Prasugrel as a Safe Alternative for Clopidogrel-Associated Arthritis

ABSTRACT: Clopidogrel is a thienopyridine derivative antiplatelet compound. The antiplatelet effects of clopidogrel originate through noncompetitive antagonism of the platelet ADP receptor, P2Y12, resulting in inhibition of platelet activation. Clopidogrel is now widely used in acute coronary syndromes and after percutaneous coronary interventions to reduce the risk of subsequent cardiovascular events. We report a case of acute migratory polyarthritis associated with the use of clopidogrel. This serves as only the second documented case of clopidogrel-associated arthritis in the United States, and the first to show that prasugrel may be considered as an alternative agent without short-term reoccurrence.

J INVASIVE CARDIOL 2011;23:E137–E138

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Clopidogrel is a thienopyridine derivative antiplatelet compound. The antiplatelet effects of clopidogrel originate through noncompetitive antagonism of the platelet ADP receptor, P2Y12, resulting in inhibition of platelet activation. Clopidogrel is now widely used in acute coronary syndromes (ACS) and after percutaneous coronary interventions (PCI) to reduce the risk of subsequent cardiovascular events.¹ Although clopidogrel is generally well tolerated, rare side effects include indigestion, nausea, vomiting, diarrhea, rashes, bleeding, abnormal liver function, and neutropenia. We report a case of acute migratory polyarthritis associated with the use of clopidogrel.

Case Report. A 52-year-old white male, with a history of coronary artery disease, myocardial infarction 17 years previously treated only with thrombolytic therapy, dyslipidemia, hypertension and gastritis, presented for an outpatient visit with 6 months of progressive angina. His medications included lisinopril, atenolol, omeprazole, niacin, aspirin, rousuvastatin, and sublingual nitroglycerin as needed. He had no previous known drug allergies. The patient admitted to infrequent alcohol intake and had a previous smoking history. Due to progressive symptoms despite maximal medical management, coronary angiography with possible PCI was recommended. Clopidogrel was started at 75 mg daily on the day of the original visit. Two weeks following initiation of clopidogrel, the patient began experiencing severe itching of his hands and feet without any apparent rash. This was also accompanied by intermittent fever and chills. Three days later, he developed excruciating joint pain. The pain was migratory, involving bilateral knees, hips, shoulders, hands, and elbows. His primary care physician prescribed acetaminophen and hydrocodone without any relief. Given the severe nature of the arthralgias, the patient was admitted to the hospital.

Rheumatology was consulted. Vitals signs included a temperature of 99.7 °F, blood pressure of 111/75 mmHg, pulse of 109 bpm, and respiratory rate of 20/min. There was severe synovitis, tenderness and warmth affecting the wrists, knees, hips, shoulders, elbows, interphalangeal and metacarpophalangeal joints. There was a decrease in active and passive range of motion secondary to pain. Cardiovascular, respiratory and gastrointestinal examinations were unremarkable. No lymphadenopathy was noted. There was no associated tenderness or indurations over the temporal artery. The differential diagnosis at that time included drug reaction, acute rheumatoid arthritis, viral hepatitis, reactive arthritis, SLE, infectious arthritis, pseudogout, gonococcemia and serum sickness.

Laboratory findings revealed a normal complete blood count, liver function tests, electrolytes, renal function, urinalysis, antinuclear antibody, anti-cyclic citrullinated peptide antibodies, and serum immunofixation. Both the C-reactive protein (CRP-hs) and erythrocyte sedimentation rate (ESR) were increased to 171.7 mg/L (0.2–10 mg/L) and 68 mm/hr (0–20 mm/hr), respectively. Serologies for parvovirus B19, rheumatoid factor, and hepatitis A, B and C were negative.

Clopidogrel was immediately discontinued and the patient was begun on intravenous methylprednisolone. Within 24–48 hours, the patient’s symptoms dramatically improved. Upon discharge, the patient was given prednisone 60 mg orally daily, slowly tapering the dose over 2 weeks. He was also given instructions to avoid clopidogrel in the future.

One month after the original bout of arthralgias, the patient remained joint-pain free and was scheduled for a diagnostic coronary angiogram. The left main was angiographically normal. The mid left anterior descending artery had a focal 40% stenosis. The second obtuse marginal branch of the circumflex had 2 proximal tandem lesions of 70% and 90%. The right coronary artery was dominant and was proximally occluded. The patient was then started on prasugrel with plans to monitor for recurrent arthralgias over the next 3 weeks in preparation for future PCI. At 3-week telephone follow-up, the patient remained free of arthralgias and then underwent PCI of the second obtuse marginal branch with a drug-eluting stent. Six weeks post-stent implantation, the patient was still free of arthralgias and also experienced resolution in his anginal symptoms.

Discussion. Only a few cases of clopidogrel-associated arthritis have been reported in the literature.^2–9 The onset of symptoms seems to occur within the first 10–20 days upon initiating the medication. In those few cases where a loading dose was administered, symptoms occurred earlier, at an average of 2–3 days. The most common symptoms accompanying the arthritis included fever and pruritis. Although a rechallenge of clopidogrel in our patient would have confirmed the associated arthritis, the temporal correlation of symptom onset in relation to beginning clopidogrel provides at least a probable association. The use of ticlopidine as an alternative to clopidogrel was considered; however, there has been one documented case of ticlopidine-associated arthritis.¹⁰ Prasugrel is a relative newly approved thienopyridine indicated for PCI in ACS.¹¹ However, there have been no documented cases of arthritis with prasugrel. Thus, it was chosen as an alternative agent. This serves as only the second documented case of clopidogrel-associated arthritis in the United States, and the first one to show that prasugrel may be considered as an alternative agent without short-term reoccurrence.

References

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From the ¹School of Public Health Sciences and Professions, Ohio University, Athens, Ohio, ²Community Heart and Vascular, Community Health Network, Indianapolis, Indiana, and ³MidOhio Cardiology & Vascular Consultants, Athens, Ohio.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted August 27, 2010, provisional acceptance given October 12, 2010, final version accepted October 26, 2010.
Address for correspondence: Vipin B. Koshal, DO, MidOhio Cardiology & Vascular Consultants, 65 Hospital Drive, Cornwell Center, Athens, OH 45701. Email: vkoshal@gmail.com