Clinical importance of aspirin and clopidogrel resistance

Table 1 The role of clopidogrel and statin interaction based on recent clinical trials

Study	Sample size	Comparison	Primary end point	Comment
CREDO substudy[66]	1159	Post hoc analysis categorizing baseline statin use to those predominantly metabolized by CYP3A4 or not	1 yr composite endpoint of death, myocardial infarction and stroke	No detrimental effect
GRACE[67]	15 693	Four groups: group I received aspirin alone, group II aspirin and clopidogrel, group III aspirin and statin and group IV aspirin, clopidogrel and statin	6 mo mortality adjusted for baseline characteristics, in-hospital medications and procedures, re-hosp and revascularization	No detrimental effect
MITRA plus[68]	2086	Two groups: group I received atorvastatin and clopidogrel, group II other statins (both lipophilic and non-lipophilic) and clopidogrel	Long-term mortality	No detrimental effect
Mukherjee et al[69]	1651	Two groups: group I received CYP3A4 statin plus clopidogrel, group II received non-CYP3A4 statin plus clopidogrel	In-hospital and 6 mo mortality	No detrimental effect
Brophy et al[70]	2927	Two groups: group I received clopidogrel and atorvastatin, group II clopidogrel alone	30-d rates of adverse cardiovascular events (composite of death, myocardial infarction, unstable angina, stroke or transient ischaemic attack and repeat revascularization procedures)	Worse outcome associated with statins
CHARISMA substudy[71]	10 078	Post hoc analysis categorizing baseline statin use to those predominantly metabolized by CYP3A4 or not	Composite of myocardial infarction, stroke or cardiovascular death at median follow-up of 28 mo	No detrimental effect

Taken from Bhindi R, Ormerod O, Newton J, Banning AP, Testa L. Interaction between statins and clopidogrel: is there anything clinically relevant? QJM 2008; 101: 915-925[72].

Table 2 Clinical studies based on optical aggregometry

Study	Method	Patient population	Dosage	Adjunct antiplatelet therapy	No. of patients (clopidogrel sensitive/clopidogrel resistant)	Outcome measures	Result
Geisler et al[96]	Optical aggregometry	PCI	600 mg	No	363 (341/22)	Cardiovascular event within a 3-mo follow-up	Low responder had a significantly higher risk of major cardiovascular events (22.7 vs 5.6%, OR, 4.9, 95% CI: 1.66–14.96, P = 0.004)
Buonamici et al[97]	Optical aggregometry	PCI	Loading dose of clopidogrel followed by 75 mg daily	GP IIb/IIIa inhibitor, 325 mg aspirin	804 (699/105)	Stent thrombosis during a 6-mo follow-up	The predictors of stent thrombosis was: nonresponsiveness to clopidogrel (HR 3.08, 95% CI: 1.32-7.16, P = 0.009)
Müller et al[98]	Optical aggregometry	PCI	600 mg loading dose followed by 75 mg daily	100 mg aspirin	105 (90/15)		Their data showed that 5 patients who developed a stent thrombosis were non-responders
Wenaweser et al[99]	Optical aggregometry	PCI	300 mg loading dose followed by 75 mg daily	100 mg aspirin	82 (60/21)	Presence of stent thrombosis	Combined ASA and clopidogrel resistance was more prevalent in patients with stent thrombosis (52%) compared with controls (38%, P = NS) and volunteers (11%, P < 0.05)
Soffer et al[100]	Optical aggregometry	PCI	450 mg clopidogrel before the procedure	325 mg aspirin	72 (divided into two groups based on angina classification)	Angina class	In multivariate analysis, higher angina class was independently associated with lower inhibition of platelet aggregation (P = 0.018)
Buonamici et al[97]	Optical aggregometry	PCI	600 mg loading dose followed by 75 mg daily	GP IIb/IIIa inhibitor, 325 mg aspirin	804 (699/105)	Stent thrombosis	The incidence of stent thrombosis was 8.6% in nonresponders and 2.3% in responders (P < 0.001)

ASA: Acetylsalicylic acid; GP: Glycoprotein; NS: Not significant.

Table 3 Clinical studies based on optical aggregometry combined with another method

Study	Method	Patient population	Dosage	Adjunct antiplatelet therapy	No. of patients (clopidogrel sensitive/clopidogrel resistant)	Outcome measures	Result
Lev et al[62]	Optical aggregometry, RPFA	Elective PCI	300 mg clopidogrel followed by 75 mg daily	No	150 (114/36)	Markers of myonecrosis	Myonecrosis occurred more frequently in clopidogrel-resistant vs clopidogrel-sensitive patients (32.4% vs 17.3%, P = 0.06)
Bliden et al[101]	Optical aggregometry, TEG	PCI	Previously 75 mg daily, 300-600 mg loading dose followed by 75 mg daily	325 mg	100	Cardiovascular event/revascularisation	Patients receiving chronic clopidogrel therapy who exhibit high on-treatment ADP-induced platelet aggregation are at increased risk for postprocedural ischemic events
Gurbel et al[102]	Optical aggregometry, TEG	PCI	300-600 mg loading dose followed by 75 mg daily	325 mg aspirin	192 (154 patients without and 38 patients with ischaemic events)	Cardiovascular outcome/revascularisation	Posttreatment ADP-induced aggregation by LTA (63% ± 12% vs 56% ± 15%, P = 0.02) was significantly higher) in patients with events (n = 38)
Matetzky et al[59]	Optical aggregometry, cone and platelet analyzer	PCI	300 mg clopidogrel followed by 75 mg daily	300 mg of aspirin followed by 200 mg/d	60 (patients were stratified into 4 quartiles)	Cardiovascular event	Whereas 40% of patients in the first quartile sustained a recurrent cardiovascular event, only 1 patient (6.7%) in the second quartile and none in the third and fourth quartiles suffered a cardiovascular event (P = 0.007)

ADP: Adenosine diphosphate.

Table 4 Clinical studies based on optical aggregometry combined with activation-dependent changes on the platelet surface or with vasodilator-stimulated phosphoprotein phosphorylation

Study	Method	Patient population	Dosage	Adjunct antiplatelet therapy	No. of patients (clopidogrel sensitive/clopidogrel resistant)	Outcome measures	Result
Bonello et al[103]	VASP phosphorylation	PCI	300 mg loading dose followed by 75 mg daily	100 mg aspirin	144 patients were divided into quintiles according to PRI	Cardiovascular events	Patients in quintile 1 of VASP analysis had a significantly lower risk of MACE as compared with those among the four higher quintiles (0 vs 21, P < 0.01)
Barragan et al[104]	VASP phosphorylation	PCI	Ticlopidin or clopidogrel	250 mg aspirin	36 (20 healthy volunteers and 16 stented patients)	Presence of stent thrombosis	VASP phosphorylation analysis may be useful for the detection of coronary SAT
Serebruany et al[105]	Optical aggregometry, and whole blood flow cytometry	AICS or ischaemic stroke	75 mg	81-325 mg aspirin	359 (359/0)		Lack of nonresponse
Gurbel et al[106]	Optical aggregometry, GP IIb/IIIa receptor, VASP phosphorylation	PCI	300-600 mg loading dose followed by 75 mg daily	No information	120 (20 patients with stent thrombosis and 120 patients without stent thrombosis	Stent thrombosis	The SAT patients had significantly higher mean platelet reactivity than those without SAT by all measurements
Cuisset et al[107]	Optical aggregometry, P-selectin	NSTEMI followed by PCI	300-600 mg loading dose followed by 75 mg daily	160 mg aspirin	106 (94 patients without and 12 with cardiovascular event)	Cardiovascular event	Low responders to dual antiplatelet therapy had increased risk of recurrent CV events
Cuisset et al[108]	Optical aggregometry, P-selectin	NSTEMI followed by PCI	300-600 mg loading dose followed by 75 mg daily	160 mg aspirin	392 (146 patients with 300 mg loading dose clopidogrel and 300 patients with 600 mg loading dose of clopidogrel)	Cardiovascular event	The ADP-induced platelet aggregation and expression of P-selectin were significantly lower in patients receiving 600 mg than in those receiving 300 mg. During the 1-mo follow-up, 18 CV events (12%) occurred in the 300-mg group vs 7 (5%) in the 600-mg group (P = 0.02); this difference was not affected by adjustment for conventional CV risk factors (P = 0.035)

VASP: Vasodilator-stimulated phosphoprotein; GP: Glycoprotein; ADP: Adenosine diphosphate.