Rash with Both Clopidogrel and Ticlopidine in Two Patients
Following Percutaneous Coronary Intervention with
Kathy Makkar, Robert L Wilensky, Maureen Burke Julien, Howard C Herrmann, and Sarah A Spinler
OBJECTIVE: To describe 2 cases of rash that occurred following oral administration of both clopidogrel and ticlopidine and to review
previously published case reports.
CASE SUMMARY: Two patients developed maculopapular pruritic rashes that began on the abdomen and spread to the back, neck,
and face following clopidogrel administration after placement of a drug-eluting intracoronary stent. Following recurrence of the rash
after ticlopidine was initiated, thienopyridines were discontinued, and the patients were treated for 3–6 months with aspirin,
cilostazol, and enoxaparin or warfarin for prevention of stent thrombosis and reinfarction. One patient self-discontinued cilostazol,
reinitiated clopidogrel, and redeveloped a rash.
DISCUSSION: While there have been several published cases of thienopyridine-associated rash, there have been only 2 reported
cases of cross-sensitivity between orally administered clopidogrel and ticlopidine. Preliminary reports suggest that clopidogrel
desensitization may be accomplished in selected patients several months to years following thienopyridine rash using an allergy
desensitization protocol, with close monitoring for anaphylaxis. An objective causality assessment using the Naranjo probability
scale indicated that both ticlopidine and clopidogrel were probable causes of the rash in the first patient; in the second patient,
clopidogrel was judged a definite cause and ticlopidine was a probable cause of the rash.
CONCLUSIONS: In a patient who develops a rash following clopidogrel treatment after intracoronary stent placement, ticlopidine
therapy should be attempted, provided the initial reaction did not include life-threatening symptoms. In a patient who experiences
rash with both clopidogrel and ticlopidine and does not have a contraindication to cilostazol or anticoagulation, therapy with aspirin,
cilostazol, and either enoxaparin or warfarin may be administered for 2–6 months following placement of a drug-eluting stent.
KEY WORDS: cilostazol, clopidogrel, desensitization, drug-eluting stent, enoxaparin, ticlopidine.
Ann Pharmacother 2006;40:1204-7.
Published Online, 9 May 2006, www.theannals.com, DOI 10.1345/aph.1G587
iclopidine and clopidogrel are thienopyridine deriva- Case Reports
T tives that inhibit platelet aggregation by blocking the
adenosine diphosphate receptor that is responsible for initi- CASE 1
ating platelet adhesion and aggregation.1,2 Both agents A 94 kg, 60-year-old man with a medical history of polio, type 2 dia-
have been widely used for the prevention of coronary stent betes mellitus, and coronary artery bypass graft surgery presented to an
thrombosis in patients with coronary artery disease.3 Rash outside hospital with ischemic chest pain. Medications taken at the time
of presentation included aspirin, atenolol, atorvastatin, fosinopril,
is one of the most frequently reported adverse events in pa-
glimepiride, metformin, and docusate sodium (doses not known). Coro-
tients treated with these antiplatelet agents, occurring in nary angiography revealed significant proximal and distal left circumflex
4% of patients receiving ticlopidine and 5.1% of patients coronary artery stenoses; the patient underwent percutaneous transluminal
receiving clopidogrel.2,4 Thienopyridine rash has been re- coronary balloon angioplasty (PTCA). Just prior to PTCA, an oral load-
ported to occur within minutes of exposure5 as well as up to ing dose of clopidogrel 300 mg was administered, and eptifibatide (dose
3 months following initiation.6 We describe 2 patients who not known) was initiated. Following angioplasty, the clopidogrel dosage
was decreased to 75 mg daily. Eptifibatide was discontinued prematurely
experienced extensive rashes secondary to both clopidogrel
secondary to an abrupt decrease in platelet count. Within 24 hours follow-
and ticlopidine following percutaneous coronary interven- ing PTCA, the patient developed recurrent ischemic chest pain. Eptifi-
tion (PCI) with stent placement. batide was restarted, and the patient’s symptoms resolved. Repeat angiog-
raphy revealed thrombotic occlusion of the distal left circumflex artery,
and elevated cardiac enzymes indicated a myocardial infarction. Repeat
Author information provided at the end of the text. PTCA of the left circumflex coronary artery was performed, and the pa-
1204 I The Annals of Pharmacotherapy I 2006 June, Volume 40 www.theannals.com
tient was transferred to our hospital for further medical management. eluting stent was placed. The patient was discharged the following morn-
Medications at time of transfer included oral aspirin 325 mg daily, meto- ing on aspirin 162 mg daily, clopidogrel 75 mg daily, ramipril 5 mg daily,
prolol, and clopidogrel 75 mg daily; intravenous therapy included nitro- extended-release metoprolol 100 mg daily, and atorvastatin 40 mg daily.
glycerin and eptifibatide 2 µg/kg/min. His physical examination was sig- Two days following discharge, the patient reported that a pruritic rash
nificant for a maculopapular, pruritic rash on the abdomen, back, and had developed on his posterior thorax the afternoon of discharge and
neck. His platelet count was 54 × 103/mm3. The rash was treated with hy- spread to his stomach and anterior thorax that evening and to his face
drocortisone 1% cream and oral hydroxyzine 50 mg 4 times daily. and neck the next day. He also reported eyelid swelling, but denied
On hospital day 5, the patient was discharged; however, the rash re- throat swelling, wheezing, or difficulty breathing. The patient was pre-
mained unchanged. On the day of discharge, clopidogrel was discontin- scribed diphenhydramine 25 mg orally every 6 hours and advised to dis-
ued secondary to rash, and ticlopidine 250 mg twice daily was initiated. continue ramipril secondary to possible angioedema. The next morning,
Other discharge medications included aspirin 325 mg daily, glimepiride he reported that the swelling had subsided and the pruritus had dimin-
4 mg twice daily, extended-release metformin 500 mg twice daily, ished, but the rash was still extensive. The patient continued taking
atenolol 12.5 mg daily, ramipril 2.5 mg daily, isosorbide dinitrate 5 mg diphenhydramine for the next 2 days without relief. On day 5 following
twice daily, amlodipine 2.5 mg daily, docusate sodium 100 mg twice dai- discharge, clopidogrel was discontinued and oral ticlopidine 250 mg
ly, hydroxyzine 50 mg 4 times daily as needed for itching, and hydrocor- twice daily was administered.
tisone 1% cream applied to the rash 3 times daily as needed. His platelet Ten days following discharge and 5 days following initiation of ticlo-
count at the time of discharge was 120 × 103/mm3. pidine, the rash worsened. Ticlopidine was discontinued and oral cilosta-
Three days following discharge, the patient presented to our emergen- zol 100 mg twice daily was initiated. Ramipril was restarted without
cy department with substernal chest pain; a resolving rash on his ab- event. The rash resolved 3 days following discontinuation of ticlopidine.
domen, back, and neck; and a new maculopapular rash on his legs and The patient self-discontinued cilostazol and restarted clopidogrel ap-
arms. His medications were the same as at discharge 3 days previously. proximately 4 weeks after discharge. The rash reappeared and he discon-
His platelet count was 341 × 103/mm3. The new rash worsened thereafter, tinued clopidogrel and restarted cilostazol. At the time of this report, the
and on hospital day 2, prednisone 40 mg followed by a taper to discontin- patient had continued on warfarin, cilostazol, aspirin, atorvastatin, and
uation was added to the oral hydroxyzine and hydrocortisone cream regi- ramipril and remained symptom free 3 months following hospitalization.
men. On hospital day 3, ticlopidine was discontinued and oral cilostazol
100 mg twice daily was started secondary to suspected ticlopidine allergy.
On hospital day 4, the patient had 2 sirolimus drug-eluting stents Discussion
placed in each of the left circumflex and the superior obtuse marginal
branch coronary arteries. Fourteen hours following the procedure, he de- While there have been several published cases of thieno-
veloped chest pain and diaphoresis associated with electrocardiographic pyridine-associated rash,5-11 there have been only 2 reported
changes including ST-segment depression and T-wave inversion in leads cases of cross-sensitivity between orally administered clopi-
V2 and V3. Repeat coronary angiography was performed immediately
dogrel and ticlopidine.11 In our cases, both patients with prior
and revealed subacute thrombosis of the obtuse marginal stent. Addition-
al sirolimus eluting stents were placed proximal and distal to the prior
rash to clopidogrel experienced a new rash with ticlopidine.
stent. Heparin infusion was initiated for 48 hours to protect against recur- The occurrence of rash in the first patient was classified as
rence of subacute thrombosis. A subcutaneous injection of enoxaparin probable with each agent, according to the Naranjo probabil-
100 mg twice daily was added on hospital day 5. ity scale.12 In the second patient, the occurrence of rash was
The patient was discharged on hospital day 7 on a treatment regimen classified as definite with clopidogrel and probable with
of aspirin, glimepiride, metformin, atenolol, isosorbide dinitrate, doc-
ticlopidine. As of April 18, 2006, this is the first report de-
usate sodium, cilostazol, and enoxaparin (at the same dosages mentioned
previously), as well as oral fosinopril 10 mg daily and sliding-scale dos- scribing an alternative antithrombotic therapy strategy in a
es of regular insulin. At the time of discharge, the rash was not pruritic; patient unable to take thienopyridines following PCI.
therefore, prednisone and hydrocortisone cream were discontinued. The There have been 7 previously published case reports de-
rash on the lower extremities subsided after 10 days, but the rash on the scribing rash with either ticlopidine or clopidogrel.5-11 In
back persisted for up to 2 months following hospital discharge. Enoxa-
the first report, a 66-year-old woman taking ticlopidine
parin was discontinued after 3 months. The patient remains on cilostazol.
No additional episodes of acute coronary syndrome or rash occurred dur- 250 mg twice daily to prevent intracoronary stent throm-
ing that time. bosis following PCI presented 3 weeks later with an acute,
febrile, pruritic rash that began on the trunk and spread to
CASE 2 the extremities.7 Ticlopidine was stopped, and the rash re-
solved within one week. Patch tests with ticlopidine 5%
A 76.4 kg, 57-year-old Asian man with dilated cardiomyopathy (ejec- and 10% produced a positive reaction within 72 hours. It is
tion fraction 35%), New York Heart Association Class I heart failure,
unknown whether challenge with another antiplatelet in-
and chronic atrial fibrillation was admitted to the coronary catheteriza-
tion laboratory for elective angiography following an outpatient adeno- hibitor or anticoagulant was attempted.
sine stress test that showed a small inferior reperfusion defect suggestive In the second report, a 58-year-old white woman was
of myocardial ischemia. His medication regimen included warfarin, as- given clopidogrel 300 mg orally one day following PCI.5
pirin, and extended-release metoprolol. Warfarin had been discontinued Twenty minutes later, the patient experienced itching and
for 5 days prior to admission. Angiography revealed luminal irregulari-
developed a flare reaction followed by a rash on the face
ties in the left main, left anterior descending, and right coronary arteries as
well as 80–90% proximal right coronary artery stenosis. Eptifibatide, in- and dorsal part of her body. Thirty minutes to one hour af-
travenous unfractionated heparin, and clopidogrel 600 mg were adminis- ter receiving diphenhydramine 25 mg orally, her signs and
tered. The patient underwent uncomplicated PCI, and a paclitaxel drug- symptoms resolved. Rechallenge was not attempted, and
www.theannals.com The Annals of Pharmacotherapy I 2006 June, Volume 40 I 1205
K Makkar et al.
initiation of additional antiplatelet and anticoagulant thera- not been well studied in patients with drug-eluting stents.13-17
py was not described. Enoxaparin has also been shown in one trial to reduce the
A systemic inflammatory response syndrome occurring rate of myocardial infarction when extended therapy is giv-
after the first dose of clopidogrel was also described in 2 en for 2 weeks following bare metal stent placement.18
patients receiving oral clopidogrel 300 mg prior to PCI.9,10 Desensitization was not thought to be an option in our
These patients developed a rash, high fever, and impaired patients. However, Camara and Almeda11 described 3 cas-
liver function. One of the patients also developed thrombo- es of successful clopidogrel desensitization. In the first
cytopenia and lymphopenia. Both patients experienced re- case, desensitization was attempted 5 months following in-
currence of symptoms following rechallenge. tracoronary stent placement and occurrence of clopidogrel
In the fifth report, a 68-year-old woman experienced se- rash. While in an intensive care unit and under the care of
vere itching and developed a rash on the palms and majori- an allergy specialist, the patient received repeated escalat-
ty of her body 3 weeks after initiating clopidogrel for stent ing doses of clopidogrel starting with 0.005 mg and ending
thrombosis prevention following PCI.8 The patient was ad- with 75 mg. The desensitization was uneventful, and the
mitted to the hospital, clopidogrel was stopped, and antihis- authors reported that the patient was successfully receiving
tamines and oral and topical corticosteroids were adminis- clopidogrel 3 years later. In the second case, the patient un-
tered for 5 days. Enoxaparin 1 mg/kg was administered derwent clopidogrel desensitization 4 years after intracoro-
subcutaneously twice daily for 4 days. Oral ticlopidine 250 nary stenting and development of a rash after use of both
mg twice daily was initiated. Signs and symptoms resolved clopidogrel and ticlopidine as described above. Using the
within 2 weeks. Length of follow-up was not specified. As same clopidogrel allergy desensitization protocol, the pa-
of April 18, 2006, this is the only prior report describing tient was successfully desensitized. She continued to re-
successful initiation of ticlopidine in a patient with a history ceive clopidogrel more than one year later. In the third
of rash secondary to clopidogrel. This report describes no case, the patient underwent desensitization 2 months fol-
cross-sensitivity like that experienced by our patients. lowing rash to both clopidogrel and ticlopidine. However,
In the sixth case report, a 54-year-old woman devel- in this case, the patient underwent the procedure as an out-
oped a pruritic erythematous rash on her back 3 months af- patient and developed a pruritic erythematous rash on her
ter initiation of ticlopidine for cerebrovascular disease.6 lower abdomen 10 minutes after receiving clopidogrel 5
Skin testing for sensitivity to both ticlopidine and clopido- mg. Thirty minutes later, after the rash subsided, redesensi-
grel was performed, and ticlopidine testing was positive. tization was performed, starting with a 2.5 mg dose and
Patch testing and oral challenge of clopidogrel were nega- concluding successfully with a 75 mg dose. The authors
tive. Therefore, this case described successful clopidogrel reported that she had successfully taken clopidogrel daily 5
therapy following ticlopidine rash. months following the desensitization procedure. The au-
Finally, 2 patients have been described who developed thors recommended that desensitization not be attempted if
the patient has a history of Stevens–Johnson syndrome, ex-
rashes with clopidogrel following intracoronary and ab-
foliative dermatitis, or toxic epidermal necrolysis.
dominal aneurysm stenting and subsequently developed
They also recommended withholding β-blockers during
rashes with ticlopidine treatment.11 In the first case, a 68-
desensitization, as they are associated with increased mast
year-old woman developed a pruritic macular rash on her
cell synthesis, histamine release, and unopposed α-adren-
abdominal wall following repeat intracoronary stenting
ergic stimulation should an allergic response occur.11 We
and ticlopidine administration 10 months after intracoro-
did not attempt desensitization in our patients, as there had
nary stenting and a maculopapular abdominal wall rash
been no published reports of desensitization at the time our
following clopidogrel administration. Alternative an-
patients were treated.
tithrombotic therapy after the initial clopidogrel-associated
rash appeared was not described. In the second case, a 71-
year-old woman developed an erythematous macular rash
in the abdominal area 3 weeks after clopidogrel adminis- On the basis of our experiences described here, patients
tration for abdominal aneurysm stenting. The rash resolved who develop rash associated with both clopidogrel and
following a short duration of prednisone treatment. Ticlo- ticlopidine and do not have a contraindication to cilostazol
pidine was initiated; within one week, the woman devel- or anticoagulation may be treated with aspirin, cilostazol,
oped a rash on her face and lower extremities that resolved and enoxaparin or warfarin for 2–6 months after drug-elut-
one week after discontinuing ticlopidine. ing stent placement. Preliminary reports suggested that
Following the development of rashes in our patients, we clopidogrel desensitization may be accomplished in certain
chose to use alternative antithrombotic therapy. Limited data patients several months to years following thienopyridine
suggest that cilostazol has some efficacy in the prevention of rash using an allergy desensitization protocol, with close
stent thrombosis with bare metal stents, but this theory has monitoring for anaphylaxis.
1206 I The Annals of Pharmacotherapy I 2006 June, Volume 40 www.theannals.com
Rash with Both Clopidogrel and Ticlopidine Stent Placement
Kathy Makkar PharmD, Resident in Pharmacy Practice, Mercy EXTRACTO
Suburban Hospital, Norristown, PA OBJETIVO: Describir 2 casos de pacientes que presentaron una erupción
Robert L Wilensky MD, Associate Professor of Medicine, De- después de la administración oral de clopidogrel y de ticlopidina.
partment of Medicine, Cardiovascular Division, University of Penn- También, revisar otros casos similares publicados anteriormente en la
sylvania, Philadelphia, PA literatura médica.
Maureen Burke Julien MSN CRNP, Nurse Practitioner, Interven-
RESUMEN DEL CASO: Dos pacientes desarrollaron erupción prurítica
tional Cardiology, Cardiovascular Division, Hospital of the Universi-
ty of Pennsylvania, Philadelphia maculopapular que se inició en el abdomen y se diseminó hacia la
espalda, el cuello, y la cara después de la administración de clopidogrel
Howard C Herrmann MD, Professor of Medicine, Department of
posteriormente a la colocación de un stent (tubo delgado) intracoronario.
Medicine, Cardiovascular Division, University of Pennsylvania
Después de la reaparición de la erupción con la administración de la
Sarah A Spinler PharmD FCCP, Professor of Clinical Pharmacy, ticlopidina, las tienopiridinas fueron suspendidas y los pacientes tratados
Philadelphia College of Pharmacy, University of the Sciences in con aspirina, cilostazol, y enoxaparina o warfarina para prevenir una
Philadelphia, Philadelphia; Adjunct Professor of Pharmacy in
trombosis y un reinfarto. Uno de los paciente que suspendió el cilostazol
Medicine, Department of Medicine, Cardiovascular Division, Uni-
versity of Pennsylvania sin auntorización médica y reinició el tratamiento con el clopidogrel
tuvo una reaparición de la erupción.
Reprints: Dr. Spinler, University of the Sciences in Philadelphia,
600 S. 43rd St., Philadelphia, PA 19104-4495, fax 215/596-8586, DISCUSION: Se revisaron los casos publicados de erupción asociada al
firstname.lastname@example.org clopidogrel y la ticlopidina, incluyendo 3 casos de desensitización al
Dr. Spinler serves as a consultant to Bristol-Myers Squibb and Sanofi- clopidogrel. En el primer caso, una evaluación de causalidad objetiva
Aventis. Dr. Wilensky is on the speaker’s bureau of Pfizer, Inc. sugiere que la erupción debida a la ticlopidina y al clopidogrel fue
probable y en el segundo caso, definitiva para el clopidogrel y probable
para la ticlopidina.
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intracoronario desarrolla una erupción a consecuencia del clopidogrel,
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labo and Bristol–Myers Squibb Partnership, November 2004.
reacción inicial no produjo síntomas de graves consecuencias. En un
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Inc., March 2001.
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RÉSUMÉ DU CAS: Deux patients ont développé une éruption
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series. Catheter Cardiovasc Interv 2005;65:525-7. des patients, a de son propre chef, recommencé le clopidogrel et
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ized trials. Am Heart J 2004;148:990-7. le clopidogrel et probable avec la ticlopidine.
15. Hashiguchi M, Ohno K, Nakazawa R, Kishino S, Mochizuki M, Shiga T. CONCLUSIONS: Lorsqu’un patient développé un érythème suite à
Comparison of cilostazol and ticlopidine for one-month effectiveness l’administration de clopidogrel, la ticlopidine peut être essayée en autant
and safety after elective coronary stenting. Cardiovasc Drugs Ther 2004; que la réaction initiale ne mettait pas la vie du patient en danger. Si le
18:211-7. patient développé aussi un érythème à la ticlopidine, les alternatives sont
16. Sekiguchi M, Hoshizaki H, Adachi H, Ohshima S, Taniguchi K, le cilostazol ou l’anticoagulation, l’aspirine, le cilostazol ou l’enoxaparin
Kurabayashi M. Effects of antiplatelet agents on subacute thrombosis ou la warfarine pendant 2 à 6 mois après l’installation de l’endoprothèse.
and restenosis after successful coronary stenting: a randomized compari-
Des résultats préliminaires suggèrent qu’il est possible de désensibiliser
son of ticlopidine and cilostazol. Circulation 2004;68:610-4.
certains patients de leur allergie au clopidogrel.
17. Park SJ, Shim WH, Ho DS, et al. A paclitaxel-eluting stent for the pre-
vention of coronary restenosis. N Engl J Med 2003;17;348:1537- 45. Suzanne Laplante
18. Batchelor WB, Mahaffey KW, Berger PB, et al. ATLAST Trial Investi-
gators. A randomized, placebo-controlled trial of enoxaparin after high-
risk coronary stenting: the ATLAST trial. J Am Coll Cardiol 2001;38:
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