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

2. 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.

3. 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.

4. Baseline Clinical Characteristics According to Responsiveness to Clopidogrel
Overall Resp. Non- Resp. p value
n=804 n=699 n=105
Age 69 ± ± ±
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±

5. 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
Thrombotic lesion 177 (13) 166 (24) 11 (10) <.001
Bifurcation lesion 371 (27) 318 (27) 53 (27) 0.909
Chronic total occl (8) 86 (7) 20 (10) 0.180
Lesion length > 20 mm 359 (26) 294 (25) 65 (33) 0.022
Total stent length (mm) 38 ± ± ±
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

6. 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 (1.7) 7 (1.0) 7 (6.7) < 0.001
Time of stent thrombosis
Early
Subacute 16 (2.0) 12 (1.7) 4 (3.8) 0.152
Late 9 (1.1) 4 (0.6) 5 (4.8) < 0.001

7. 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

8. Cox multivariate analysis: Predictors of Stent Thrombosis
HR (95% CI) p value
Non-responsiveness to clopidogrel ( ) 0.009
Acute myocardial infarction 2.41 ( ) 0.041
Total stent length (mm) ( ) 0.010
LVEF per 1 % increase ( ) 0.001

9. (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)

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