri Harvard Medical School

2. Disclosures Study Funding – The Medicines Company Grant Support/Pharma • Schering-Plough - Eli Lilly - BMS/Sanofi • CV Therapeutics - Baxter Grant Support/Devices • Cordis - Boston Scientific • Edwards Lifesciences - Worldheart Grant Support/Federal • NHLBI - NINDS DJC: 10/06

3. ACUITY Econ Background • Previous studies have demonstrated that parenteral Gp2b/3a inhibitors can substantially reduce ischemic complications in pts with ACS undergoing an early invasive strategy. However, many patients do not currently receive these agents because of concerns about bleeding complications and cost • Recently, the ACUITY trial has validated the use of bivalirudin with provisional Gp2b/3a blockade as an anticoagulation strategy for intermediate and high risk patients with ACS • The overall cost-effectiveness of this novel strategy is unknown

4. ACUITY Econ Objectives • To compare the in-hospital and 30-day costs for high risk patients with ACS using 3 alternative anticoagulation regimens: • Heparin/LMWH with Gp2b/3a inhibition • Bivalirudin with Gp2b/3a inhibition • Bivalirudin monotherapy 2. To determine the impact of both ischemic and bleeding complications on the cost of ACS in contemporary practice • To assess the cost-effectiveness (measured as cost per death or MI averted and also cost per life year gained) of the 5 alternative treatment strategies Stratified by upstream or cath lab initiation

5. Medical management UFH or Enoxaparin + GP IIb/IIIa PCI Bivalirudin + GP IIb/IIIa Angiography within 72h R* Bivalirudin Alone CABG Study Design – First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderate- high risk ACS Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration

6. UFH or Enoxaparin Medical management Routine upstream GPI in all pts GPI started in CCL for PCI only PCI Bivalirudin Routine upstream GPI in all pts R R GPI started in CCL for PCI only Bivalirudin Alone CABG Study Design – Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Moderate- high risk ACS Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice

7. Economic Study Methods- 1 • Economic substudy included all U.S. patients (n=7851), analyzed on an intention to treat basis • Detailed medical resource utilization collected prospectively for all patients for initial hospitalization and for 30 days after enrollment • Hospital billing data collected on ~2500 randomly selected patients as well as on all patients who experienced a major complication (death, MI, repeat revasc, or major bleed)

8. Economic Study Methods-2 • Study drug costs based on calculated bolus and infusion volumes and current wholesale cost, assuming that any wasted drug would be discarded • Cath lab procedure costs based on “bottom up” cost methodology using measured resource utilization (balloons, stents,, wires, etc.) and current unit costs • All other inpatient costs based on hospital charge for each item multiplied by cost-center specific cost-to-charge ratio • Physician costs based on Medicare Fee Schedule • All costs in 2005 US dollars

9. Baseline Characteristics: U.S. Patients P=NS for all comparisons

10. Management Strategy P=NS for all comparisons

11. Anticoagulant Use * Among patients who received the drug

12. Δ $461 Anticoagulant Costs p<0.001 for overall comparison $1537 $1315 $976 $896 $515

13. In-Hospital Ischemic Events: Death/MI/Unplanned Revascularization P=NS for overall comparison Heparin + Upstream GPI Heparin + Cath Lab GPI Bivalirudin + Upstream GPI Bivalirudin + Cath Lab GPI Bivalirudin Alone

14. ACUITY Scale Major Bleeding P<0.001 for overall comparison Heparin + Upstream GPI Heparin + Cath Lab GPI Bivalirudin + Upstream GPI Bivalirudin + Cath Lab GPI Bivalirudin Alone

15. Hospital Length of Stay(trimmed means) P=0.02 for overall comparison Heparin + Upstream GPI Heparin + Cath Lab GPI Bivalirudin + Upstream GPI Bivalirudin + Cath Lab GPI Bivalirudin Alone

16.  $297/pt  $827/pt Mean Initial Hospitalization Costs $15,258 $14,953 $14,423 $14,448 $14,126 p<0.001 for overall comparison

17. Net Savings $828/pt Cost Savings(Bivalirudin Alone vs. Heparin + Upstream GPI) Anticoagulation Cath LabProcedures Room/OR/Nursing/Ancillary MD fees Total Savings

18. Net Savings $297 Cost Savings(Bivalirudin Alone vs. Heparin + Cath Lab GPI) Anticoagulation Cath LabProcedures Room/OR/Nursing/Ancillary MD fees Total Savings

19. 97.6% Index Hospital Cost Difference: Bivalirudin Alone vs. Heparin + Upstream GPI Cumulative Probability Results based on 1000 bootstrap replicates

20. 75.5% Index Hospital Cost Difference: Bivalirudin Alone vs. Heparin + Cath Lab GPI Cumulative Probability Results based on 1000 bootstrap replicates

21. Independent Predictors of Hospital Cost * Also adjusted for age, gender, and diabetes Model 2A

22. Summary • Among ~8000 US patients enrolled in the ACUITY trial, anticoagulant-related costs were lowest with heparin + catheterization laboratory initiated GP2b3a inhibition. Bivalirudin monotherapy beginning upstream and continuing through definitive therapy was associated with drug cost increases of ~$400/pt vs. heparin + cath lab initiated 2b3a inhibition. • Similar to the overall trial results, in the U.S. cohort, bivalirudin monotherapy resulted in similar rates of ischemic complications and lower rates of major and minor bleeding complications compared with alternative treatment regimens

23. Summary- 2 • As a result, bivalirudin monotherapy resulted in significant reductions in hospital length of stay and costs for other hospital services compared with heparin + 2b3a inhibition • Despite higher drug treatment costs, aggregate hospital costs were lowest with bivalirudin monotherapy, with overall cost savings of ~$300-$800/patient • If these findings are maintained at 30-days and 1-year, bivalirudin alone in patients with NSTE-ACS managed with an early invasive strategy should be considered a highly economically attractive antithrombotic regimen compared with the current US standard of care

24. Special Thanks ACUITY Steering Committee and Operations • Gregg Stone, M.D. (PI) • Roxanna Mehran, M.D. The Medicines Company • Stephanie Plent, M.D. • Anne Marie Galli HCRI EQOL Group • Duane Pinto, M.D. • Elizabeth Schneider, M.P.H. • Chunxue Shi, M.Sc. • Joshua Walczak • David Machon • Meghan York, M.D. • Ronna Berezin, M.P.H.