Antiplatelet Therapy After PCI: How Much and How Long? Adnan Kastrati Deutsches Herzzentrum, Munich, GERMANY
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.
Antiplatelet Therapy after PCI: How much and how long? Maintenance Dose Duration of Therapy
A Patient with Stent Thrombosis While on Clopidogrel Therapy
A Patient with Stent Thrombosis and Clopidogrel Resistance A B -20-20 Light Transmission (%) 0 20 40 60 80 baseline 6 h after 16 h after Light Transmission (%) 0 20 40 60 80 600 mg Clopidogrel 6 h after 16 h after 100 100 baseline 0 100 200 300 0 100 200 300 Time (s) Time (s) Stent Thrombosis Patient Control Individual Beckerath et al, Thromb Haemost 2005
Antiplatelet Therapy after PCI: How much and how long? Does increased maintenance dose help?
Are 75 mg of Clopidogrel the Optimal Dose? ADP (5µmol/L)-Induced Aggregation, % 100 80 60 40 20 0 600 mg Loading in Pts on 75 mg Chronic Therapy Before loading P<0.001 After loading 600 mg Clopidogrel Kastrati et al, Circulation 2004
Are 75 mg of Clopidogrel the Optimal Dose? - ISAR-CHOICE 2-60 Patients 150 mg 75 mg No. of patients 31 29 0 30 days 600 mg clopidogrel assessment of platelet function (LT aggregometry, Point of care test: Verify Now) ISAR-CHOICE 2, EHJ 2007
LT Aggregometry VerifyNow TM P2Y12 Assay ISAR-CHOICE 2, EHJ 2007
Fighting Low-Response by Increased Dose - OPTIMUS Trial - OPTIMUS, Circ 2007
Fighting Low-Response by Increased Dose - OPTIMUS Trial - OPTIMUS, Circ 2007
The clinical benefit of an increased maintenance dose of clopidogrel is not known and 75 mg still remain the standard dose for chronic therapy.
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
Duration of Therapy in PCI Patients - CREDO - 15 1 year results (MI, Stroke, or Death) COMBINED ENDPOINT OCCURRENCE (%) 10 5 0 Placebo* # Clopidogrel* 0 3 6 9 12 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
DES Era AHA/ACC/SCAI/ACS/ADA Science Advisory (cardiologists, surgeons, dentists)
Endothelialization in DES vs BMS From autopsies of 23 patients treated with DES > 30 days and 25 matched BMS-treated autopsies. Endothelization (%) 100 90 80 70 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 11 15 16 17 20 >40 Duration (months) BMS DES Joner, Virmani, JACC 2006
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
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
Is an excess of risk of stent thrombosis with DES vs. BMS?
DES vs BMS Thrombosis - The Truth in the Light of ARC Definition - Cumulative incidence (%) 3 2 1 0 P=.70 Sirolimus Stent (ARC) Bare-metal stent 0 180 360 720 1080 1440 Days after initial procedure Sirolimus stent 1.7% 1.5% No. at risk Sirolimus stent 878 863 848 823 788 Bare-metal stent 870 853 842 825 789 Cumulative incidence (%) 3 2 1 P=.52 Paclitaxel Stent (ARC) Paclitaxel stent Bare-metal stent 0 0 180 360 720 1080 1440 Days after initial procedure 1.8 % 1.4 % 878 863 848 823 788 870 853 842 825 789 Mauri et al, NEJM 2007
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 (0.70-1.33) 0.88 (0.51-1.52) Kastrati & Schömig, JACC 2007
Do We Need Dual Antiplatelet Therapy Beyond 6 Months After DES? Patients on double antiplatelet therapy (%) Thrombosis rate (%) 100 80 60 40 20 0 0 1 2 3 4 5 4.2 97.6 30 d 180 d 360 d 540 d 0.9 0.8 80.7 42.8 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. 23.2 0.3 0.2 0.4 0.1 0.4 Thrombosis rate without thienopyridine Thrombosis rate with thienopyridine Airoldi F, et al. Circulation. 2007;116:745-754.
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
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.
ISAR-REBOUND Intracoronary Stenting and Antithrombotic Regimen: REBOUND Platelet Aggregation After Discontinuation of Long-Term Clopidogrel Treatment
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 2 4 5 6 7 8
ISAR-CAUTION in discontinuing clopidogrel therapy
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
ISAR-CAUTION Randomization: Tapered vs. abrupt interruption of clopidogrel therapy PCI Randomization Discont. of study drug Clopidogrel Clopidogrel tapered abrupt -6-5 -4-3 -2-1 0 1 2 3 time (months) 30-day Follow-up 3-month Follow-up