Hypersensitivity reactions to clopidogrel

INTRODUCTION — Clopidogrel is a thienopyridine drug that inhibits platelet aggregation by blocking the adenosine diphosphate P2Y₁₂ receptor. The drug plays an essential therapeutic role in a variety of cardiovascular conditions including acute coronary syndromes, percutaneous coronary interventions with stents, stroke, and peripheral arterial disease [1]. The most frequent use of clopidogrel is to prevent potentially fatal thrombosis of newly implanted coronary stents. Accordingly, hypersensitivity reactions to clopidogrel have particular importance in this setting, since the timing typically coincides with the period of heightened vulnerability for stent thrombosis. The most common hypersensitivity reactions to clopidogrel are dermatologic eruptions, although severe systemic reactions can also occur.

The incidence and clinical manifestations of clopidogrel reactions are discussed here. Management options for dermatologic eruptions are also reviewed. Therapeutic use of clopidogrel in the management of atherosclerotic arterial disease is reviewed separately:

●(See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)

●(See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

●(See "Acute ST-elevation myocardial infarction: Antiplatelet therapy".)

●(See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

●(See "Antithrombotic therapy for elective percutaneous coronary intervention: General use".)

INCIDENCE — Hypersensitivity reactions to clopidogrel are reported in up to 6 percent of patients who receive the drug [2-4].

CLINICAL MANIFESTATIONS — Several types of hypersensitivity reactions have been described in patients receiving clopidogrel and other thienopyridines [5]. The most common is a delayed skin rash [6].

Most common signs and symptoms — Clopidogrel hypersensitivity most commonly presents as an erythematous, macular, morbilliform rash, beginning on the face, chest, or abdomen (picture 1) [7]. It may or may not be pruritic. The rash usually spreads and becomes confluent, sometimes involving the proximal and then distal extremities. In one series, one-third of patients eventually had involvement of the entire body, including palms and soles [7]. Other observations about dermatologic eruptions include the following:

●The median time from drug introduction to appearance of symptoms is between 5 and 10 days, with a peak incidence of onset at 6 days [3,7,8].

●In the largest available series, some patients had mild elevations in leukocytes, neutrophils, or platelet counts or decreases in lymphocyte counts [3].

●The exact nature of the reaction is unclear, with biopsy data suggesting a lymphocyte-mediated reaction in many cases [3]. This is consistent with the delayed onset that is most commonly reported.

Other cutaneous reactions — Other cutaneous reactions include the following:

●Localized areas of rash/dermatitis, either unilaterally or bilaterally with a symmetric distribution, usually involving the face, neck, trunk, axillae, palms, or soles [3]

●Urticaria [9], isolated angioedema [10], or both

●Pruritus without rash [7,11]

●Acute generalized exanthematous pustulosis (AGEP) [12] (see "Acute generalized exanthematous pustulosis (AGEP)")

The overall severity of cutaneous reactions is variable. In a large multicenter comparison of over 19,000 patients receiving aspirin (ie, acetylsalicylic acid or ASA) and clopidogrel, cutaneous symptoms were considered severe enough to warrant drug discontinuation in 4 percent [4].

More serious types of systemic reactions — Other more serious types of reactions have been described in patients receiving clopidogrel. Although these are not discussed further in this review, and a lymphocyte driven model of the underlying pathophysiology makes anaphylaxis unlikely in any single given case, clinicians should be aware that the following have been associated with clopidogrel therapy in small numbers of cases:

●Stevens-Johnson syndrome (SJS) begins with a prodrome of malaise and fever, followed by the development of mucosal blistering and erythematous or purpuric macules and plaques on the skin [13]. There is no validated skin test model for diagnosing drug-induced SJS or implicating a specific drug in the pathophysiology. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

●Systemic hypersensitivity syndromes, which consists of rash accompanied by fever, thrombocytopenia, and neutropenia [2,14,15]. The liver and lungs may also be involved, and eosinophilia is variably seen. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)

●Aplastic anemia, which presents with fatigue and increasing anemia with a reduced absolute number of reticulocytes. This is accompanied by neutropenia and thrombocytopenia. Bacterial infections may be a presenting feature [16,17]. (See "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation'.)

●Severe and persistent leukopenia, which may be initially asymptomatic or present with symptoms of infection [18,19]. (See "Drug-induced neutropenia and agranulocytosis".)

●Serum sickness-like reaction, which presents with rash, fever, malaise, polyarthralgias, and/or polyarthritis, beginning one to two weeks after first exposure [20]. This is an uncommon complication of unclear pathophysiology, associated with elevated markers of inflammation, such as the erythrocyte sedimentation rate [21-23]. Patients have been successfully managed by substitution of prasugrel [21-23] and ticlopidine [24], although a similar syndrome has been reported with ticlopidine use [25]. (See "Serum sickness and serum sickness-like reactions".)

●Anaphylaxis, which is a rapidly progressing multisystem reaction characterized by flushing, urticaria, angioedema, bronchospasm, laryngeal edema, and/or hypotension, is mentioned in the prescribing information as reported in postmarketing data, although the authors are not aware of detailed published reports (table 1) [26]. (See "Anaphylaxis: Emergency treatment".)

In contrast, evidence from reports of drug-induced thrombotic microangiopathy (DITMA, also called drug-induced thrombotic thrombocytopenic purpura [TTP]) ascribed to clopidogrel is not considered strong enough to implicate a drug-induced etiology. (See "Drug-induced thrombotic microangiopathy (DITMA)".)

The remainder of this topic focuses on the pathogenesis, diagnosis, and management of the most common form of clopidogrel hypersensitivity (ie, an erythematous macular rash starting on the trunk and spreading to the extremities).

PATHOGENESIS — The pathogenesis of uncomplicated dermatologic reactions to clopidogrel is not known, and specific risk factors have not been identified. The loading dose of clopidogrel does not appear to impact the risk of hypersensitivity [3]. The signs and symptoms are most suggestive of a T cell-mediated mechanism, but other types of reactions (such as urticaria and angioedema) indicate that several mechanisms are possible [6].

Allergy evaluations have been performed in a small number of studies to begin to assess the pathogenesis of clopidogrel reactions [3,27]. In the largest study involving allergy testing, 62 patients underwent extensive allergy testing after they had been empirically treated through their clopidogrel reactions, completed therapy, and were free of the drug for at least four weeks [3]. The testing was performed for the purpose of better defining the pathophysiology of clopidogrel reactions, but some important controls were lacking. Evaluation consisted of prick/puncture and intradermal testing (with a clopidogrel solution of 0.75 mg/mL) for immediate-type reactions, as well as delayed (24 hours) reading of intradermal tests. Delayed reading of intradermal tests is sometimes used to evaluate delayed-onset cutaneous reactions, although this testing method has not been validated. Patch testing (clopidogrel 20 percent in petrolatum alba and 30 percent in water) was undertaken for delayed reactions, with readings at 72 hours and up to seven days [3]. Skin biopsy was obtained in some patients. Testing results were available for 42 patients. None had positive skin prick tests. Three had positive-immediate (ie, <30 minutes) intradermal tests, all of whom had presented with urticaria or angioedema. Patch testing was positive in 81 percent. However, all patients were managed in the same way. Of note, this study did not evaluate nonreacting patients or nonexposed individuals as controls to determine the optimal concentration for skin testing or the incidence of sensitization without clinical disease, which are significant limitations. This study is discussed more below. (See '"Treating through"' below.)

DIAGNOSIS — The diagnosis of the most common form of cutaneous reaction to clopidogrel is made clinically based upon suggestive signs and symptoms and appropriate time course [2,7]. An appropriate skin examination should be performed based on the extent of the symptoms and the nature of the complaints. The most common presentation is an erythematous, macular, morbilliform rash, beginning on the face, chest, or abdomen, and appearing 5 to 10 days after the drug is initiated (picture 1) [7]. (See 'Clinical manifestations' above.)

Several laboratory tests may be helpful in excluding more serious forms of hypersensitivity reactions, since rash can be a feature of various types of reactions. The decision to obtain these tests should be based on the severity and clinical features of the patient's reaction:

●Complete blood counts with differential to evaluate for eosinophilia or cytopenias

●Liver function tests, blood urea nitrogen, and serum creatinine to detect liver or renal involvement

●Urinalysis to look for renal involvement, microscopic hematuria, or urine eosinophilia

●Skin biopsy for persistent, atypical, or severe cutaneous features

Allergy testing — Allergy testing is not necessary for the diagnosis of straightforward dermatologic reactions and is often not readily available. Studies that have examined allergy testing for clopidogrel reactions are reviewed above. (See 'Pathogenesis' above.)

Differential diagnosis — The differential diagnosis primarily consists of reactions to other drugs. Many patients will have been recently exposed to other medications, such as aspirin (ASA), beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, statins, agents used in procedures (radiographic contrast), and drugs eluting from coronary stents. Each of these agents has been implicated in maculopapular rashes. Delayed rashes to radiocontrast agents generally resolve without treatment [28,29]. When the cause of an apparent drug eruption is unclear, initial interventions include discontinuing noncritical medications or changing to different agents.

MANAGEMENT — For patients who develop a dermatologic reaction to clopidogrel, there are three options for continuing antiplatelet therapy (other than aspirin [ASA] monotherapy):

●Treating through without stopping clopidogrel (see '"Treating through"' below)

●Stopping clopidogrel and reintroducing it using a desensitization protocol (see 'Desensitization' below)

●Stopping clopidogrel and treating with a different antiplatelet agent (see 'Alternate therapies' below)

The initial step in managing clopidogrel hypersensitivity reactions is deciding whether clopidogrel should be stopped because there are signs or symptoms of a potentially dangerous (ie, life-threatening) hypersensitivity reaction or if it can be continued using one of the first two options. Collaboration between the consulting cardiologist and allergist is encouraged to guide management decisions [30].

Reactions that necessitate stopping clopidogrel — Until more is known about the pathogenesis of clopidogrel reactions, the authors and editors of UpToDate suggest that clopidogrel be promptly discontinued and not reintroduced if any of the following signs or symptoms of a serious reaction are present:

●Signs and symptoms of anaphylaxis, such as flushing, urticaria, or angioedema, accompanied by upper or lower airway compromise, bronchospasm, and/or hypotension (figure 1). Note that isolated urticaria and/or angioedema, without other symptoms, can represent a cutaneous reaction, and these patients have been managed with ongoing therapy. Anaphylaxis for this particular medication has not been consistently described.

●Involvement of mucous membranes, as seen in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

●Blistering skin rash, which is a feature of SJS, TEN, and other severe drug reactions.

●Involvement of organs other than the skin (eg, lungs, liver).

●Isolated fever unassociated with infection (suggesting drug fever).

●Persistent, severe hematologic changes, specifically eosinophilia, neutropenia, or thrombocytopenia. Note that some patients with dermatologic reactions have mild elevations in leukocytes, neutrophils, and/or platelets or mild decrements in lymphocyte counts at the onset of the skin changes, so patients' cell counts should be evaluated carefully. (See 'Most common signs and symptoms' above.)

Referral — Clopidogrel reactions are often successfully managed by clinicians with experience using this medication (cardiologists, neurologists) [11]. However, we suggest involving an allergy or dermatology specialist with experience in drug allergy if the patient demonstrates one or more of the signs and symptoms of a more serious type of reaction. Most desensitization procedures are carried out by allergy specialists. The opinion of an allergy specialist would also be helpful in cases of isolated urticaria and/or angioedema. If a severe form of hypersensitivity is suspected, then changing to an alternative agent is the safest option. (See 'More serious types of systemic reactions' above and 'Reactions that necessitate stopping clopidogrel' above.)

"Treating through" — The administration of systemic glucocorticoids and antihistamines to reduce symptoms while continuing clopidogrel therapy is referred to here as "treating through" [3,8]. For patients with uncomplicated cutaneous reactions to clopidogrel and recently placed intracoronary stents, the authors and editors generally prefer treating through without stopping clopidogrel, rather than desensitization or changing to another therapy.

Advantages — The primary advantage of treating through is that antiplatelet therapy is continued without interruption. This is particularly important for patients with recently placed intracoronary stents in whom the risk for stent thrombosis is significantly increased if antiplatelet agents are stopped in the first days or weeks after stent placement [31,32].

●In a series of 25 patients from the authors' center, 21 had rash attributed to clopidogrel as the primary presentation [8]. Two had rash accompanied by urticaria or angioedema, and three had isolated urticaria. None had other signs suggestive of anaphylaxis. Subjects were mostly outpatients and received different combinations of antihistamines and glucocorticoids. The exact agents and doses were left to the discretion of the supervising clinician, and attempts to optimize the antiallergy regimen were not the focus of the protocol. Patients most commonly received a methylprednisolone six-day dose pack and some combination of first- and second-generation H1 antihistamines. If symptoms recurred, doses of glucocorticoids were increased and given for a longer period, and montelukast (10 mg daily) was added.

In this series, 22 patients were successfully treated and tolerated clopidogrel, and 3 failed. Among the successfully treated patients, the mean duration of glucocorticoid treatment was 10±8 days. One patient required 30 days of glucocorticoid therapy, and 7 received additional drugs to suppress the reaction. All successfully treated patients were able to complete the target duration of prolonged dual antiplatelet therapy recommended by American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Clopidogrel was discontinued in the 3 patients who failed because of angioedema, desquamating rash, and uncontrollable pruritus. The investigators devised a medication protocol based on this experience (table 2) [8].

●In a subsequent larger series, 62 patients were managed by treating through [3]. Complete blood count and differential, platelet aggregation studies, and punch biopsy of affected skin were obtained. Presentations included generalized macular rash (49 subjects, confined to the trunk in 40), localized skin reaction, sometimes with peeling of the affected area (10 patients), and generalized urticaria or angioedema of the tongue or lips (3 patients). Subjects with urticaria and angioedema developed symptoms within one day of drug introduction, while the other reactions began after a median of five days of therapy. Two patients reported fever and arthralgia. Some patients had elevations in leukocytes, neutrophils, and/or platelets or depressed lymphocyte counts at the onset of symptoms (note that these hematologic changes are different from those described with hypersensitivity syndrome, which is characterized by thrombocytopenia and neutropenia). Eosinophilia was not observed. (See 'More serious types of systemic reactions' above.)

All patients were managed as outpatients, except one with angioedema who was treated under observation in the intensive care unit (ICU) [3]. All were given prednisone 30 mg twice daily for five days, followed by a decrease of 5 mg twice daily every third day for 15 more days. In addition, patients received diphenhydramine, 25 to 50 mg every six to eight hours, as needed for pruritus. All patients finished the 20-day course of prednisone, during which 95 percent had resolution of symptoms at 5±2 days. All patients were able to complete the minimum required period of clopidogrel treatment (ie, four weeks for bare metal stents and 12 months for drug-eluting stents). Four patients restarted clopidogrel at a later date, and all had recurrences of hypersensitivity, which again responded to glucocorticoids and antihistamines. Once clopidogrel therapy was completed, allergy testing was performed on approximately two-thirds of the patients. Results were reviewed previously. (See 'Pathogenesis' above.)

Desensitization — Drug desensitization is a procedure which temporarily alters the immunologic reaction to a medication and results in short-term tolerance, allowing the patient to receive a continued course of the medication safely. Drug desensitization is best studied in immunoglobulin E (IgE)-mediated drug reactions, but it has been applied to other types of reactions as well [33]. As noted above, the case for IgE-mediated immediate hypersensitivity has not been consistently demonstrated.

Advantages — The primary advantage of desensitization, compared with treating through, is that glucocorticoid therapy is not required. This may be important for some patients, provided they can be switched temporarily to another antiplatelet agent while desensitization is performed. Alternative antiplatelet agents are discussed below. (See 'Protocol' below.)

Types of clopidogrel reactions that have been managed with desensitization — The types of reactions that have been managed with desensitization are the same as those managed with treating through. In the largest series, 24 consecutive patients who had undergone placement of an intracoronary stent were treated with desensitization. Patients were excluded if their clopidogrel reaction was anaphylaxis, angioedema involving the upper or lower airway, irritation or blistering of mucous membranes, or blistering skin rash. No patient had fever as part of his/her reaction. (See 'More serious types of systemic reactions' above.)

Protocol — Various desensitization protocols have been developed [7,34-37]. In the largest series of 24 patients, the protocol used required eight to nine hours and was performed in the outpatient setting, except when the patient was currently hospitalized for other reasons (table 3) [7]. An oral solution of clopidogrel was prepared by finely crushing the drug into a liquid vehicle. Other smaller series have described longer and shorter protocols [37,38]. No head-to-head comparisons of different protocols have been performed. With such small numbers, it is difficult to make strong recommendations concerning the safety of outpatient desensitization without there being availability of intensive treatment for anaphylaxis. However, as noted, well-characterized reports of anaphylaxis are not readily identified with clopidogrel challenge. In many instances outside of specialized research centers, such care can only be found in a hospital setting, such as an ICU or emergency department. With heightened risk if a patient with coronary disease needed intervention for anaphylaxis.

Glucocorticoids are not required during desensitization, and no other premedications were given in the 24-patient series [7]. Antihistamines and antileukotriene drugs were discontinued for seven days before the procedure. Beta-blockers are usually withheld for one to two days prior to desensitization, because beta-blockade can interfere with the ability of the patient to respond to epinephrine, were it to be required during the desensitization.

In the 24-patient series, clopidogrel was discontinued for five days before desensitization to allow the drug to wash out of the patient's body, during which time the rash usually resolved [7]. This wash-out period was felt to be important, since patients who did not complete the wash-out period were more likely to react during the desensitization, although it is also possible that this reflected more severe hypersensitivity in those patients whose symptoms persisted.

During the wash-out period, alternative antiplatelet agents are given to patients with recently placed intracoronary stents to prevent stent thrombosis. The safest alternative antiplatelet agent during this process is unclear. In the 24-patient series, subjects were given ticlopidine 250 mg twice daily for five days [7]. Other alternative drugs would include prasugrel or ticagrelor, although there are no published reports for either of these drugs in this specific setting. (See 'Alternate therapies' below.)

Once desensitization has been performed, patients are obligated to take clopidogrel daily for as long as the drug is needed. If several doses are missed (the refractory period is not precisely defined), the patient will again theoretically be at risk for recurrence of the hypersensitivity reaction, and desensitization should be performed again.

Success rate — In the series of 24 patients, all were successfully desensitized, although 1 patient required continued antihistamines, and 2 required repetition of the procedure [7]. Only 4 patients had reactions (all cutaneous) during desensitization. All patients were able to continue therapy for six months, although 1 had mild intermittent symptoms that were managed with antihistamines, and 2 were noncompliant and required repeat desensitization. Thus, desensitization is a highly successful, although more complicated approach, compared with suppressing the reaction by treating through.

ALTERNATE THERAPIES — Another approach to managing clopidogrel hypersensitivity reaction is simply switching to a different antiplatelet agent, such as ticagrelor, prasugrel, or ticlopidine. The alternatives to clopidogrel for management of various cardiovascular disorders are reviewed separately.

●(See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Use of alternative antiplatelet agents'.)

●(See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

●(See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'P2Y12 use'.)

●(See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving fibrinolytic therapy'.)

●(See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Problems with clopidogrel use'.)

Other P2Y12 inhibitors — While ticlopidine, prasugrel, and ticagrelor represent potential alternatives to clopidogrel, important caveats exist regarding their clinical use.

●Ticlopidine was the first thienopyridine to be approved. Its clinical utility has been significantly hindered by adverse reactions. Over 20 percent of patients on ticlopidine discontinue therapy due to hypersensitivity reactions, gastrointestinal disturbances, neutropenia, or thrombocytopenia [11]. Because hematologic abnormalities occur in >2 percent of patients, complete blood counts are recommended every two weeks for the first three months of therapy.

●Prasugrel is approved for use in patients with acute coronary syndromes treated with stent placement and is associated with fewer cardiovascular events compared with clopidogrel in this setting [39]. However, prasugrel is contraindicated with prior stroke or transient ischemic attack, age >75 years, weight <60 kg, or increased bleeding risk. As both prasugrel and clopidogrel are thienopyridines, some patients display cross-reactivity to the two drugs [3,40]. (See 'Cross-reactivity among drugs' below.)

●Ticagrelor is a reversible P2Y₁₂ inhibitor, which is a nonthienopyridine. Ticagrelor is approved for use in patients with acute coronary syndromes (with or without stent placement) or a history of myocardial infarction due to its superior efficacy in reducing cardiovascular events compared with clopidogrel [41]. Information about cross-reactivity with clopidogrel is limited. (See 'Cross-reactivity among drugs' below.)

Both ticagrelor and prasugrel are more potent antiplatelet agents than clopidogrel, and both are also associated with higher risk of bleeding [39,42]. It is also important to note that ticagrelor and prasugrel are approved for patients with acute coronary syndromes but are not approved for patients treated with elective stent placement for stable coronary artery disease.

Cross-reactivity among drugs — There are limited studies of potential cross-reactivity between clopidogrel and related P2Y₁₂ inhibitors [3,40,43,44]. Briefly, evidence suggests that up to one-third of patients with reactions to clopidogrel will have similar reactions to ticlopidine. Less is known about cross-reactivity between clopidogrel and other drugs (prasugrel, ticagrelor).

●A study of 52 patients with hypersensitivity or hematologic reactions to clopidogrel found that 27 percent of patients developed a similar (although not more severe) reaction when given ticlopidine [43].

●Prasugrel has been successfully used in patients with clopidogrel hypersensitivity [44-46]. A review of the literature identified 11 published case studies of patients with clopidogrel hypersensitivity who were subsequently treated with prasugrel [47]. All had undergone coronary stenting procedures. Prasugrel was successfully used without cross-reactivity in 9 of the 11 patients (82 percent). However, other case reports described patients with clopidogrel hypersensitivity who developed either a similar rash or angioedema to prasugrel or ticagrelor [40,48]

●Other case reports described successful use of ticagrelor as an alternative agent in patients with clopidogrel hypersensitivity [49,50].

COMMON CLINICAL SCENARIOS — The issue of clopidogrel hypersensitivity typically arises in one of two clinical scenarios. In the first and more common scenario, clopidogrel is initiated at the time of coronary stent placement, and the patient develops a hypersensitivity reaction during the first week of therapy. In the second scenario, a patient who has a prior remote history of allergy to clopidogrel and is no longer taking the drug develops a new cardiovascular condition warranting clopidogrel therapy.

Reactions soon after initiation — Clopidogrel hypersensitivity is particularly problematic in patients with recently implanted coronary stents, since the risk of stent thrombosis from interruption of antiplatelet therapy is greatest during this period. Given its relative simplicity and effectiveness, we favor the treating through strategy for such patients, since this allows uninterrupted continuation of the drug (table 2). (See '"Treating through"' above.)

While most patients achieve a lasting response to a single short course of glucocorticoids, some patients will have a recrudescence of their rash after the glucocorticoid course is completed. In these occasional cases, referral to an allergy specialist, reinstitution of a longer course of glucocorticoids, or switching to an alternative P2Y₁₂ inhibitor would be appropriate options. (See 'Desensitization' above and 'Alternate therapies' above.)

Retreatment after a past reaction — Patients with a previous allergy to clopidogrel who are no longer on the drug may develop a cardiovascular condition where clopidogrel is again indicated. Simply reinstituting clopidogrel is not recommended, as this will typically result in a recurrent hypersensitivity reaction [3]. Options for management are significantly impacted by the patient's clinical presentation and cardiac diagnosis:

●In patients presenting with an acute coronary syndrome, particularly if coronary stenting is performed, use of one of the newer alternative P2Y₁₂ inhibitors would be the preferred approach. Not only would the likelihood of another allergic reaction be reduced, but also these agents improve cardiac outcomes in this clinical setting [39,42]. Theoretically, ticagrelor might be slightly advantageous over prasugrel, since the latter is a thienopyridine with some potential for cross-reactivity [3,40]. Both ticagrelor and prasugrel carry a higher risk of bleeding compared with clopidogrel. (See 'Alternate therapies' above.)

●In patients with past clopidogrel hypersensitivity who do not have an acute coronary syndrome, we suggest desensitization (table 3). Use of ticagrelor or prasugrel, with the concomitant higher risk of bleeding, would be less justifiable in this lower acuity scenario. (See 'Desensitization' above.)

SUMMARY AND RECOMMENDATIONS

●The most common form of hypersensitivity to clopidogrel presents as an erythematous macular rash starting on the trunk and spreading to the extremities, beginning approximately one week after the initiation of clopidogrel (picture 1). The pathogenesis is not known, although a lymphocyte-mediated response is suspected. (See 'Clinical manifestations' above and 'Pathogenesis' above.)

●Clopidogrel has also been implicated in a variety of potentially life-threatening types of hypersensitivity reactions, some of which include rash. (See 'More serious types of systemic reactions' above.)

●The diagnosis of clopidogrel hypersensitivity is made clinically, based upon appropriate signs, symptoms, and timing. Laboratory studies are performed to exclude more serious types of reactions. (See 'Diagnosis' above.)

●For most patients with uncomplicated cutaneous reactions to clopidogrel, there are three options for future antiplatelet therapy:

•Treating through without stopping clopidogrel (table 2) (see '"Treating through"' above)

•Stopping clopidogrel and reintroducing it using a desensitization protocol (table 3) (see 'Desensitization' above)

•Stopping clopidogrel and treating with a different antiplatelet agent (see 'Alternate therapies' above)

●For patients with uncomplicated cutaneous reactions to clopidogrel and recently placed intracoronary stents, we suggest treating through without stopping clopidogrel, rather than desensitization (Grade 2C). (See 'Reactions soon after initiation' above.)

●For patients with uncomplicated cutaneous reactions to clopidogrel who require the drug for secondary prevention of stroke or other manifestations of cardiovascular disease and who are at risk for complications of glucocorticoid therapy or wish to avoid glucocorticoids for other reasons, we suggest stopping clopidogrel and reintroducing it using a desensitization protocol, rather than treating through (Grade 2C).

●For patients with past clopidogrel hypersensitivity who stopped the drug and then later developed an acute coronary syndrome, we suggest treatment with one of the newer alternative P2Y₁₂ inhibitors, such as ticagrelor or prasugrel (Grade 2C), rather than administering clopidogrel again. Theoretically, ticagrelor might be the better choice, since prasugrel is a thienopyridine with some potential for cross-reactivity. (See 'Retreatment after a past reaction' above.)

●For patients with past clopidogrel hypersensitivity who stopped the drug and then later developed a need for clopidogrel other than an acute coronary syndrome, we suggest desensitization (table 3) (Grade 2C). (See 'Retreatment after a past reaction' above.)