Harvard Medical School Cost-Effectiveness in Acute Coronary Syndromes The 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

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

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 costPrevious 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 ACSRecently, 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 unknownThe overall cost-effectiveness of this novel strategy is unknown ACUITY Econ

Objectives 1.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 inhibitionHeparin/LMWH with Gp2b/3a inhibition Bivalirudin with Gp2b/3a inhibitionBivalirudin with Gp2b/3a inhibition Bivalirudin monotherapyBivalirudin monotherapy 2. To determine the impact of both ischemic and bleeding complications on the cost of ACS in contemporary practice 3.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 ACUITY Econ Stratified by upstream or cath lab initiation

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

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

Economic Study Methods- 1 Economic substudy included all U.S. patients (n=7851), analyzed on an intention to treat basisEconomic 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 enrollmentDetailed 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)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)

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 discardedStudy 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 costsCath 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 ratioAll 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 SchedulePhysician costs based on Medicare Fee Schedule All costs in 2005 US dollarsAll costs in 2005 US dollars

Baseline Characteristics: U.S. Patients P=NS for all comparisons Heparin + upstream GP2b3a (n=1301) Heparin + Cath Lab Gp2b3a (n=1308) Bivalirudin + upstream GP2b3a (n=1325) Bivalirudin + Cath Lab Gp2b3a (n=1302) Bivalirudin Alone (n=2615) Age (yrs) Male (%) Diabetes (%) Prior CABG (%) Previous MI (%)

Management Strategy P=NS for all comparisons Heparin + upstream GP2b3a Heparin + Cath Lab Gp2b3a Bivalirudin + upstream GP2b3a Bivalirudin + Cath Lab Gp2b3a Bivalirudin Alone Diagnostic Angiography (%) Planned PCI (%) Planned CABG (%) Planned Medical Therapy (%) # Vessels Attempted (PCI)

Heparin + upstream GP2b3a Heparin + Cath Lab Gp2b3a Bivalirudin + upstream GP2b3a Bivalirudin + Cath Lab Gp2b3a Bivalirudin Alone Bivalirudin given (%)3.7%3.3%98.8%99.1%99.5% Bivalirudin vials * Gp2b/3a given (%)98.2%53.7%97.7%54.2%7.6% Eptifibatide (%)96.1%88.8%96.1%91.4%77.5% Tirofiban (%)3.8%0.7%4.0%0.6%2.5% Abciximab (%)0.2%10.5%0.2%8.4%20.5% Eptifibatide vials * Anticoagulant Use * Among patients who received the drug Heparin + upstream GP2b3a Heparin + Cath Lab Gp2b3a Bivalirudin + upstream GP2b3a Bivalirudin + Cath Lab Gp2b3a Bivalirudin Alone Bivalirudin given (%)3.7%3.3%98.8%99.1%99.5% Bivalirudin vials * Gp2b/3a given (%)98.2%53.7%97.7%54.2%7.6% Eptifibatide (%)96.1%88.8%96.1%91.4%77.5% Tirofiban (%)3.8%0.7%4.0%0.6%2.5% Abciximab (%)0.2%10.5%0.2%8.4%20.5% Eptifibatide vials *

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

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

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

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

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

Cost Savings (Bivalirudin Alone vs. Heparin + Upstream GPI) Cath Lab Procedures Room/OR/ Nursing/ Ancillary MD feesAnticoagulationTotal Savings Net Savings $828/pt

Cost Savings (Bivalirudin Alone vs. Heparin + Cath Lab GPI) Cath Lab Procedures Room/OR/ Nursing/ Ancillary MD feesAnticoagulationTotal Savings Net Savings $297

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

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

Independent Predictors of Hospital Cost Model 2A * Also adjusted for age, gender, and diabetes VariableCost/EventP-value Death$8958<0.001 MI$3334<0.001 ACUITY major bleed $7278<0.001 Other bleed $2122<0.001 Unplanned revascularization $12,224<0.001 Planned PCI strategy $8409<0.001 Planned CABG strategy $29,506<0.001

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.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 regimensSimilar 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

As a result, bivalirudin monotherapy resulted in significant reductions in hospital length of stay and costs for other hospital services compared with heparin + 2b3a inhibitionAs 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/patientDespite 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 careIf 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 Summary- 2

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