Clopidogrel Desensitization:

Case Report and Review of Published Protocols

Phillip Owen, Pharm.D., John Garner, M.D., Lawrence Hergott, M.D., FACC, and
Robert Lee Page, II, Pharm.D., FCCP, FAHA

The antiplatelet drug clopidogrel is an oral thienopyridine derivative that has

been extensively used for the treatment and secondary prevention of a variety
of cardiovascular diseases. Although clopidogrel is well tolerated by most
patients, rare but serious hypersensitivity reactions have been documented,
including cutaneous reactions and angioedema. An alternative thienopyridine
that may be substituted for clopidogrel is ticlopidine; however, deleterious
side effects from ticlopidine may occur, including diarrhea, neutropenia, and
thrombocytopenia purpura, and cross-reactivity has been documented
between these two thienopyridines. In cases of bare-metal stent deployment,
cilostazol may be a safe and effective alternative; however, limited therapeutic
data are available. In such cases, providers may need to administer a
clopidogrel desensitization protocol; three clopidogrel desensitization
protocols have been published. We describe a 58-year-old man who
developed a generalized diffuse rash along his abdomen within 2 weeks of
exposure to clopidogrel after drug-eluting stent placement. Clopidogrel was
discontinued, and ticlopidine was begun. The rash resolved within 3 days of
clopidogrel discontinuation. Using the Naranjo adverse drug reaction
probability scale, we determined that the probability of clopidogrel causing
the rash was probable (score of 8). Ticlopidine was subsequently
discontinued due to severe diarrhea. Because of the patient’s implanted stent
and high risk for possible thrombosis, an 8-hour clopidogrel desensitization
protocol was devised and successfully used in this patient, who continued to
receive clopidogrel over the next year without rash recurrence. Based on our
experience and the literature reviewed, administration of a clopidogrel
desensitization protocol in patients with a history of isolated cutaneous
hypersensitivity reactions, including angioedema, to clopidogrel can be a safe
therapeutic alternative to ticlopidine or cilostazol.
Key Words: clopidogrel, desensitization protocol, acute coronary syndromes.
(Pharmacotherapy 2008;28(2):259–270)

From the School of Pharmacy, Mercer University, Atlanta, Clopidogrel is an oral thienopyridine derivative
Georgia (Dr. Owen); and the School of Pharmacy (Dr. that exerts its potent antiplatelet effects through
Page), and the Divisions of Cardiology (Dr. Hergott),
Physical Medicine (Dr. Page), and Internal Medicine (Dr.
noncompetitive antagonism of the platelet
Garner), School of Medicine, University of Colorado Health adenosine diphosphate receptor. Since its initial
Sciences Center, Denver Colorado. approval by the United States Food and Drug
Address reprint requests to Robert L. Page, II, Pharm.D., Administration in 1997, clopidogrel has been
FCCP, FAHA, FASCP, University of Colorado, Denver Schools
of Pharmacy and Medicine, Academic Office Building 1,
evaluated and prescribed for the treatment and
12631 East 17th Avenue, Room L15-1415, P.O. Box 6511, secondary prevention of a variety of cardio-
Aurora, CO 80045; e-mail: [email protected]. vascular diseases.1 As monotherapy, clopidogrel
260 PHARMACOTHERAPY Volume 28, Number 2, 2008
offers an attractive alternative for persons who desensitization protocol, as well as examine the
are intolerant to aspirin and has been shown to literature surrounding the use of three published
moderately decrease rates of death and ischemic protocols.
events in patients with recent myocardial
infarction, ischemic stroke, or symptomatic Case Report
peripheral arterial disease. 2 Current evidence
supports the use of either aspirin or clopidogrel, A 58-year-old man with a history of significant
but not both, as first-line agents for cerebro- coronary artery disease was admitted to our
vascular disease.3 Dual antiplatelet therapy with institution for an elective cardiac catheterization
aspirin and clopidogrel is clearly beneficial in because of an abnormal stress test. His medical
preventing stent thrombosis after percutaneous history was also significant for hyperlipidemia,
coronary intervention (PCI). In acute coronary hypertension, and aortic valve disease. One
syndromes, this is most evident during the early month earlier, a coronary catheterization had
phase of stent deployment when the efficacy documented three-vessel luminal irregularities
benefits outweigh the risk of bleeding.4–9 In and an obtuse marginal branch occlusion.
January 2007, a scientific advisory from the However, no intervention or additional antiplatelet
American Heart Association (AHA), American therapies other than aspirin were started at that
College of Cardiology (ACC), Society for time. The patient’s long-term drug therapy on
Cardiovascular Angiography and Interventions admission consisted of metoprolol succinate 25
(SCAI), American College of Surgeons, and mg/day, hydrochlorothiazide 12.5 mg/day,
American Dental Association stressed the amlodipine 10 mg/day, atorvastatin 40 mg at
importance of 1 year of dual antiplatelet therapy bedtime, extended-release potassium 10 mEq/day,
with clopidogrel and aspirin after placement of a lisinopril 5 mg/day, and aspirin 81 mg/day. He
drug-eluting stent due to risks associated with had no documented drug allergies and was a
possible stent thrombosis.7 current smoker with a 10 pack-year history. On
Although clopidogrel is well tolerated by most presentation, the patient had a blood pressure of
patients, rare but serious hypersensitivity 134/71 mm Hg and a heart rate of 46 beats/
reactions have been documented in the course of minute. Results of a basic metabolic panel,
postmarketing surveillance. 1 Recently, case complete blood count, liver function tests, and
reports of cutaneous hypersensitivity reactions, thyroid panel were all within normal limits.
including angioedema, have also been documented During the elective cardiac catheterization,
with clopidogrel.10–19 Given the large number of occlusion of a mid–left anterior descending artery
patients with indications for the use of was managed with deployment of a paclitaxel
clopidogrel, many practitioners will likely face drug-eluting stent (Taxus; Boston Scientific
the dilemma of managing patients with such Corp., Boston, MA). Other findings included a
hypersensitivity. Unfortunately, therapeutic right coronary artery lesion with proximal 50%
alternatives for clopidogrel are limited, making ulcerative plaque that was thought to be non-
clopidogrel desensitization a strategy to consider. obstructive. Intraprocedural drugs administered
Therefore, we conducted a literature search for consisted of iodixanol (Visipaque 320; General
pertinent references addressing clopidogrel Electric Co., Princeton, NJ) 60 ml, intravenous
desensitization protocols. An EMBASE, MEDLINE, heparin 5000 U (total), eptifibatide bolus of 180
and PREMEDLINE search (1950–November 27, µg/kg followed by an infusion at 2 µg/kg/minute,
2007) of the medical literature with use of the intracoronary nitroglycerin 300 µg (total),
search terms clopidogrel, cilostazol, ticlopidine, fentanyl 250 µg (total), midazolam 4 mg (total),
hypersensitivity, rash, and protocol; a review of and clopidogrel 300 mg.
English-language literature; and an analysis of After the procedure, the patient experienced
references of these articles, product information, frequent sinus pauses of 3–6 seconds in length
and abstracts were employed. Based on this accompanied by sinus bradycardia (heart rate 44
search strategy, three clopidogrel desensitization beats/min), hypotension (blood pressure 115/66
protocols were discovered.10, 11, 14, 18 mm Hg), and light-headed episodes. He was
We report the case of a patient with a cutaneous subsequently sent to the intermediate care ward,
hypersensitivity to clopidogrel, who warranted where his metoprolol and amlodipine were
desensitization to clopidogrel, since a drug- withheld. Otherwise, all long-term outpatient
eluting stent had been recently deployed. We drugs were reinstated, and clopidogrel 75 mg/day
also describe our specific institutional clopidogrel and a nicotine patch 21 mg/day were started.
 CLOPIDOGREL DESENSITIZATION Owen et al 261
The aspirin dose was changed to 325 mg/day and Table 1. 8-Hour University of Colorado Hospital
his atorvastatin to 80 mg at bedtime. Twenty- Clopidogrel Desensitization Protocol
four hours after the procedure, the patient was Dose Oral Volume
discharged receiving hydrochlorothiazide 12.5 (mg) Concentration (ml)
mg/day, amlodipine 5 mg/day, atorvastatin 40 mg 0.0005 5 µg/ml 0.1
0.0015 0.3
at bedtime, extended-release potassium 10 0.005 50 µg/ml 0.1
mEq/day, lisinopril 5 mg/day, aspirin 325 mg/day, 0.01 0.2
and clopidogrel 75 mg/day. The metoprolol was 0.02 0.4
not restarted because of the previous episodes of 0.04 0.8
bradycardia. 0.08 0.5 mg/ml 0.16
0.16 0.32
Two weeks later, the patient contacted his 0.3 0.6
cardiologist complaining of a rash covering his 0.6 5 mg/ml 0.12
abdomen and back. He denied hives, pruritic 1.2 0.24
discharge, shortness of breath, blistering, or 2.5 0.5
wheezing. Suspecting clopidogrel as the possible 5 1
10 2
culprit, the cardiologist switched the clopidogrel 20 4
to ticlopidine 250 mg twice/day. Within 3 days 40 8
of clopidogrel discontinuation, the rash 75 75 mg 1 tablet
completely resolved; however, it was replaced Oral suspensions should be prepared in the following
concentrations: 5 mg/ml, 50 µg/ml, 0.5 mg/ml, and 5 µg/ml using a
with severe diarrhea. Ticlopidine was discontinued, 75-mg clopidogrel tablet and sterile water for injection. All doses
and within 2 days the diarrhea ceased. Since the should be given immediately after preparation and discarded after
patient had a drug-eluting stent and the risk of 24 hours. Doses are given sequentially every 30 minutes if no
adverse reactions occur; all doses must be administered. A total of
possible thrombosis was high, he was readmitted 8 hours are needed to complete the entire desensitization protocol,
to the hospital for clopidogrel desensitization. and the patient should be monitored in an intensive care unit
On this second admission, the patient’s vital continually for any signs of anaphylaxis. Vials of diphenhydramine
50 mg and epinephrine 1:1000 should be kept at the bedside. The
signs were a blood pressure of 149/71 mm Hg, house officer should be called immediately if any of the following
heart rate 73 beats/minute, respiratory rate 24 develop: rash, hives, swelling, shortness of breath, wheezing,
breaths/minute, and oxygen saturation 97% on change in oxygen saturation, change in cardiac status, change in
mental status, abdominal pain, vomiting or diarrhea. If any of the
room air, with some evidence of wheezes. The above reactions occur, intravenous diphenhydramine 50 mg with
patient was admitted to the medical intensive intramuscular epinephrine 0.3 mg should be administered to the
care unit (ICU) where he underwent an 8-hour patient’s lateral thigh.
clopidogrel desensitization procedure (Table 1).
The patient had an uneventful procedure and was
discharged home 24 hours later receiving
clopidogrel 75 mg/day. One year later, the
patient was still taking clopidogrel with no an IgE-mediated reaction. 22 In the case of
recurrence of his rash. clopidogrel hypersensitivity, reported clinical
manifestations have included fever, rash, pruritis,
Discussion abdominal pain, neutropenia, and angioedema.10–19, 25
These symptoms appear within 3 days to 1
Clopidogrel and Hypersensitivity
month of clopidogrel exposure and can reappear
Hypersensitivity reactions are immunologically within hours of drug rechallenge.10–19, 25 From
mediated reactions caused by exposure to an worldwide postmarketing experience, anaphylactoid
antigen. Hypersensitivity to antibiotics has a reactions have been reported in less than 1% of
well-documented history in the literature.20–24 In cases.26 Unfortunately, the precise immunologic
patients with an antibiotic allergy, the mechanism mechanism of these hypersensitivity reactions
of anaphylaxis is believed to be an immuno- has not been fully elucidated. However, as
globulin (Ig) E–mediated occurrence. These reports of positive intradermal skin testing with
reactions can be life threatening in nature, involving clopidogrel have been documented in patients
severe bronchospasm, cardiac dysfunction, or even with clopidogrel hypersensitivity, the hypersensi-
death.20–23 One approach to avoid exposing a tivity has been postulated to be an IgE-mediated
patient to a drug that could cause anaphylaxis is process.10, 11 Other potential mechanisms consist
to perform an immunologic test. Skin test of direct mast cell activation, complement
methods can identify patients at risk and prevent activation, immune complex formation, and T
the administration of a drug that would induce cell activation.10
262 PHARMACOTHERAPY Volume 28, Number 2, 2008
Therapeutic Alternatives to Clopidogrel Anticoagulation versus Aspirin and Ticlopidine
(FANTASTIC) study, the authors randomized,
In patients with clopidogrel hypersensitivity
from 13 medical centers, 485 patients who had
who are undergoing intracoronary stent
planned or unplanned coronary stent implantation
placement, therapeutic options are limited. An
to either an antiplatelet or anticoagulation
alternative thienopyridine that may be
treatment strategy. 41 Before intervention, all
considered is ticlopidine.27–29 Like clopidogrel, patients were pretreated with aspirin 100–300
ticlopidine has been used successfully for the mg/day at the investigator’s discretion along with
secondary prevention of stroke and myocardial bolus doses of heparin. After stent implantation,
infarction and for the prevention of graft patients received either ticlopidine 500 mg
occlusion and thrombosis associated with bare- administered in the catheterization laboratory
metal stent deployment.30–33 Limited but positive followed by 250 mg twice/day for 6 weeks, or
data have been published regarding the use of warfarin adjusted to an international normalized
ticlopidine for thrombosis prevention with drug- ratio (INR) of 2.5–3.0 for 6 weeks. All patients
eluting stent deployment.34 Overall, ticlopidine’s were prescribed lifelong aspirin therapy
usefulness has been limited by its adverse effects: (100–325 mg/day) at discharge. At 6 weeks,
gastrointestinal problems (diarrhea, abdominal patients receiving warfarin with aspirin had a
pain, nausea, and vomiting), neutropenia in 2.4% significantly higher rate of bleeding or peripheral
of patients, severe neutropenia in 0.8% of vascular complications compared with those
patients, and, rarely, thrombotic thrombocytopenia randomized to ticlopidine with aspirin (21% vs
purpura. Monitoring warrants a complete blood 13.5%, p=0.03). No significant difference was
count that includes a differential count every 2 found in the overall rate of myocardial infarction,
weeks for the first 3 months of therapy.35–37 death, or stent occlusion. However, when
Furthermore, cross-reactivity may occur stratified by acute (≤ 24 hrs) versus subacute
between both clopidogrel and ticlopidine. This (> 24 hrs) stent occlusion, those receiving
hypothesis is intuitive as the only structural antiplatelet therapy had a nonsignificant increase
differences between these two drugs is a in the rate of acute occlusions (2.4% vs 0.4%,
carboxymethyl side group substituted on p=0.06) and a significantly lower rate of subacute
clopidogrel.13, 38 Unfortunately, the true occurrence occlusions (0.4% vs 3.5%, p=0.01) compared
of this cross-reactivity remains unknown and is with those receiving anticoagulation. Patients
only substantiated by case reports.10, 13, 18 Nonetheless, receiving antiplatelet therapy also had a
the ACC-AHA recommend clopidogrel over significantly shorter median hospital stay than
ticlopidine as the preferred thienopyridine those randomized to anticoagulation (3 vs 6
because of its extensive published evidence, more days, p<0.00001). At 6 months, no significant
rapid onset of action (especially after a loading difference was found in the rates of death,
dose), and better tolerability profile.39 Specifi- myocardial infarction, coronary artery bypass
cally, for prevention of stent thrombosis, the surgery, or repeat target lesion angioplasty.
American College of Chest Physicians (ACCP), In another study, 517 patients who had just
the ACC-AHA-SCAI 2005 guideline update for undergone placement of intracoronary stents
PCI, and the AHA-ACC 2007 guidelines for the were randomly assigned to receive either an
management of unstable angina and non–ST- antiplatelet strategy consisting of aspirin 100 mg
segment elevation myocardial infarction and plus ticlopidine 250 mg both given twice/day, or
2004 guidelines for the management of ST- anticoagulant therapy with aspirin 100 mg
segment elevation myocardial infarction, all twice/day plus phenprocoumon adjusted to an
recommend ticlopidine as an alternative to INR of 3.5–4.5 for 4 weeks.42 Compared with
clopidogrel for bare-metal stent placement.27, 29, 33, antiplatelet therapy, more patients receiving
39, 40
Although used in clinical practice, aspirin with warfarin experienced the composite
ticlopidine’s role is not specifically addressed for end point of cardiovascular death or myocardial
drug-eluting stent placement by these national infarction, coronary artery bypass surgery, or
organizations. repeated angioplasty (6.2% vs 1.6%, relative risk
For patients receiving a bare-metal stent, [RR] 0.25, p=0.01). With antiplatelet therapy,
another therapeutic option includes the use of a patients exhibited an 82% lower risk for
vitamin K antagonist with aspirin. Four myocardial infarction (p=0.02) and a 78% lower
prospective studies have addressed the use of this need for repeat interventions (p=0.01).
anticoagulant strategy. 30, 41–43 In the Full Furthermore, compared with those receiving
 CLOPIDOGREL DESENSITIZATION Owen et al 263
anticoagulant therapy, patients receiving with high-dose aspirin alone is inferior to dual
antiplatelet therapy had a lower risk for stent antiplatelet therapy with a thienopyridine for the
occlusion (0.8% vs 5.4%, RR 0.14, p=0.004) and prevention of stent thrombosis.30 Although the
for the composite of death from noncardiac ACC-AHA and the ACC-AHA-SCAI do not
causes, cerebrovascular accidents, severe address the combination of warfarin with aspirin
hemorrhage, and peripheral vascular events as a potential alternative for prevention of bare-
(1.2% vs 12.3%, RR 0.09, p<0.001). metal stent thrombosis, the ACCP does
In a randomized trial, 350 high-risk patients recommend the combination of aspirin with a
received either aspirin 250 mg/day with thienopyridine derivative over systemic
ticlopidine 250 mg twice/day or aspirin 250 anticoagulation therapy. 27, 29, 33, 39, 40 To our
mg/day with warfarin dosed to an INR of 2.5–3.0, knowledge, no data exist supporting the use of
administered 6 hours after intracoronary stent warfarin after drug-eluting stent placement.
implantation, and continued for 30 days.43 The In addition, four prospective, randomized trials
composite end point was defined as cardio- have been published regarding cilostazol plus
vascular death, myocardial infarction, or repeated aspirin. Through selective inhibition of 3′5′-
revascularization at 30 days. On study completion, cyclic-nucleotide phosphodiesterase III, cilostazol
5.6% of patients in the aspirin plus ticlopidine exhibits both antiplatelet and vasodilating effects.
group reached the primary end point compared In addition, in vitro data suggest that cilostazol
with 11% in the aspirin with warfarin group (RR may inhibit vascular smooth muscle cell
1.9, p=0.07). The secondary end point of major proliferation, thereby providing a possible role in
vascular access site and/or bleeding complications prevention of stent thrombosis. 44 In the
was reached by 1.7% in the aspirin plus Cilostazol for Restenosis Trial (CREST), the
ticlopidine group compared with 6.9% in those authors randomly assigned 705 patients who had
receiving aspirin plus warfarin (RR 4.1, p=0.02). undergone bare-metal stent implantation to
Finally, in the Stent Anticoagulation Restenosis receive cilostazol 100 mg twice/day or placebo
Study (STARS), the authors randomly assigned for 6 months.45 After the procedure, all patients
1653 patients who underwent coronary stent received clopidogrel 75 mg/day for 1 month, as
placement to one of three 30-day treatment well as 6 months of aspirin (dosage not stated).
regimens: aspirin 325 mg/day, aspirin 325 At the 6-month follow-up, minimum coronary
mg/day with ticlopidine 250 mg twice/day, or lumen diameter was significantly larger in the
aspirin 325 mg/day with warfarin adjusted to an cilostazol group compared with the placebo
INR of 2.0–2.5.30 The investigators evaluated the group (1.77 vs 1.62 mm, p=0.01) and mean
composite primary end point of death, revascu- percentage diameter stenosis was smaller among
larization of the target lesion, angiographically patients assigned to cilostazol compared with
evident thrombosis, or myocardial infarction placebo (37.8% vs 42.0%, p=0.01). In-segment
within 30 days. This primary end point was seen restenosis rates were 22% in patients receiving
in 3.6%, 2.7%, and 0.5% of patients receiving cilostazol and 34.5% in patients receiving placebo
aspirin, aspirin with warfarin, and aspirin with (p=0.002); similarly, in-stent restenosis was
ticlopidine, respectively (p=0.001 for the significantly less frequent with cilostazol (20%)
comparisons of all groups). Hemorrhagic than with placebo (30%, p=0.03). No significant
complications were observed in 1.8%, 6.2%, and difference existed between the groups in rates of
5.5% of patients receiving aspirin, aspirin with bleeding, rehospitalization, myocardial infarction,
warfarin, and aspirin with ticlopidine, target-vessel revascularization, or death.45
respectively (p<0.001 for the comparisons of all In the second trial—Randomized Prospective
groups). Finally, 2.9%, 2.7%, and 0.5% of Antiplatelet Trial of Cilostazol Versus Ticlopidine
patients receiving aspirin, aspirin with warfarin, in Patients Undergoing Coronary Stenting
and aspirin with ticlopidine, respectively, (RACTS)—the authors evaluated the use of
demonstrated angiographically evident stent either ticlopidine 250 mg twice/day for 1 month
thrombosis (p<0.001 for the comparisons of all or cilostazol 100 mg twice/day for 6 months in
groups). 397 patients who had undergone bare-metal stent
Based on these data, the use of warfarin with implantation.46 All patients received aspirin 100
aspirin appears to exhibit only marginal benefits mg/day for 6 months. Compared with the
over aspirin alone and to be statistically inferior ticlopidine group, 6-month coronary angio-
to the ticlopidine with aspirin combination.30, 42, 43 graphic data revealed that those treated with
The STARS data also highlight that monotherapy cilostazol tended to have larger minimal luminal
264 PHARMACOTHERAPY Volume 28, Number 2, 2008
diameters (2.3 vs 2.10 mm, p=0.057) and lower Antiplatelet therapies consisted of aspirin with
restenosis rates (23.3% vs 30.9%, p=0.086). At 9 ticlopidine (120 patients), clopidogrel (18
months after stent implantation, no significant patients), or cilostazol (37 patients). Clopidogrel,
difference was found between groups in the ticlopidine, or cilostazol were continued for 1
composite end point of death, myocardial infarc- month at two centers and 6 months at the third
tion, stroke, and stent thrombosis. However, center. All patients received aspirin. Unfortunately,
target-lesion revascularization rate was signifi- doses for these antiplatelet agents were not
cantly lower in the cilostazol-treated group reported. At the 30-day follow-up, only one
compared with those receiving ticlopidine patient in the ticlopidine and clopidogrel groups
(22.9% vs 32.7%, p=0.03). No significant combined experienced a major adverse cardiac
difference existed between groups in drug-related event, consisting of a non–Q-wave myocardial
adverse effects. infarction. Of the 37 patients receiving cilostazol,
Similar results were found in a third trial in one death, four subacute thromboses, and three
which patients who had undergone bare-metal non–Q-wave myocardial infarctions were
stent implantation were randomly assigned to documented.
receive 1 month of either a cilostazol 200-mg Presently, the ACC-AHA and the ACC-AHA-
loading dose followed by 100 mg twice/day, or a SCAI do not address the use of cilostazol plus
clopidogrel 300-mg loading dose followed by 75 aspirin for prevention of stent thrombosis.
mg/day.47 Both groups were given aspirin 200 However, the ACCP does suggest that either
mg/day. At 30 days, no significant difference was clopidogrel or ticlopidine should still be
found between groups regarding the rates of considered over cilostazol for bare-metal stent
subacute stent thrombosis; major adverse cardiac placement. Furthermore, it is important to note
events, including death, myocardial infarction, that cilostazol is not without its own limitations.
and target-lesion revascularization; or drug- The agent is contraindicated in patients with
related adverse effects such as major bleeding, heart failure of any severity and must be adjusted
vascular complications, neutropenia, and for patients taking potent inhibitors of
thrombocytopenia. cytochrome P450 3A4 inhibitors.51
Finally, in the fourth study, patients undergoing
elective bare-metal stent implantation were Overview of Desensitization
randomly assigned to receive cilostazol 100 mg
twice/day for 6 months or ticlopidine 250 mg An alternative approach to management of
twice/day for 1 month, starting 2 days before the clopidogrel hypersensitivity would be to
stent implantation procedure. 48 All patients desensitize the patient to the agent. Regrettably,
received concomitant aspirin 100 mg/day. At 6 the complexities of the underlying molecular
months, no significant difference was found mechanisms of desensitization remain ambiguous.
between groups regarding restenosis rate or In the case of an allergic inflammatory reaction,
coronary angiographic results: minimum lumen however, certain characteristic features are
diameter, later lumen loss, and lumen stenosis. present, including IgE production as well as
At 3 years, however, the rate of major cardiac and recruitment and activation of effector cells such
cerebrovascular events was significantly lower in as mast cells, basophils, and eosinophils. All of
the cilostazol group than in the ticlopidine group these specific events are controlled by a distinct
(16% vs 36%, p=0.023), as was the 3-year event subset of T lymphocytes called T helper cells,
rate of death, myocardial infarction, stent which, when stimulated, produce cytokines, such
thrombosis, any revascularization, and stroke as interleukin (IL)-4 and IL-5. These cytokines
(p=0.0275). are responsible for the maturation, activation,
Unfortunately, the data surrounding the and survival of eosinophils.52–54 Through the
combination of cilostazol plus aspirin for use in introduction of the known allergen, a transient
drug-eluting stent placement is limited only to increase in allergen-specific IgE and IgG
case reports and observations from one study.13, 49, antibodies occurs. This process in turn induces a
50
In a multicenter, randomized, controlled, multipathway negative feedback cascade. For
triple-blind study, the authors evaluated the example, the elevation in allergen-specific IgG
effects of paclitaxel-eluting stent implantation antibodies appears to block IgE-dependent
compared with control stents on intimal basophil histamine release, as well as IgE-
hyperplasia and resultant restenosis in 175 facilitated antigen presentation and T cell
patients with discrete coronary lesions. 50 activation. In addition to these alterations in
 CLOPIDOGREL DESENSITIZATION Owen et al 265
antibody production, effector cell recruitment Table 2. 7-Hour Clopidogrel Desensitization Protocol14, 18
and activation are suppressed at mucosal Dose Oral Volume
surfaces.52–54 To stimulate this negative feedback (mg) Concentration (ml)
effect and enhance the regulatory pathways 0.005 0.5 mg/ml 0.01
against IgE-mediated reactions, desensitization 0.01 0.02
0.02 0.04
protocols were put into practice. Usually the 0.04 0.08
process begins with aliquots of 1/100,000 or less 0.08 0.16
of the therapeutic dose of the drug to which 0.16 0.32
desensitization is desired, then the drug is 0.3 0.60
administered at a 10-fold higher dose every 30 0.6 1.20
1.2 5 mg/ml 0.24
minutes.24 2.5 0.5
5 1
Published Clopidogrel Desensitization Protocols 10 2
20 4
Three clopidogrel desensitization protocols have 40 8
been published in the literature.10, 11, 14, 18 One report 75 75 mg 1 tablet
described three patients, two of whom required All doses should be given orally and sequentially every 30 minutes
for approximately 7 hours if no adverse reaction occurs. Patient
intracoronary stent placement and one who needs to be monitored closely during the procedure, with
required abdominal aneurysm stent implantation.18 equipment available to treat anaphylaxis. If any adverse reaction
Unfortunately, the authors did not specify the occurs during the procedure, the allergist should be notified
immediately for adjustments to the protocol. Patient should be
specific type of stents deployed. In the first case, kept under observation for at least 1 hour after the last dose.
the patient developed a generalized pruritic
erythematous macular rash 7 days after receiving
clopidogrel. The clopidogrel was subsequently
discontinued and replaced with ticlopidine. Two macular rash along her abdominal wall 3 weeks
weeks later, the patient developed severe after receiving clopidogrel for placement of an
neutropenia, fever, and sinusitis, warranting abdominal aneurysm stent.18 The clopidogrel
discontinuation of the ticlopidine. Five months was stopped, and the rash resolved with a short
after stopping the ticlopidine, the patient course of prednisone. She too was given
required placement of a second intracoronary ticlopidine and, after 1 week, developed a similar
stent, and a clopidogrel desensitization protocol rash along her face and lower extremities; she
was started (Table 2). The patient was admitted also experienced vomiting. One week after
to the ICU and followed by an allergy specialist. ticlopidine discontinuation, the rash resolved.
The desensitization was uneventful and allowed Five months later, the patient underwent
the patient to continue to take clopidogrel for an clopidogrel desensitization as an inpatient for an
additional 3 years. unspecified procedure. Three weeks after
The second patient developed a similar rash desensitization, she complained of mild generalized
along her lower abdominal wall 3 days after itching, bruising, and melena. The clopidogrel
receiving clopidogrel. 18 After clopidogrel was again stopped. After another 5 months, the
discontinuation and a short course of prednisone, patient was rechallenged with the same
the rash resolved. Ten months later, the patient clopidogrel desensitization protocol, but this
underwent repeat stent placement for in-stent time as an outpatient. During the procedure, she
restenosis and was given ticlopidine. After the developed a pruritic erythematous rash along her
second ticlopidine dose, she developed a pruritic lower abdominal wall within 10 minutes of
macular rash along her lower abdominal wall. taking the 5-mg clopidogrel dose. Ceritizine 10
The rash subsequently resolved after ticlopidine mg was administered. After waiting 30 minutes
discontinuation and another course of prednisone. for the itching and redness to diminish, the
Three years later, the patient underwent protocol was restarted at 2.5 mg and completed
outpatient clopidogrel desensitization with the at the 40-mg dose for a total cumulative dose of
same protocol as in the previous case. The exact 87 mg. No further complications were noted.
indication for clopidogrel was not stated. The next day, the patient was instructed to take
Nonetheless, the patient was successfully half of a 75-mg clopidogrel tablet and the other
desensitized and was able to continue her half 1 hour later. The patient was maintained
clopidogrel for an additional year. with 75 mg/day for the following 5 months with
The third patient developed an erythematous no further complaints.
266 PHARMACOTHERAPY Volume 28, Number 2, 2008
Another group reported a case of a 68-year-old Table 3. 2-Hour Clopidogrel Desensitization Protocol11
man who developed a generalized pruritic Dose Oral Volume
maculopapular rash 7 days after receiving (mg) Concentration (ml)
clopidogrel for PCI with stent placement, the 0.02 0.5 mg/ml 0.04
type of which was not specified. 14 After 0.05 0.10
0.15 0.30
discontinuation of the clopidogrel, the rash 0.5 1.0
subsequently resolved. Unfortunately, the patient 1.5 5 mg/ml 0.3
was readmitted for anginal symptoms, which 5 1
required PCI with stent deployment. Before the 15 3
procedure, the patient underwent clopidogrel 45 9
75 75 mg 1 tablet
desensitization with the same protocol as used in The escalating doses of clopidogrel are to be given at intervals of 15
the three above-mentioned cases18 (Table 2). The minutes, without any missed doses.
desensitization was successful, and the patient
underwent cardiac catheterization and stent
placement the following day, with clopidogrel 75
mg/day thereafter. Unfortunately, no mention patient, the authors decided to readminister the
was made regarding the specific duration of desensitization protocol the following day, but
clopidogrel therapy after desensitization. modified it so that lower initial doses of
The authors of a case series of eight patients10 clopidogrel and 30-minute spacing between
and those of a single-case report11 used a very doses, as well as premedication with cimetidine,
different clopidogrel desensitization strategy. prednisone, and diphenhydramine, were used. A
Compared with our 8-hour protocol and the three-dose graded challenge to clopidogrel after
above-described 7-hour protocol, 14, 18 these premedication was performed on the third day
authors used a much quicker desensitization and was well tolerated. On the fourth day, the
protocol that lasted approximately 2 hours, with patient received clopidogrel 75 mg without
an initial dose that was larger and increasing premedication. All eight patients continued to
aliquots of clopidogrel that became larger over a receive clopidogrel without reemergence of
shorter period of time (Table 3 and 4).11, 25 The hypersensitivity reactions or major adverse
protocol described in Table 4, by the same cardiac events for a median duration of 7.5 months.
authors as the case series,10 provides the most in- Since this initial case series report, the same
depth and useful information regarding product authors have subsequently desensitized five
preparation and patient monitoring.25 additional patients with the same desensitization
In the case series of eight patients exposed to protocol.25 Although the specific indications for
clopidogrel, pruritis with maculopapular rash
developed in two patients; generalized pruritis in
one; urticaria with angioedema in one; a
maculopapular rash in one; urticaria, pruritis, Cutaneous reaction likely related to No
Inappropriate patient
clopidogrel?
and angioedema in one; and a maculopapular
rash with urticaria in two.10 These symptoms Yes
Yes
appeared within 3 days to 3 weeks of introducing Desquamative reaction? Inappropriate patient
clopidogrel. Four of the patients had planned No
PCI, three had recent deployment of a drug- Indication for clopidogrel therapy? No
Inappropriate patient
eluting stent, and one had deployment of a drug- No acceptable alternative agent?

eluting stent during primary PCI for an anterior Yes

ST-segment elevation myocardial infarction. Of Not taking antihistamines for 3 days? No

Not taking steroids for 3 days? Delay desensitization
the eight patients desensitized, no major Not taking β-blockers for 4 days?
hypersensitivity reactions occurred during Yes
administration of the protocol. However, one Hypersensitivity reaction sufficiently No
patient did have mild pruritis after the third dose resolved to allow detection of Delay desensitization
recurrent reaction?
of the clopidogrel protocol that responded to a
Yes
single dose of oral hydroxyzine. Another patient
developed urticaria and itching after the last dose Proceed with desensitization

of the protocol but had resolution of symptoms Figure 1. Algorithm for appropriate patient selection of
after receiving oral cimetidine and prednisone clopidogrel desensitization based on previously developed
with intravenous diphenhydramine. In that criteria. (Adapted from reference 25 with permission.)
 CLOPIDOGREL DESENSITIZATION Owen et al 267
Table 4. In-Depth Description of the 2-Hour Clopidogrel Based on the totality of their experiences, these
Desensitization Protocol10, 25 authors have devised specific criteria for patient
Steps in preparation of solution: selection (Figure 1).25
1. Prepare solution on day of desensitization and discard In the single-case report, a 49-year-old woman
after 24 hrs.
2. Label a 3-oz plastic amber bottle for each respective dose. developed a pruritic maculopapular rash after
Uncap only the bottle for the current dose being prepared. receiving five days of clopidogrel 75 mg/day for
3. Triturate a clopidogrel 75-mg tablet to a fine powder. transient ischemic attacks. 11 She was
4. Transfer powder to a 100-ml graduated cylinder. Rinse subsequently hospitalized and administered the
remaining powder in mortar with sterile water for oral clopidogrel desensitization protocol (Table
irrigation and transfer to graduate.
5. Add q.s. to 25 ml with sterile water and label graduate 3) without any complaints or adverse events. No
3 mg/ml (solution no. 1). information was provided regarding the length of
6. Shake bottle well before preparing each solution. time the patient continued to take clopidogrel.
7. Prepare doses 8, 7, 6, and 5 with solution no. and volume
as designated below. Add required volume of clopidogrel
3 mg/ml to plastic amber bottle and q.s. to 30 ml with
Published Studies Evaluating Clopidogrel
with sterile water. Desensitization
8. Transfer 1 ml of clopidogrel 3-mg/ml solution
(solution no. 1) to new graduate and q.s. to 30 ml with Only one study, to our knowledge, has been
sterile water and label graduate 0.1 mg/ml (solution no.2). published that evaluated the safety and efficacy of
Discard remaining 3-mg/ml solution (solution no. 1). the use of a clopidogrel desensitization protocol.55
9. Prepare doses 4, 3, 2, and 1 with solution no. and volume In a prospective, observational study, the authors
as designated below. Add required volume of clopidogrel identified 24 patients with clopidogrel hyper-
0.1-mg/ml solution (solution no. 2) to plastic amber
bottle and q.s. to 30 ml with sterile water for irrigation. sensitivity after drug-eluting stent deployment.
Dose Dose Solution Oral Volume
Patients were excluded if they had toxic
No. (mg) No. (ml) epidermal necrolysis, Stevens-Johnson syndrome,
1 0.02 2 0.2 anaphylaxis, upper- or lower-respiratory
2 0.05 2 0.5 compromise including angioedema or respiratory
3 0.15 2 1.5 failure, or other life-threatening reactions with
4 0.5 2 5.0 clopidogrel exposure. When possible, clopidogrel
5 1.5 1 0.5
6 5 1 1.7
was discontinued, and patients were transitioned
7 15 1 5 to ticlopidine 250 mg twice/day for 5 days before
8 45 1 15 desensitization. The authors employed the
q.s. = quantity sufficient. desensitization protocol described in Table 2 but
The escalating doses of clopidogrel are to be given at intervals of 15 with more stringent stipulations. For example,
minutes, without any missed doses. Patients should discontinue
steroids and antihistamines for 3 days, and b-blockers should be the protocol was administered by a dedicated
discontinued for at least 4 days. Heart rate, respiratory rate, and drug-desensitization nurse and was overseen by
blood pressure are monitored at baseline, after each clopidogrel an allergist. Steroids, antihistamines, and
dose, and 1 hour after the final dose of the protocol. Vials of
epinephrine, diphenhydramine, ranitidine, and methylprednisolone antileukotrienes were stopped 7 days before
are kept at the bedside. Supplemental oxygen, albuterol nebulizer desensitization, and b-blockers were held on the
solution, and an intubation kit should be kept close at hand. All day of desensitization. Patients were monitored
patients are monitored in the intensive care unit for at least 1 hour
after the last clopidogrel dose and overnight in a step-down for adverse drug reactions. If an allergic reaction
cardiology unit after completion of the protocol. If a occurred, oral or intravenous diphenhydramine
hypersensitivity reaction should occur, the protocol is stopped and or oral certirizine was administered. If the
appropriate interventions made for patient stabilization. The
patient is immediately evaluated by an allergist who directs reaction did not reappear and 30 minutes had
treatment. At the allergist’s discretion, the protocol can be lapsed since the last clopidogrel dose, then the
continued, aborted, or modified. The next morning, the patient can desensitization protocol was continued. If
be discharged home 1 hour after receiving clopidogrel 75 mg if
tolerating the drug. symptoms recurred, antihistamines were
Adapted with permission from reference 25. readministered, and once symptoms subsided
and 30 minutes had lapsed, then clopidogrel was
restarted at 50% of the dose that provoked the
reaction. After desensitization, follow-up was
clopidogrel and type of intracoronary stent conducted at 2–4 weeks and again at 6 months.
deployed were not provided, the authors stated Of the 24 patients identified, 20 had their
that no significant hypersensitivity reactions or clopidogrel desensitization performed as
major adverse cardiac events were reported, and outpatients. Initial presenting hypersensitivity
all five patients were successfully desensitized. reactions occurred within a median time of 6
268 PHARMACOTHERAPY Volume 28, Number 2, 2008
days from clopidogrel exposure and were desensitization be followed by an immunology or
typically characterized by a pruritic macular allergy specialist and be admitted to the hospital
erythematous confluent rash beginning on the where proper monitoring can be achieved.
face, chest, or abdomen. During desensitization, Standard drugs used for treating an anaphylactic
three patients developed pruritus, one patient attack, including intravenous and oral
had both pruritus and rash, and one patient had diphenhydramine and epinephrine, should be
angina that resolved with one sublingual kept at the patient’s bedside, as well as an airway
nitroglycerin tablet. Only two patients warranted or endotracheal intubation kit. These protocols
repeat clopidogrel desensitization. At the 6- should not be used in patients with severe
month follow-up, all 24 patients continued to exfoliative dermatitis reactions such as Stevens-
receive clopidogrel 75 mg/day, with 23 remaining Johnson syndrome and toxic epidermal
free of their original clopidogrel-induced allergic necrolysis, as no adequate treatment exists for
symptoms. these types of reactions if they should appear
during the desensitization procedure. 10, 25
Our Patient and Protocol Because none of these protocols were adminis-
tered in patients with clopidogrel hypersensitivity
In our case report, the patient developed a rash reactions characterized by gastrointestinal,
covering his abdomen and back, with an absence systemic (e.g., anaphylactic or anaphylacticoid),
of hives, pruritis, or shortness of breath, within or respiratory symptoms outside of angioedema,
14 days of starting clopidogrel. As with the other extreme caution is warranted if these protocols
published cases, symptoms completely resolved are used in such cases. 10, 11, 14, 18, 25 Also, b-
within 3 days of clopidogrel discontinuation. In blockers should be withheld preferably for 4 days
our patient’s case, using the Naranjo adverse drug before desensitization, as they have been
reaction probability scale,56 which assesses the associated with increased mast cell synthesis,
probability of a drug causing an adverse event, a histamine release, and unopposed a-adrenergic
score of 8 was determined, indicating a probable stimulation should an allergic response occur.25, 57
adverse drug reaction. Our clopidogrel desensi- Steroids and antihistamines should also be
tization protocol was derived from principles discontinued 3 days before desensitization, as
involving antibiotic desensitizing processes and suppression drugs may mask a reaction during
requires a total of 17 clopidogrel doses adminis- the desensitization.10, 18 Furthermore, adequate
tered over 8 hours (Table 1). We developed a discharge planning should be devised and
longer protocol because failures have been implemented before discharge. Patients should
documented with two of the three shorter be educated regarding signs and symptoms of
published protocols.10, 18 Vials of diphenhydramine hypersensitivity reactions and instructed to either
and epinephrine are kept at the bedside in case of call 911 or go immediately to the emergency
an anaphylactic reaction. As with the other room if such reactions should appear. If possible,
desensitization protocols, patients are admitted elective PCIs should be delayed 2–4 weeks after
to the ICU during protocol administration and desensitization. This precaution allows for
are then transferred to an intermediate step-down adequate detection of delayed hypersensitivity
unit for 24-hour monitoring. reactions.25 Finally, adherence with drug therapy
The major limitation to the our case report and and medical follow-up appointments should be
other published cases is a lack of validation to highly stressed to the patient. The dose of
these desensitization methods. Although these clopidogrel should be taken for the entirety of
data appear to be encouraging, the safety and the protocol and continued without interruption.
efficacy of these protocols need to be further Otherwise, the desensitized state may be lost, and
validated by a larger cohort of patients. As seen the procedure must be repeated.10, 18, 25
in Tables 1–4, no standard intraprocedural and
postprocedural measures, such as inpatient or
Conclusion
outpatient status for protocol administration,
length of monitoring time, discontinuation of Based on our experience and the literature
drugs before protocol initiation, and specific reviewed, administration of a clopidogrel
mediations at the patient’s bedside, exist among desensitization protocol in patients warranting
the three protocols. deployment of a bare-metal stent or drug-eluting
In light of these limitations, we recommend stent who have a history of isolated cutaneous
that patients who are to receive clopidogrel hypersensitivity reactions, including angioedema,
 CLOPIDOGREL DESENSITIZATION Owen et al 269
to clopidogrel can be a safe therapeutic option to exclusive article]. Heart 2004;90:e14. Available from
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2005;80:1368–70.
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Pharm.D., BCPS, for reviewing the manuscript. human lung mast cell desensitization. J Immunol 1987;139:
501–5.
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