Pre-treatment platelet reactivity: Some studies have defined a poor response to clopidogrel on the basis of a comparison of pre and post-treatment platelet response to ADP (21,163). The majority of studies take an absolute value on clopidogrel treatment as the definition. Two studies (164,165) have shown that high pre-treatment platelet reactivity predicts a lower absolute inhibition to ADP on treatment. However, in the clinical environment it may be impractical to measure pre-treatment response. In addition, the factors that predict a high pre- treatment platelet reactivity have not been clearly determined save for the presence of diabetes mellitus.
Patient co-morbidities: Increased platelet reactivity on clopidogrel therapy in patients with Braunwald classification grade II or III angina has been reported. Data from several studies
Page | 64 have shown increased platelet reactivity and a concomitant reduced response to clopidogrel in patients with ACS (128). There is also evidence that patients with diabetes have higher baseline platelet reactivity and a reduced inhibition of platelet function following the introduction of clopidogrel (147,166,167).
Body mass index (BMI): Although earlier smaller studies have not shown a significant association between BMI and clopidogrel response assessed by LTA and VASP
(159,160,168), the larger POPULAR (Do Platelet Function Assays Predict Clinical Outcomes in Clopidogrel-Pretreated Patients Undergoing Elective PCI?) study did show that patients with a higher BMI had a significantly increased residual platelet reactivity on clopidogrel assessed by LTA (5 and 20 àmol), VerifyNow P2Y12 and Plateletworks assays (167).
Concurrent medication: As described above, clopidogrel, as a prodrug, requires activation by cytochrome P450 isoenzymes in order to achieve a therapeutic effect. Several small ex- vivo studies have suggested an association with impaired inhibition of platelets when
clopidogrel is administered concurrently with a lipophilic statin (169,170). Against this data, other studies have not found any interaction (154,171) and post hoc analyses of large clinical studies including CREDO and CHARISMA have not shown any association between the co- prescription of these medications and clinical outcome (27,172).
More recently, concern has been raised regarding a possible negative interaction between clopidogrel and proton pump inhibitors. A single study has demonstrated an increase VASP- PRI in patients taking both clopidogrel and omeprazole (173). Furthermore, evidence has emerged to suggest an increased risk of recurrent myocardial infarction in patients taking both therapies (174). Two subsequent meta-analyses have produced conflicting evidence and there remains uncertainty for clinicians trying to balance the risk of thromboembolic events against the risk of bleeding on DAPT (175,176).
Smoking: The early study by Matetsky et al suggested an association between smoking and increased antiplatelet effects of clopidogrel (69). Cigarette smoking is known to induce the liver enzyme CYP1A2 which is one of the enzymes that converts clopidogrel to its active metabolite (177). This association was confirmed in a study of 259 patients undergoing elective coronary stenting (178). Platelet aggregation and platelet expression of activated
Page | 65 GPIIbIIIa receptor were both reduced in current smokers taking clopidogrel. Interestingly, a further analysis of data from the CHARISMA study showed a significant reduction in mortality for current smokers with established cardiovascular disease who were prescribed clopidogrel (179). There was also an associated increase in moderate or severe bleeding episodes in this group. This clinical data is in keeping with the suggestion from platelet studies of an increased antiplatelet effect of clopidogrel in smokers although it is subject to the
acknowledged limitations of subgroup analysis.
Genetics: Polymorphisms in the hepatic enzymes involved in the oxidation of clopidogrel to an active metabolite have been described and are associated with clopidogrel response. Frere et al, in particular, studied over 600 patients with acute coronary syndrome and found that ADP induced platelet LTA and VASP-PRI were associated with polymorphisms in the hepatic enzyme CYP2C19*2 (180). Subsequent clinical studies of this polymorphism found a
significant increase in the risk of death, MI or stroke in patients treated with clopidogrel (181,182). A recent meta-analysis, however, has not supported this association (183). It has also been proposed that variations in the genetic coding of platelet membrane receptors themselves may influence both baseline platelet reactivity and response to antiplatelet therapies that target these receptors. However, the data regarding common P2Y12
polymorphisms is not consistent and a study by Angiolillo et al found no association between clopidogrel response and the P2Y12 34CT and 52GT polymorphisms (184). Studies continue to investigate genetic variation in the membrane glycoproteins that are integral to platelet activation and aggregation.
Compliance: As with aspirin, and indeed all cardiovascular therapies, there remains a
significant issue regarding patient compliance. In most cases, assessing complicance relies on patient self-reporting which is notoriously unreliable. A meta-analysis of stroke patients on secondary prevention antiplatelet therapy has suggested non-compliance rates of between 12%
and 52% (185). A retrospective study on clopidogrel metabolites in stored samples from patients with either CAD or previous stroke has supported non-compliance rates of 20% in the 6 months following introduction of clopidogrel therapy (186). Interestingly, non-compliance of patients participating in studies for more than 6 months was much less, suggesting that non- compliant patients may withdraw and discontinue study medication before then.