Antiplatelet Therapy After PCI: How Much and How Long?

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1 Antiplatelet Therapy After PCI: How Much and How Long? Adnan Kastrati Deutsches Herzzentrum, Munich, GERMANY

2 Antiplatelet Therapy after PCI: How much and how long? The simplest and extreme response: Give the highest possible dose for life!!! Safety concerns related to bleeding risk. No proven effectiveness.

3 Antiplatelet Therapy after PCI: How much and how long? Maintenance Dose Duration of Therapy

4 A Patient with Stent Thrombosis While on Clopidogrel Therapy

5 A Patient with Stent Thrombosis and Clopidogrel Resistance A B Light Transmission (%) baseline 6 h after 16 h after Light Transmission (%) mg Clopidogrel 6 h after 16 h after baseline Time (s) Time (s) Stent Thrombosis Patient Control Individual Beckerath et al, Thromb Haemost 2005

6 Antiplatelet Therapy after PCI: How much and how long? Does increased maintenance dose help?

7 Are 75 mg of Clopidogrel the Optimal Dose? ADP (5µmol/L)-Induced Aggregation, % mg Loading in Pts on 75 mg Chronic Therapy Before loading P<0.001 After loading 600 mg Clopidogrel Kastrati et al, Circulation 2004

8 Are 75 mg of Clopidogrel the Optimal Dose? - ISAR-CHOICE 2-60 Patients 150 mg 75 mg No. of patients days 600 mg clopidogrel assessment of platelet function (LT aggregometry, Point of care test: Verify Now) ISAR-CHOICE 2, EHJ 2007

9 LT Aggregometry VerifyNow TM P2Y12 Assay ISAR-CHOICE 2, EHJ 2007

10 Fighting Low-Response by Increased Dose - OPTIMUS Trial - OPTIMUS, Circ 2007

11 Fighting Low-Response by Increased Dose - OPTIMUS Trial - OPTIMUS, Circ 2007

12 The clinical benefit of an increased maintenance dose of clopidogrel is not known and 75 mg still remain the standard dose for chronic therapy.

13 Duration of Therapy in PCI Patients - PCI-CURE - No true PCI trial (only a subset) Pretreatment in the long-term arm Mean clopidogrel therapy duration 8 months

14 Duration of Therapy in PCI Patients - CREDO year results (MI, Stroke, or Death) COMBINED ENDPOINT OCCURRENCE (%) Placebo* # Clopidogrel* MONTHS FROM RANDOMIZATION 11.5% 8.5% 27% RRR p = 0.02 Pretreatment in the long-term arm 33 cases of ischemic complications prevented, but 22 cases of major bleeding added CREDO, JAMA 2002

15 DES Era AHA/ACC/SCAI/ACS/ADA Science Advisory (cardiologists, surgeons, dentists)

16 Endothelialization in DES vs BMS From autopsies of 23 patients treated with DES > 30 days and 25 matched BMS-treated autopsies. Endothelization (%) >40 Duration (months) BMS DES Joner, Virmani, JACC 2006

17 Early Discontinuation of Antiplatelet Therapy and DES Thrombosis Overall stent thrombosis = 1.3% (N=2229) 29.0% Incidence (%) 1.4% 2.0% 2.5% 3.3% 3.6% 6.2% 8.7% Unstable angina Thrombus Diabetes Unprotected left main Bifurcation Renal failure Prior brachy Rx Premature antiplatelet discont d Iakovou et al, JAMA 2005

18 Minimum Duration of Clopidogrel Therapy in DES Pivotal Randomized Trials SIRIUS (Cypher): TAXUS IV (Taxus): ISAR-TEST (ISAR I DES): ENDEAVOR II (Endeavor): SPIRIT III (Xience): 3 months 6 months 6 months 3 months 6 months

19 Is an excess of risk of stent thrombosis with DES vs. BMS?

20 DES vs BMS Thrombosis - The Truth in the Light of ARC Definition - Cumulative incidence (%) P=.70 Sirolimus Stent (ARC) Bare-metal stent Days after initial procedure Sirolimus stent 1.7% 1.5% No. at risk Sirolimus stent Bare-metal stent Cumulative incidence (%) P=.52 Paclitaxel Stent (ARC) Paclitaxel stent Bare-metal stent Days after initial procedure 1.8 % 1.4 % Mauri et al, NEJM 2007

21 Off-Label Use and Safety of DES - Meta-Analysis of Cypher vs. BMS Trials - Cypher vs BMS Off-Label (13 Trials) Death Stent Thrombosis 0.97 ( ) 0.88 ( ) Kastrati & Schömig, JACC 2007

22 Do We Need Dual Antiplatelet Therapy Beyond 6 Months After DES? Patients on double antiplatelet therapy (%) Thrombosis rate (%) d 180 d 360 d 540 d Discontinuation of thienopyridine therapy was the major determinant of ST within the first 6 months, but insufficient information is available to determine whether there is benefit in continuing a thienopyridine beyond 6 months Thrombosis rate without thienopyridine Thrombosis rate with thienopyridine Airoldi F, et al. Circulation. 2007;116:

23 Optimal Duration of Clopidogrel Therapy After DES ISAR-SAFE A Multi-Center, Randomized, Double-Blind Trial 6000 DES Patients 6-month therapy 12-month therapy Primary end point at 15 months A composite of death, MI, stent thrombosis, stroke, major bleeding

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26 The findings of this study, coupled with prior physiological studies, support the hypothesis of a possible clopidogrel rebound effect from rebound platelet activation following clopidogrel withdrawal.

27 ISAR-REBOUND Intracoronary Stenting and Antithrombotic Regimen: REBOUND Platelet Aggregation After Discontinuation of Long-Term Clopidogrel Treatment

28 Protocol Overview double-blinded treatment 60 Patients Off group Tapering group 1 st week: 1/0/1/0/1/0/1 2 nd week: 0/0/1/0/0/1/0 3 rd week: 0/1/0/0/0/1/0 4 th week: 0/0/1/0/0/0/1 0 weeks after randomization

29 ISAR-CAUTION in discontinuing clopidogrel therapy

30 Optimal Duration of Clopidogrel Therapy After DES ISAR-CAUTION A Randomized, Double-Blind Trial 3000 DES Patients Tapering No tapering Primary end point at 3 months A composite of cardiac death, MI, stent thrombosis, stroke, major bleeding or rehospitalization for ACS

31 ISAR-CAUTION Randomization: Tapered vs. abrupt interruption of clopidogrel therapy PCI Randomization Discont. of study drug Clopidogrel Clopidogrel tapered abrupt time (months) 30-day Follow-up 3-month Follow-up