The Impact of prolonged antiplatlelet therapy Following DES Ron Waksman, MD Washington Hospital Center

Ron Waksman, MD DISCLOSURES Consulting Fees Grants/Contracted Research Abbott Vascular, Biotronik, Medtronic CardioVascular, Inc, Boston Scientific Corporation Grants/Contracted Research Abbott Vascular, Biotronik, Boston Scientific Corporation, The Medicines Company, GlaxoSmithKline, Schering-Plough, sanofi-aventis U.S. LLC

IMPACT OF PROLONGED ANTIPLATELET THERAPY Efficacy: Reduction of Ischemic events and stent thrombosis Safety: Increased the risk of bleeding major minor and nuisance, Rebound phenomenon? Need for interruption Cost and cost effectiveness the trade off efficacy versus safety

Antiplatelet Trialists’ Collaboration. BMJ 1994;308:81–106.

McFadden EP et al. Lancet 2004; 364:1519–21

ACC/AHA/SCAI Guidelines Class 1 Level of Evidence B* For all post-PCI stented patients receiving a DES, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. Does Prolonged DAPT Prevent Stent Thrombosis ??? Within 6 months, yes-numerous studies have shown that thienopyridine discontinuation within 6 months after DES is a major risk factor for stent thrombosis After 6 months, who knows? 7

DES (but not BMS) Pts Who Are Event-free at 6 Months on Clopidogrel have Lower 2 Year Death/MI Eisenstein EL et al. JAMA. 2007;297:159-168

Spertus JA et al. Circulation 2006;113:2803-9.

Airoldi F et al. Circulation 2007;116:745-54

Airoldi F et al. Circulation 2007;116:745-54

Outcomes by Stent Type & Clopidogrel Duration in Diabetics 6-Month Landmark Analysis in event-free pts (N=749) Brar SS et al. JACC. 2008;51:2220-7

Serebrauny V. JACC 2004 13

Rebound CV Events After Clopidogrel Discontinuation 3137 pts with ACS were discharged from 127 VA hospitals on clopidogrel (50% after PCI, 50% medical Rx) in whom clopiodgrel was subsequently d/c’d at mean 302 days (medically treated pts) and 278 days (PCI treated pts). Pts were then followed ~6 mos off clopidogrel. Instantaneous rate of death or MI per person-day Ho PM et al. JAMA 2008;299:532-9

Safety of Long-term Clopidogrel 3 Placebo Controlled Trials

The Impact of “Nuisance” Bleeding on Clopidogrel Compliance in Patients undergoing Intracoronary Drug-Eluting Stent Implantation Ron Waksman, Probal Roy, Laurent Bonello, Rebecca Torguson, Axel de Labriolle, Gilles Lemesle, Tina L. Pinto Slottow, Daniel H. Steinberg, Kimberly Kaneshige, Zhenyi Xue, Lowell F. Satler, Kenneth M. Kent, William O. Suddath, Augusto D. Pichard, Joseph Lindsay. Washington Hospital Center, Washington DC, USA Mister the chairmen Ladies and gentlemen I particularly appreciate to be here at the AHA congress and to present to you the result of our study entitled: … Roy P, Waksman R, American Journal of Cardiology 2008 18

Incidence of Bleeding 837 patients reported bleeding events (cumulative incidence 32.4%). Percentage distribution of bleeding types (nuisance, internal and alarming) 0.7% 13.6% 85.7% Roy P, Waksman R, American Journal of Cardiology 2008 19

Time and duration of Nuisance Bleeding Majority of the patients have daily episodes of Nuisance bleeding Roy P, Waksman R, American Journal of Cardiology 2008

Aspirin and Clopidogrel discontinuation as a result of bleeding type. Alarming and internal bleeding was associated with higher rates of anti-platelet discontinuation. In patients with “nuisance” bleeding, 11.1% and 5.0% ceased clopidogrel and aspirin, respectively Roy P, Waksman R, American Journal of Cardiology 2008 21

THE SENS STUDY Outcome of Non-cardiac Surgical Procedure and Brief Interruption of DAPT within 12 Months Following Endeavor Implantation

SENS Outcome of Non-cardiac Surgical Procedure and Brief Interruption of DAPT within 12 Months Following Endeavor Implantation Purpose To examine the safety of the Endeavor stent associated with non-cardiac surgical procedure and brief interruption of dual anti-platelet agents within 12 months following stent implantation Study Design Retrospective study of the 194 out of 3099 patients (6.2%) who had a brief interruption of DAPT1 due to a noncardiac surgical procedure Trial locations: 11 sites in South Korea Primary endpoint: 30-day MACE including death, MI and TLR Primary investigator: Jin Won Kim, MD 1 Both clopidogrel and ASA

Early Surgery vs Late Surgery Early surgery group (3 months, n = 34) Late surgery group (3-12 months, n = 160) P Value Age (yrs), Male (%) 62.2/63.5 63.1/50.9 NS Lesion type (B2/C) (%) 73.6 72.8 Stent number 1.4 1.5 Stent diameter (mm) 3.11 ± 0.52 3.08 ± 0.47 Total stent length (mm) 33.0 ± 16.7 29.2 ± 19.5 Major surgery (%) 20.5 22.6 Days from stenting to surgery 56.5 233.7 <0.001 DAP withdrawal (days) 13.4 14.8 NS = not significant; DAP = dual antiplatelet agents

MACE Early Surgery vs Late Surgery Late Surgery Group Early Surgery Group 8.9% 3/34 2 Death 1 MI 0.6% 1/159 P < 0.001

Incremental Costs/Cost Offsets with Prasugrel* Rehospitalization Costs Other Vasc. Interventions $12 Bleeding $69 Other $82 Angina $20 CABG -$21 MI (no PCI) -$57 Total -$517 PCI -$621 Prasugrel Clopidogrel Difference (P-C) Index Hospitalization Costs $19,740 $19,752 -$12 Rehospitalization Costs $4,465 $4,982 -$517 Study Drug Costs $1,862 $1,554 $308 TOTAL COSTS $26,067 $26,288 -$221

Cost-Effectiveness: Days 1-30 Cost = -$192 D Life Exp. = 0.056 yr ICER = Dominant % Dominant: 89.7% D Cost (Prasugrel – Clopidogrel) % <$50,000/LY: 97.7% D Life Years (Prasugrel – Clopidogrel)

Cost-Effectiveness: Days 31-EOS Cost = -$28 D Life-Exp = 0.053 yr ICER = Dominant % Dominant: 54.3% D Cost (Prasugrel – Clopidogrel) % <$50,000/LYG: 96.6% D Life Years (Prasugrel – Clopidogrel)

Impact of Generic Clopidogrel Treatment Over Full Trial Duration Cost of Generic Clopidogrel = $1/day Cost = +$996 D Life-years= 0.102 ICER = $9,727/LYG % Dominant: 0% D Cost (Prasugrel – Clopidogrel) % <$50,000/LYG: 98.2% D Life Years (Prasugrel – Clopidogrel)

Conclusions For patients undergoing PCI in the ACS setting, treatment with prasugrel compared with clopidogrel is highly cost-effective– and in many cases cost- saving– over both the subacute and longer term phases of treatment Compared with generic clopidogrel (expected cost $1/day), prasugrel was cost saving during the first 30 days but resulted in higher costs (by ~$800/pt) beyond this time period. Nonetheless, formal cost-effectiveness analysis suggests that this higher cost may be justified based on projected gains in long-term survival