Resistance to antiplatelet agents is a well-described phenomenon, consisting either of presence of inadequate platelet inhibition or the occurrence of a recurrent event while on a therapeutic dose of an antiplatelet agent. More recently, the term resistance has been restricted to the laboratory evidence of high on-treatment platelet reactivity (HTPR), while the clinical presence of a recurrent event has been termed treatment failure [31
Resistance to clopidogrel is a well-recognized phenomenon, with 15–30% of patients having inadequate platelet inhibition while on a therapeutic dose. This poor responsiveness to clopidogrel in certain patient population, as assessed by platelet function testing, has led to studies looking at the potential causes for resistance, the correlation of hypo- or nonresponsiveness to therapy with clinical outcomes (major adverse cardiac events) and at ways to overcome this problem (either by increased dosing or by a prescribing a different antiplatelet agent).
Several mechanisms are involved in resistance to clopidogrel: inadequate dosing or absorption, drug interactions, and genetic polymorphisms.
Inadequate dosing can be a factor of resistance in obese patients. Absorption can be impaired in patients with cardiogenic shock or with loss of the P-glycoprotein transporter function [33
]. Other patient population demonstrating an inadequate response to clopidogrel are the diabetic or insulins resistant patients [35
]. In these patients, the normal effects of insulin on the platelet leading to aggregation are impaired.
Drug interactions represent a major component of clopidogrel resistance. Statins, proton pump inhibitors (PPIs), ketoconazole, and erythromycin interact with different CYP enzymes, thereby decreasing the conversion of clopidogrel to the active metabolite [36
Clopidogrel is metabolized to its active form by the CYP enzymes, a super family of microsomal drug-metabolizing enzymes. Functional CYP polymorphisms consist of deletions, duplications, and mutations creating inactive gene products leading to increased or decreased metabolism of the drug. Clopidogrel's metabolism involves 2 steps. The first step leads to the formation of 2-oxo-clopidogrel, which subsequently is transformed into the active metabolite [41
]. Enzymes involved in the metabolism of clopidogrel include CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5. CYP2C19, with its gene located on chromosome 10, seems to be the most important enzyme involved in clopidogrel's metabolism. The CYP2C19
1 allele is associated with full enzyme activity while CYP2C19
3 variants are most frequently associated with poor responsiveness to clopidogrel. These alleles have been termed “loss of function alleles” and are more frequent in the Asian rather than in the Caucasians population. Many studies have confirmed an impaired response to clopidogrel either in healthy volunteers or patients carrying the CYP2C19
3 allele, evidenced by platelet function tests or by an increased incidence of MACE [41
] (). More importantly, the difference in clopidogrel metabolism appears to be present not only in homozygous patients but also heterozygote patients [43
]. Due to this evidence, the FDA has added a black box warning for patients with genetic variants of the CYP2C19 gene who are poor metabolizers and receive clopidogrel therapy. These patients are at particular high risk of a poor response to therapy and thus an increased rate of cardiovascular events [45
Studies assessing genetic polymorphism and response to clopidogrel.
On the other hand, the
17 allele (gain-of-function allele) is associated with CYP enzyme upregulation, increasing the clopidogrel metabolism by 30%, therefore, leading not only to an adequate antiplatelet response but also to potentially increased bleeding episodes [46
]. However, a recent meta-analysis did not find any association between the genotype (
17) and the rate of cardiovascular events or bleeding [49
ABCB1 is another gene receiving attention as potentially responsible for clopidogrel resistance. ABCB1 encodes the P-glycoprotein efflux transporter responsible for the intestinal absorption of clopidogrel. A certain genetic variant (ABCB1 3435C-T) has been linked to an increased ischemic event while on clopidogrel, but other studies have not confirmed it [50
Paraoxonase 1 (PON1) is a HDL-associated enzyme that is involved in the second step of clopidogrel metabolism. Its common polymorphism, Q192R, influences platelet inhibition [52
]. Recent studies offer contradictory information regarding the association between PON1 polymorphism and a lower degree of platelet aggregation or an increased risk of stent thrombosis [53
The relationship between polymorphisms of the gene encoding the P2Y12
receptor and a response variability to clopidogrel therapy was also studied, but the data remains inconclusive [42
Resistance to prasugrel is less prevalent, with fewer than 6% of patients qualifying as poor responders on a maintenance dose of prasugrel of 10
mg daily. In the setting of PCI, a significant number of patients did not achieve adequate platelet inhibition after a loading dose of 60
mg of prasugrel, thus, being at an increased risk for MACE [55
]. However, as compared to clopidogrel, prasugrel's metabolism depends mostly on CYP3A4 and CYP2B6 enzymes and to a lesser extent on CYP2C9 and CYP2C19 [56
]. On the other hand, prasugrel's metabolism involves just one step versus 2 steps for clopidogrel. These differences in metabolism as well as its increased potency relative to clopidogrel make prasugrel less susceptible to resistance. Patients demonstrating “resistance” to clopidogrel, based on HTPR, seem to have an adequate response to prasugrel therapy [60
]. Possible mechanisms responsible for prasugrel resistance include poor patient compliance, drug absorption disturbances, drug interactions (the concomitant use of CYP3A4 inhibitors), drug underdosing, increased platelet turnover, and P2Y12
receptor polymorphism [64
Ticagrelor is primarily metabolized via the cytochrome CYP3A4 enzyme, which leads to faster, greater, and more consistent antiplatelet effects as compared to clopidogrel. Ticagrelor therapy can also overcome nonresponsiveness in patients with treatment failure while on clopidogrel. Its pharmacodynamics is not influenced by CYP2C19 and ABCB1 genotypes. As such, patients resistant to both clopidogrel and prasugrel seem to be effectively treated with ticagrelor [67