CLOPIDOGREL AND RELATED AGENTS
- USES: Clopidogrel and prasugrel are thienopyridines used as platelet inhibitors following intravascular stenting procedures. They are also used for cardiovascular and cerebrovascular thrombosis prophylaxis in patients with allergies to aspirin. PHARMACOLOGY: The thienopyridines are irreversible P2Y12 receptor inhibitors; they prevent adenosine diphosphate (ADP) to binding to the platelet cell surface and inhibit platelet aggregation. Clopidogrel and prasugrel are pro-drugs requiring hepatic metabolism for activation. TOXICOLOGY: Toxicity is largely an extension of the therapeutic effects leading to bleeding complications. EPIDEMIOLOGY: Bleeding associated with clopidogrel is common. Major bleeding complications are uncommon. Intentional overdose is rare. MILD TO MODERATE TOXICITY: Very little overdose data are available. In general, no clinical bleeding is expected in the absence of pre-existing bleeding pathology or trauma. Nausea and vomiting are likely to be present after significant acute overdose. Ecchymosis, gum bleeding, and inhibited wound clotting is possible in overdose. SEVERE TOXICITY: Patients with associated trauma or gastrointestinal bleeding may have prolonged bleeding and large volume blood loss. ADVERSE EFFECTS: Minor bleeding is observed in approximately 3% to 5% of patients taking clopidogrel therapeutically. Major bleeding occurs in approximately 1% to 3% of patients taking clopidogrel therapeutically. Cytopenias and hepatitis have been reported as adverse effects from clopidogrel administration in therapeutic doses. Several rash morphologies have been associated with clopidogrel administration, though these reactions are rare. Hemolytic uremic syndrome is rarely associated with clopidogrel therapy.
Range of Toxicity:
CLOPIDOGREL AND RELATED AGENTS
- TOXICITY: No toxic dose has been established. CLOPIDOGREL: Ingestions of 1650 mg and 1050 mg by adults resulted in no toxicity, and a 6300 mg ingestion caused minimal toxicity. In the absence of additional anticoagulants or traumatic injury, no clinical bleeding is expected in the vast majority of cases. THERAPEUTIC DOSE: CLOPIDOGREL: For patients with a recent myocardial infarction, recent stroke, or established peripheral arterial disease, the recommended dose is 75 mg/day. For patients with acute coronary syndrome (unstable angina, non-Q-wave myocardial infarction), clopidogrel should be started with an oral loading dose of 300 to 600 mg, followed by 75 mg once daily with aspirin (75 mg to 325 mg) once daily. PRASUGREL: The recommended dose is a single 60 mg loading dose followed by 10 mg daily with aspirin (75 mg to 325 mg); consider prasugrel 5 mg daily in patients weighing less than 60 kg.
CLOPIDOGREL AND RELATED AGENTS
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: No intervention should be instituted for patients with mild to moderate bleeding complications since blood product transfusion may be associated with more risk than benefit in these patients. If discontinuation is necessary due to adverse effects from the drug, alternative anti-platelet therapy should be instituted. MANAGEMENT OF SEVERE TOXICITY: Management of patients with major bleeding complications is difficult. Platelet transfusion has not been shown to improve outcomes and is associated with higher risks of infections, cerebrovascular accidents, and death. It may be impractical to provide enough platelets to overcome the active drug. A more practical approach would be to identify the source of bleeding and provide local hemostasis whenever possible. When local hemostatic control is not practical, red blood cell and platelet transfusions must be considered. Desmopressin has been shown to increase platelet aggregation in patients taking clopidogrel, and administration has a theoretical advantage of bypassing the ADP inhibition leading to subsequent platelet activation. However, no randomized clinical trials exist to support desmopressin use at this time. Epsilon aminocaproic acid (EAPC), aprotinin, and tranexamic acid (TA) have all been used with variable success for prophylaxis of post-surgical bleeding or reversal of platelet inhibition in the setting of cardiac bypass grafting. At this time, aprotinin and TA are clinically available in the United States only under compassionate use applications through the FDA (1-888-842-2937). There is little evidence to support their use in bleeding patients due to clopidogrel toxicity at this time.
- Decontamination: PREHOSPITAL: Activated charcoal can be considered in alert patients with recent, substantial overdose. HOSPITAL: Administration of activated charcoal is recommended if a patient presents early after an intentional overdose. No decontamination is warranted for patients with inadvertent ingestion of extra doses. Gastric lavage has no role in the management of clopidogrel overdose or toxicity.
- Airway management: No airway compromise is anticipated from clopidogrel toxicity, though co-ingestions should be considered, and care should be taken not to cause airway trauma during attempts at airway management.
- Antidote: None
- Monitoring of patient: No laboratory studies are needed in asymptomatic patients. Serial CBCs are recommended in bleeding patients. No single laboratory test is able to adequately measure platelet function. In patients with significant bleeding, thromboelastography in combination with platelet count and PT/INR studies may give a general estimation of a patient’s hemostasis potential, though no one test is well correlated with the in-vivo coagulation propensity.
- Enhanced elimination procedure: The serum half-life of clopidogrel is relatively short and the duration of action is prolonged, therefore removal by extracorporeal methods is not likely to significantly change a patient’s course and may, in fact, put them at higher risk of bleeding complications from catheter replacement.
- Patient disposition: HOME CRITERIA: Inadvertent ingestion of extra clopidogrel doses may be managed at home with referral for signs of bleeding. OBSERVATION CRITERIA: Observation for 4 hours should be sufficient in most cases given the expected pharmacokinetic peak at 30 to 60 minutes in therapeutic doses. At the end of the observation period, the physician should assess for signs of bleeding such as tachycardia, shortness of breath, hematochezia, or headache. ADMISSION CRITERIA: Patients with evidence of active bleeding should be admitted for serial hematocrits. CONSULT CRITERIA: Hematology should be consulted for patients with major bleeding associated with clopidogrel toxicity. Cardiology should be consulted in patients with coronary stents placed within 1 year in whom reversal of clopidogrel is considered. A toxicologist should be consulted in all overdose cases with significant toxicity.