Antiplatelet agents – P2Y12 receptor inhibitors
ATC code: B01AC04 (Clopidogrel)
A prodrug. Bioactivated in the liver by two sequential oxidations involving CYP2C19, CYP3A4, CYP2B6 and CYP1A2 into a thiol active metabolite, which irreversibly inhibits the platelet P2Y12 ADP receptor – blocking ADP-dependent aggregation for 7–10 days. In carriers of the defective CYP2C19*2/*3 alleles, activation is reduced – with a clinically meaningful loss of antiplatelet effect ( black box). Used as monotherapy or as part of dual antiplatelet therapy after ACS or stenting.
First line
Clopidogrel plus aspirin (DAPT) is the standard after acute coronary syndrome and percutaneous coronary intervention. The CURE trial showed a 20 % reduction in the composite of vascular death, MI, and stroke. DAPT duration is 6–12 months depending on stent type and bleeding risk. Clopidogrel monotherapy is an alternative when aspirin is not tolerated.
After ACS, given as part of dual antiplatelet therapy (DAPT) with aspirin for 6–12 months.
First line
Clopidogrel is one of the antiplatelet options for secondary prevention of ischemic stroke. The CAPRIE trial demonstrated a small but statistically significant advantage of clopidogrel over aspirin in preventing ischemic events. Dose is 75 mg once daily long-term.
First line
In peripheral artery disease, clopidogrel is the preferred antiplatelet agent. Subgroup analyses from CAPRIE showed a particularly pronounced advantage over aspirin in this population. Dose is 75 mg daily.
8 pairs found. Sorted from critical to minor.
Mechanism
Additive antiplatelet action: aspirin inhibits COX-1 → thromboxane, clopidogrel blocks the P2Y12 receptor. Effective dual antiplatelet therapy after ACS or stenting, but GI bleeding risk doubles.
Management
DAPT (aspirin 75–100 mg + clopidogrel 75 mg) – 12 months after ACS, 6 months after elective stenting. Then switch to monotherapy (aspirin or clopidogrel). During DAPT, add a PPI (pantoprazole).
Sources
Mechanism
Additive antithrombotic effect on two levels: apixaban blocks factor Xa while clopidogrel inhibits platelet aggregation. Major bleeding risk (mostly GI) rises 1.5–2-fold.
Management
Dual antithrombotic therapy (DOAC + clopidogrel) for AF plus recent stenting – for 6–12 months following the AUGUSTUS/ENTRUST-AF PCI regimen, then transition to apixaban monotherapy. Add a PPI (pantoprazole).
Sources
Mechanism
Аддитивный антиагрегантный эффект и снижение защитного действия простагландинов в . Риск кровотечений.
Management
Избегать длительного курса. Краткосрочно – с и контролем признаков кровотечения. По возможности – парацетамол.
Mechanism
Аддитивный антитромботический эффект через разные механизмы (антиагрегация + антикоагуляция). Высокий риск кровотечений.
Management
Только по строгим показаниям (стент + фибрилляция предсердий) и на минимальный срок. Контроль МНО и признаков кровотечения.
Mechanism
Additive antithrombotic effect: warfarin in the coagulation cascade plus clopidogrel at the platelet P2Y12 receptor. Major bleeding risk rises 2.5–3-fold.
Management
Triple therapy (warfarin + aspirin + clopidogrel) after stenting in AF patients is limited to about 1 month, then transitioned to dual therapy (warfarin + clopidogrel or aspirin) for 6–12 months. After one year, warfarin alone. An alternative is the WOEST/PIONEER regimen with a DOAC (apixaban) + clopidogrel.
Sources
Mechanism
Omeprazole is a potent CYP2C19 inhibitor, the key enzyme for clopidogrel bioactivation. The active thiol metabolite concentration drops, weakening the antiplatelet effect. The issued a black-box warning in 2010 about increased cardiovascular events on dual antiplatelet therapy.
Management
Avoid the combination. If gastric protection is needed, choose pantoprazole or rabeprazole (less CYP2C19 inhibition) or an H2-blocker (famotidine). Esomeprazole is as risky as omeprazole.
Mechanism
Two effects: 1) clopidogrel blocks aggregation at the P2Y12 receptor while sertraline impairs primary hemostasis by inhibiting platelet serotonin reuptake; 2) sertraline weakly inhibits CYP2C19 – clopidogrel activation is slightly reduced.
Management
Watch for bleeding signs. With elevated GI risk, add a PPI (pantoprazole, not omeprazole). Antidepressant alternatives with minimal platelet effects include mirtazapine and bupropion.
Sources
Mechanism
An early study by Lau et al. (Circulation, 2003) in 44 patients showed in vitro that atorvastatin competes with clopidogrel for CYP3A4 and blunts the aggregation response. Subsequent large-scale clinical data did not confirm the hypothesis. Analysis of more than 13,000 patients from CHARISMA (Saw et al., 2007) found no difference in cardiovascular events on DAPT between CYP3A4-metabolized statins and other statins. A systematic review by Hicks et al. (BMJ, 2010) and a meta-analysis by Mukherjee et al. (Arch Intern Med, 2008) reached the same conclusion. The , , and have issued no warnings about this pair.
Management
No statin change is needed. Per ACS 2023 and / 2018 Cholesterol Guidelines, all post-ACS patients should receive high-intensity statins (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) regardless of the P2Y12 inhibitor chosen. In most DAPT patients atorvastatin remains the preferred statin.
FDA category B. Limited human data in pregnancy. Prescribed only when benefit clearly outweighs potential risk.
No data on excretion in breast milk. Decision is individualized.
clopidogrel is evaluated for the following indications with varying evidence strength: Peripheral artery disease (evidence tier A), Ischemic stroke (evidence tier A), Established ASCVD, secondary prevention (evidence tier A). See the full indication matrix with dosing and citations above on this page.
Common side effects of clopidogrel (≥ 1 in 100): Bleeding (ecchymoses, epistaxis, gingival bleeding), Dyspepsia, diarrhea, Headache. See the Safety section for uncommon and serious reactions.
FDA category B. FDA category B. Limited human data in pregnancy. Prescribed only when benefit clearly outweighs potential risk.
No data on excretion in breast milk. Decision is individualized.
clopidogrel is contraindicated in: Active bleeding (GI, intracranial); Severe hepatic impairment; Hypersensitivity to clopidogrel. Full list in the Safety section.