Delayed Clopidogrel Transit During Myocardial Infarction Evident on Angiography

Abstract: We describe the case of a patient with non-ST segment elevation myocardial infarction (NSTEMI) where a limitation of oral clopidogrel loading prior to percutaneous coronary intervention (PCI) was directly visualized on angiography. Clopidogrel is a thienopyridine antiplatelet agent used in acute coronary syndromes. It reduces platelet aggregation via inhibition of the P2Y12 receptor. Clopidogrel is an inactive metabolite that is metabolized into the active metabolite by the cytochrome P450 isoenzymes located mostly in the liver and partly in the gastrointestinal system. As such, it requires at least 2 hours to reach maximal effect.  A 63-year-old female went to an outside facility where she was diagnosed with NSTEMI and underwent angiography. She was administered 324 mg of aspirin and 600 mg of clopidogrel, and was transferred to our facility. Upon arrival, approximately 1.5 hours after the oral loading dose, the clopidogrel tablets were visualized intact in the stomach during angiography, implying a very low likelihood of adequate absorption or antiplatelet effect. This observation raises the concern that delayed gastrointestinal transit, apart from other metabolic derangements, may be a factor in achieving optimal platelet inhibition using oral agents.

J INVASIVE CARDIOL 2015;27(5):E68-E69

Key words: clopidogrel, GI motility, absorption, antiplatelet, efficacy, ACS

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Clopidogrel is an oral thienopyridine-class antiplatelet agent used in acute coronary syndromes. It irreversibly blocks the P2Y12 component of adenosine diphosphate (ADP) receptor on the platelet surface, preventing activation of the glycoprotein IIb/IIIa receptor complex and resulting in reduced platelet aggregation. This case describes a limitation of oral antiplatelet agents not previously described.

Case Report

A 63-year-old African-American female with a history of hypertension, hyperlipidemia, impaired glucose tolerance, and obesity presented to a community hospital with 3 days of worsening substernal chest pain. She initially assumed the symptoms were due to acid reflux. Her vitals signs were normal. Electrocardiogram demonstrated ST depressions in the inferior leads and leads V3-V6. Laboratory values were pertinent for positive cardiac troponin I of 6.2 ng/dL. She was administered sublingual nitroglycerin, intravenous metoprolol, atorvastatin, and morphine sulfate, which resulted in incomplete chest pain relief. The decision was made to transfer her to our percutaneous coronary intervention (PCI) facility for urgent angiography. She received 324 mg of aspirin at 17:15 and 600 mg of clopidogrel at 17:36. Coronary angiography started at 18:50, and ended approximately 2 hours after the clopidogrel loading dose. In the right anterior oblique angiographic view, two 300 mg clopidogrel tablets are noted clearly in the stomach (Figures 1A and 1B; Video 1). Angiography also revealed that the left circumflex artery was totally occluded after giving off a large first obtuse marginal. This lesion was treated with percutaneous transluminal coronary angioplasty only, with restoration of flow and residual 50% stenosis (Figure 1B). Stenting was avoided in part due to the acceptable angioplasty result and small caliber (2.0 mm) of the culprit vessel. The patient was free of chest pain at the end of the case, with near complete resolution of the ST depressions on electrocardiography. She was continued on atenolol, atorvastatin, aspirin, and clopidogrel, as well as amlodipine and losartan for hypertension.

Discussion

The 2014 American College of Cardiology/American Heart Association consensus guidelines for management of patients with non-ST elevation acute coronary syndrome (NSTE-ACS)¹ recommend a loading dose of P2Y12 inhibitor (clopidogrel 600 mg, prasugrel 60 mg, or ticagrelor 180 mg) before the procedure in patients undergoing PCI with stenting. Glycoprotein IIb/IIIa receptor inhibition is recommended if the patient has not been adequately pretreated with clopidogrel or ticagrelor. 

The guidelines also offer a class-IIb recommendation for administration of morphine sulfate intravenously to patients with NSTE-ACS if there is continued ischemic chest pain despite treatment with maximally tolerated anti-ischemic medications. 

Most clopidogrel is hydrolyzed to an inactive compound by carboxylase; the remaining 15% requires in vivo activation to the thiol metabolite via cytochrome P450 isoenzymes, a process that requires several hours to reach maximal platelet effect.^1,2 Prasugrel requires an intestinal esterase to convert to its active form. Ticagrelor is reported to reach maximal plasma concentration at 1.5 hours, but this is a median time based on only 6 healthy patients receiving 200 mg of an oral ticagrelor suspension. 

This case is noteworthy in two respects. First, patients with non-ST elevation myocardial infarction may have a totally occluded vessel, as was the case in this patient. Persistent symptoms despite adequate ischemic therapy should prompt angiography to diagnose and restore patency of the artery. Undue focus on analgesics to alleviate symptoms may delay definitive therapy with revascularization. Second, this case illustrates the fact that many patients may not adequately absorb oral medications when urgently ill or if they have received medications that reduce intestinal motility. 

While genetic polymorphisms of the CYP450 isoenzymes and the ABCB1 gene can lead to decreased active metabolite and treatment failure,^3-7 delayed digestive transit is underappreciated as a cause of inadequate drug efficacy. Specifically, patients administered oral P2Y12 receptor antagonists may not achieve adequate antiplatelet action at the time of PCI or immediately thereafter, particularly if the medication is administered at the time of PCI on a background of narcotic agents.^1,2,7-10

It stands to reason that clinicians should be judicious about administration of narcotics when oral P2Y12 medications are to be utilized, and agents with more reproducible absorption and effect may provide superior outcomes. To inform this hypothesis, we await the results of the randomized trial evaluating the effect of morphine on platelet inhibition among ST-elevation myocardial infarction patients receiving prasugrel.¹¹ 

References

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