Table 1.
Summary of factors that may affect clopidogrel pharmacokinetics, pharmacodynamics and clinical outcome.
| Potential Factors | Influence on Clopidogrel PK/PD | Influence on Clinical Outcome | |
|---|---|---|---|
| Demographics | |||
| Older Age | Higher on-treatment platelet reactivity [14, 19, 39–41]. | Increase in both cardiovascular events [5, 16, 42–44] and bleeding [45, 46]. | |
| Obesity | Lower systemic exposure to clop-AM [136] Higher on-treatment platelet reactivity [14, 41, 47]. |
Inconclusive (obesity paradox) [16, 42, 45, 52, 53]. | |
| Sex | Minimal/inconclusive [14, 19, 39, 57, 87] [40, 58]. | Minimal/inconclusive [16, 42] [5, 43, 45, 52, 59–61]. | |
| Pharmacogenetics | |||
| ABCB1 | C3435T | Minimal/inconclusive [16, 19, 21, 39, 60] | Minimal/inconclusive [16, 60, 64–67] |
| CES1 | G143E A-618C |
Lower on-treatment platelet reactivity [23, 68] Inconclusive [70, 71] |
N/A |
| CYP2C19 | G681A (*2) G636A (*3) |
Lower systemic exposure to clop-AM [4, 75–77] Higher on-treatment platelet reactivity [17, 18, 39, 58, 78–82] |
Increase of cardiovascular risk [14, 16, 18, 65, 78, 81–85] |
| C806T (*17) | Minimal/inconclusive [15, 77, 86, 87] | Minimal/inconclusive [15, 65, 74, 83, 87] | |
| CYP1A2 | *1C-1F, *7, *11, *16 and others | Minimal/inconclusive [17, 18, 75, 80] | Minimal/inconclusive [18] |
| CYP2B6 | *1B, *1C, *5, *6, *9, *11 and others | Minimal/inconclusive [18, 39] | Minimal/inconclusive [18] |
| CYP2C9 | C430T (*2) A1075C (*3) and others |
Minimal/inconclusive [18, 75, 80] | Minimal/inconclusive [18, 61] |
| CYP3A4/5 | *2, *3, *17 and others (CYP3A4) *2, *3, *6 and others (CYP3A5) |
Minimal/inconclusive [18, 75, 80, 81, 92, 93]. | Minimal/inconclusive [18, 61, 93]. |
| PON1 | Q192R | Minimal/inconclusive [24, 76, 79, 82, 96, 97], | Minimal/inconclusive [65, 79, 82, 96–98], |
| P2Y12 | H2 haplotype and others | Minimal/inconclusive [57, 100, 101, 104, 105, 108] | Minimal/inconclusive [16, 39, 105–107, 109] |
| Drug-Drug Interactions | |||
| Proton pump inhibitors | Lower systemic exposure to clop-AM [120, 121, 124] Higher on-treatment platelet reactivity [120–127]. |
Minimal impact on cardiovascular risk [118, 130–132] | |
| Statins | No negative effect on systemic exposure to clop- AM [135]. No negative effect on on-treatment platelet reactivity [127, 135, 137–145]. |
No negative effect on clinical outcome [141, 146–148] | |
| Calcium channel blockers | Minimal/inconclusive [63, 94, 150, 151, 154] | Minimal/inconclusive [94, 150–154] | |
| Anticoagulants | N/A | Decrease of cardiovascular risk while increase of bleeding events [166, 167] | |
| Antidepressants | Conflicting/inconclusive [171, 172] | Conflicting/inconclusive [169, 174–178] | |
| Comorbidities | |||
| Diabetes | Lower systemic exposure to clop-AM [182] Higher on-treatment platelet reactivity [41, 55, 82, 179, 181]. |
Increase of cardiovascular risk [41, 44, 56, 82, 181] | |
| Chronic kidney disease | Higher on-treatment platelet reactivity (more significant when using VerifyNow™ P2Y12 assay) [91, 186–191] | Increase in both cardiovascular events and bleeding [43, 44, 59, 192–196] | |