Clopidogrel

Publication Details

OVERVIEW

Introduction

Clopidogrel is an inhibitor of platelet aggregation that is used to decrease the risk of myocardial infarction and stroke in patients known to have atherosclerosis. Clopidogrel has been linked to rare instances of idiosyncratic, clinically apparent acute liver injury.

Background

Clopidogrel (kloe pid' oh grel) is an inhibitor of adenosine diphosphate (ADP)-induced platelet aggregation and is used widely to decrease the risk of myocardial infarction and stoke in patients who have documented coronary or cerebrovascular disease or previous heart attack or stroke. Activated platelets release ADP which binds to platelet receptors, causing activation of intracellular glycoprotein IIb/IIIA complex which triggers platelet adherence and aggregation. The aggregation of platelets plays an important role in the growth of atheromatous plaques, which can lead to coronary, cerebral and peripheral arterial occlusions. In large clinical trials, clopidogrel therapy has been shown to decrease the frequency of recurrence of myocardial infarction and stroke. Clopidogrel was approved for use in the United States in 1997 and is widely used, with more than 1.5 million prescriptions filled yearly. Current indications include reduction of atherosclerotic events (myocardial infarction, stroke, vascular death) in patients with documented atherosclerosis and in patients with acute myocardial infarction or unstable angina. Clopidogrel is available in 75 mg tablets generically and under the brand name of Plavix. The usual dose is 75 mg daily, sometimes with a loading dose of 300 mg on day one. Side effects are not common, but can include headache, dizziness, fatigue, gastrointestinal upset, nausea, arthralgias and rash.

Hepatotoxicity

Clopidogrel is associated with serum enzyme elevations in 1% to 3% of patients during therapy. In several large clinical trials, elevations of serum ALT were no more frequent with clopidogrel as with placebo (or in comparator arms) and no instances of clinically apparent liver injury were reported. Since marketing and release, however, there have been more than a dozen published case reports of clinically apparent liver injury attributed to clopidogrel. The onset of symptoms was within 2 to 24 weeks (averaging 6 weeks) of starting, with fatigue and jaundice. Several patients had an accompanying fever but rash and eosinophilia were not common. The usual pattern of liver enzyme elevations was hepatocellular, but cases with mixed or cholestatic enzyme elevations have also been described (Case 1). Autoantibodies were rarely present. Most cases were self-limited with recovery within 1 to 2 months, but rare cases of acute liver failure or hepatic decompensation with death or need for liver transplantation have been described.

Likelihood score: B (highly likely but rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of clopidogrel hepatotoxicity is not known, but is clearly idiosyncratic and may be due to the complex hepatic metabolism of the clopidogrel molecule. Immunoallergic features are usually not prominent, but hypersensitivity reactions to clopidogrel have been described. The effectiveness of clopidogrel is dependent upon its activation in the liver by CYP 2C19 and poor metabolizers of this enzyme may not respond adequately to its antiplatelet activity. Furthermore, it is susceptible to drug-drug interactions with agents that induce or inhibit CYP 2C19.

Outcome and Management

The severity of liver injury associated with clopidogrel ranges from transient, mild serum enzyme elevations to clinically apparent acute hepatitis that can be severe and lead to death. Most cases resolve with drug withdrawal within 1 to 3 months. Rechallenge with clopidogrel usually results in recurrence of liver injury and should be avoided. However, there does not appear to be cross sensitivity to the liver injury between clopidogrel and ticlopidine or dipyridamole.

Drug Class: Antithrombotic Agents, Antiplatelet Agents

Other Drugs in the Subclass, Antiplatelet Agents: Aspirin, Cangrelor, Dipyridamole, Prasugrel, Ticagrelor, Ticlopidine, Vorapaxar

CASE REPORT

Case 1. Acute cholestatic hepatitis due to clopidogrel.

[Modified from: Chau TN, Yim KF, Mok NS, Chan WK, Leung VK, Leung MF, Lai ST. Clopidogrel-induced hepatotoxicity after percutaneous coronary stenting. Hong Kong Med J 2005; 11: 414-6. [PubMed Citation]

A 74 year old man with a history of hypertension and ischemic heart disease presented with retrosternal chest pain and underwent cardiac catheterization which showed complete occlusion of the left anterior descending and 80% occlusion of the left circumflex artery for which he underwent successful percutaneous stenting. Clopidogrel was started in preparation of the coronary artery stenting and continued after discharge. Four weeks later and 41 days after starting clopidogrel he developed dark urine and jaundice. He had no previous history of liver disease, drug allergies, alcohol abuse, or risk factors for viral hepatitis. Other medications included aspirin, isosorbide dinitrate and metoprolol, all of which had been taken for several years. Laboratory testing showed a serum bilirubin of 5.3 mg/dL, ALT 212 U/L and alkaline phosphatase 172 U/L (Table). Serum albumin concentrations and prothrombin time were normal. Tests for acute hepatitis A, B, C (including HCV RNA) and E were negative as were smooth muscle and antinuclear antibodies. Abdominal ultrasound showed no hepatic masses or evidence of biliary obstruction. Four days after onset of jaundice, clopidogrel was stopped, while other medications were continued. Liver tests worsened for the first few days after presentation, but then began to improve and were within the normal range 3 months later.

Key Points

Laboratory Values

* Some values estimated from figure.

Comment

A typical example of an acute liver injury with jaundice attributed to clopidogrel. Typical were the time of onset (4-5 weeks), the mixed pattern of serum enzyme elevations and the mild self-limited nature of the injury, with improvement starting within a week of stopping the medication. While the liver injury from clopidogrel resembles that of ticlopidine, there are some differences. Both agents are associated with acute liver injury that usually arises within 1 to 12 weeks of starting. However, the injury tends to be more hepatocellular with clopidogrel and the time to recovery slightly shorter. Interestingly, there does not seem to be cross sensitivity to hepatic injury between clopidogrel and ticlopidine, despite their similar chemical structures and mechanisms of action.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Clopidogrel – Generic, Plavix®

DRUG CLASS

Antithrombotic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 17 October 2017

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    (53 year old woman developed fatigue, rash followed by jaundice 3 months after starting atorvastatin and 2 days after starting clopidogrel [bilirubin 5 mg/dL, ALT 1603 U/L, Alk P 408 U/L, INR 1.14], and did not improve after stopping atorvastatin [bilirubin rising to 24.5, INR 1.8], but did after stopping clopidogrel).
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    (75 year old woman developed fever 5 days after starting clopidogrel [bilirubin 1.6 mg/dL, ALT 716 U/L, Alk P 160 U/L], which resolved rapidly upon stopping and rechallenge resulted in rise in ALT [42 to 92 U/L] and AST [49 to 120 U/L] within two days).
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    (34 year old man developed jaundice 4 months after starting clopidogrel [bilirubin 5.7 mg/dL, ALT 1393 U/L, Alk P 130 U/L, INR 1.5], worsening for a week and improving thereafter on a brief course of prednisone and ursodiol).
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    (78 year old man with diabetes and renal insufficiency developed metabolic acidosis and liver test abnormalities 4 months after starting clopidogrel [bilirubin 2.1 mg/dL, ALT 106 U/L, Alk P 1441 U/L], laboratory tests improving, but not completely upon stopping).
  • Papagni S, Bonifati C, Dagostino F, Murgo AM. [Clopidogrel- induced hepatotoxicity in hemodialyzed patient: a case report]. G Ital Nefrol 2016; 33. pii: gin/33.1.7. Italian. PubMed Citation. [PubMed: 26913747]
    (71 year old diabetic on hemodialysis developed jaundice and ascites shortly after starting clopidogrel, which improved slowly upon stopping).
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    (Concurrent use of clopidogrel and omeprazole may decrease the antiplatelet activity, but the clinical significance of the effect has not been shown).