Impact of Platelet Reactivity Following Clopidogrel Administration on Drug-Eluting Stent Thrombosis

Background Dual antiplatelet regimen of aspirin and clopidogrel is the standard treatment for the prevention of stent thrombosis, and retrospective studies have shown that discontinuation of clopidogrel, even after six months or later after stent implantation, is associated with an increased risk of thrombotic events in patients with drug-eluting stents. However, stent thrombosis can occur also in patients assuming clopidogrel and aspirin, and it has been shown that patients who suffered stent thrombosis had a high in vitro post-treatment platelet reactivity despite the dual antiplatelet treatment suggesting platelet aggregation non-responsiveness to clopidogrel as a main cause of the thrombotic event. The definite demonstration of the association between low in vitro responsiveness to clopidogrel and thrombotic events is still lacking because the large majority of previous studies were retrospective, or underpowered. Moreover, post-treatment platelet reactivity may interact with one or more established clinical and procedural predictors of stent thrombosis, making difficult the definition of its role in precipitating thrombosis, and studies used different platelet reactivity assessments and definitions for determining the platelet responsiveness to clopidogrel.

Method Consecutive pts receiving DES implantation and for whom platelet reactivity after clopidogrel treatment was prospectively assessed. Blood samples for platelet reactivity assessment was obtained 12 to 18 hours from clopidogrel loading (600 mg). For patients receiving in the cath lab both the loading dose of clopidogrel and a IIb/IIIa inhibitor, blood samples were obtained after 6 days while the patient was on 75 mg maintenance dose of clopidogrel. Patients with platelet aggregation by 10 µmol ADP ≥ 90th percentile of controls (70%) were defined as non-responders. The primary end point was definite or probable stent thrombosis during a 6-month follow-up. Definite stent thrombosis was defined as acute coronary syndrome and either angiographic confirmation of thrombosis or pathological confirmation of thrombosis. Probable stent thrombosis was defined as unexplained death or myocardial infarction in the territory supplied by a stented vessel without angiographic confirmation. The secondary end point was the composite of cardiac mortality and definite or probable stent thrombosis.

Baseline Clinical Characteristics According to Responsiveness to Clopidogrel Overall Resp. Non- Resp. p value n=804 n=699 n=105 Age 69 ± 11 68 ± 11 71 ± 10 0.021 Sex (male) 602 (75) 528 (76) 74 (70) 0.265 Smokers 179 (22) 164 (24) 15 (14) 0.034 Hypertension 501 (62) 434 (62) 67 (64) 0.748 Diabetes mellitus 169 (21) 131 (19) 38 (36) <0.001 Hypercolesterol. 405 (50) 347 (50) 58 (55) 0.291 Prior MI 206 (26) 173 (25) 33 (31) 0.146 Stable angina 275 (34) 242 (35) 33 (31) 0.520 Unstable angina 312 (39) 258 (37) 54 (51) 0.004 AMI 217 (27) 199 (28) 18 (17) 0.015 Renal failure 87 (11) 73 (10) 14 (14) 0.374 LVEF % 47±12 47±12 44±14 0.008

Baseline Procedural Characteristics According to Responsiveness to Clopidogrel Overall Resp. Non- Resp. p value n=804 n=699 n=105 Multivessel disease 457 (57) 386 (55) 71 (68) 0.017 Multivessel PCI 327 (41) 273 (39) 54 (51) 0.016 Lesion treated 1369 1171 198 Thrombotic lesion 177 (13) 166 (24) 11 (10) <.001 Bifurcation lesion 371 (27) 318 (27) 53 (27) 0.909 Chronic total occl. 106 (8) 86 (7) 20 (10) 0.180 Lesion length > 20 mm 359 (26) 294 (25) 65 (33) 0.022 Total stent length (mm) 38 ± 29 37 ± 29 44 ± 32 0.015 Cypher stent 447 (56) 391 (56) 56 (53) 0.617 Taxus stent 303 (38) 264 (38) 39 (37) 0.902 Both stent types 54 (7) 44 (6) 10 (10) 0.218 Glycoprotein IIb/IIIa 349 (43) 311 (44) 38 (36) 0.110

Primary End Point Overall Resp. Non- Resp. p value Six- month FU n=804 n=699 n=105 Definite/probable 25 (3.1) 16 (2.3) 9 (8.6) < 0.001 stent thrombosis Definite 11 (1.4) 9 (1.3) 2 (1.9) 0.612 Probable 14 (1.7) 7 (1.0) 7 (6.7) < 0.001 Time of stent thrombosis Early 0 0 0 Subacute 16 (2.0) 12 (1.7) 4 (3.8) 0.152 Late 9 (1.1) 4 (0.6) 5 (4.8) < 0.001

Secondary End Point Overall Resp. Non- Resp. p value Six- month FU n=804 n=699 n=105 Cardiac death 19 (2.4) 10 (1.4) 9 (8.6) <0.001 Cardiac death 30 (3.5) 19 (2.7) 11 (10.5) <0.001 and stent thrombosis Pts with ST-elevation AMI n=217 n=199 n=18 Stent thrombosis 11 (5.1) 7 (3.5) 4 (22) < 0.001

Cox multivariate analysis: Predictors of Stent Thrombosis HR (95% CI) p value Non-responsiveness to clopidogrel 3.08 (1.32-7.16) 0.009 Acute myocardial infarction 2.41 (1.04-5.63) 0.041 Total stent length (mm) 1.01 (1.00-1.02) 0.010 LVEF per 1 % increase 0.95 (0.92-0.98) 0.001

(definite or probable stent thrombosis) Definite/Probable Stent Thrombosis for Responders and Non-Responders to Clopidogrel (Kaplan-Meyer) 80 82 84 86 88 90 92 94 96 98 100 98 ± 1 91 ± 3 Responders Non-Responders (definite or probable stent thrombosis) Event –free survival % Log rank p < 0.001 30 60 90 120 150 180 Time (days)

Conclusion Non-responsiveness to clopidogrel is a strong independent predictor of stent thrombosis in patients receiving sirolimus- or paclitaxel-eluting stents.