What is the best alternative for dual antiplatelet therapy for a patient with a clopidogrel allergy?

Comment by InpharmD Researcher

Options for patients with a clopidogrel allergy include a clopidogrel rechallenge with corticosteroids and antihistamines, desensitization to clopidogrel, or administration of an alternative antiplatelet agent (cilostazol, ticlopidine, prasugrel, and ticagrelor). Studies and case reports have described successful prasugrel, ticagrelor, and cilostazol use in patients with a clopidogrel allergy; however, papers have also described similar allergies with prasugrel and ticagrelor. Ticagrelor is a nonthienopyridine P2Y12 inhibitor, which is suspected to have a low potential for cross-allergenicity. Cilostazol is neither a thienopyridine nor a P2Y12 inhibitor, so cross-reactivity is not expected.

  

PubMed: clopidogrel allergy = 186 results; clopidogrel allergy DAPT = 3 results;

Background

Per 2012 American College of Cardiology Foundation and American Heart Association (ACCF/AHA) guidelines, unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) patients in whom an initial conservative strategy (e.g., noninvasive) is selected, if recurrent symptoms/ischemia, heart failure, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed. Either an intravenous (IV) GP IIb/IIIa inhibitor (eptifibatide or tirofiban), clopidogrel (loading dose followed by daily maintenance dose), or ticagrelor (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy before diagnostic angiography. [1]

Per 2016 American College of Cardiology and American Heart Association (ACC/AHA) focused update on dual antiplatelet therapy in patients with coronary artery disease (CAD), more potent P2Y12 inhibitors (e.g., ticagrelor, prasugrel) in place of clopidogrel in addition to aspirin for dual antiplatelet therapy (DAPT) generally result in decreased ischemic risk at the expense of increased bleeding risk. [2]

Reviews discuss various treatment strategies for the management of patients who present with allergic and hematologic adverse effects to clopidogrel following percutaneous coronary stent implantation. For patients with mild reactions such as nonpersistent urticarial rash, the authors recommend continuing clopidogrel with antihistamines and with or without oral corticosteroids. Alternatively, desensitization methods can be used, but with the discontinuation of clopidogrel. Several different desensitization protocols over the course of multiple hours or multiple days have shown to be successful, but there is not a recommendation for a specific desensitization method in patients with clopidogrel allergy. For patients with severe allergic reactions requiring discontinuation of clopidogrel therapy or for patients who develop adverse hematologic reactions including thrombotic thrombocytopenic purpura (TTP), several alternatives to clopidogrel may be permitted. [3], [4]

Potential antiplatelet alternatives to clopidogrel include cilostazol, ticlopidine, prasugrel, and ticagrelor. Clopidogrel is a thienopyridine P2Y12 inhibitor, as are prasugrel and ticlopidine. Cilostazol is a phosphodiesterase III inhibitor and does not contain a thienopyridine-like structure. Ticagrelor is a nonthienopyridine (cyclopentyltriazolopyrimidine) P2Y12 inhibitor. [3], [4]

Cilostazol was found to have no difference in the composite of death, myocardial infarction (MI), stent thrombosis, revascularization, and stroke compared to clopidogrel 300 mg in patients receiving bare-metal stent (BMS) and indefinite aspirin. Due to cilostazol’s structure and pharmacology, no cross-reactivity is expected, and it can be used for patients who cannot tolerate clopidogrel. [3], [4]

Ticagrelor has shown improved efficacy compared to clopidogrel in reducing harmful cardiovascular outcomes in patients with acute coronary syndrome (ACS) and is recommended at the time of PCI and when patients present with ST-segment elevation MI (STEMI). Due to ticagrelor’s non-thienopyridine structure that has a different binding site to thienopyridines, there may be a potential for less cross-reactivity with clopidogrel, but data are limited to case reports. [3], [4]

Prasugrel has shown improved efficacy in reducing harmful cardiovascular outcomes compared to clopidogrel and is recommended over clopidogrel in patients with acute coronary syndrome (ACS) proceeding to PCI; however, there is the potential for cross-reactivity since prasugrel is also a thienopyridine P2Y12 inhibitor. A subset of patients in a small study showed 17 % cross-reactivity with prasugrel and clopidogrel via intradermal testing. Other case reports have also reported cross-allergenicity between prasugrel and clopidogrel. [3], [4]

Ticlopidine may be considered for the recommended duration of dual antiplatelet therapy in place of clopidogrel. However, ticlopidine should not be used in patients with severe hematologic adverse reactions to clopidogrel due to the potential for cross-reactivity. There are conflicting efficacy data regarding the use of ticlopidine versus clopidogrel for the prevention of stent thrombosis, and its use is further limited by the poor tolerability of ticlopidine and potential cross-reactivity with clopidogrel. A study showed 27% (14 patients) cross-reactivity between clopidogrel and ticlopidine in 52 patients with clopidogrel allergy. [3], [4]

References:

[1] Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2012;126(7):875-910. doi: 10.1161/CIR.0b013e318256f1e0
[2] Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease:
a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2016;134(10):e123-155. doi: 10.1161/CIR.0000000000000404

[3] Beavers CJ, Carris NW, Ruf KM. Management strategies for clopidogrel hypersensitivity [published correction appears in Drugs. 2016 May;76(8):913]. Drugs. 2015;75(9):999-1007. doi:10.1007/s40265-015-0414-x
[4] Lokhandwala J, Best PJ, Henry Y, et al. Allergic reactions to clopidogrel and cross-reactivity to other agents. Curr Allergy Asthma Rep. 2011;11(1):52-57. doi: 10.1007/s11882-010-0152-9
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the best alternative for dual antiplatelet therapy for a patient with a clopidogrel allergy?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-6 for your response.

 

Prasugrel Use in A Patient Allergic to Clopidogrel: Effect of A Drug Shortage on Selection of Dual Antiplatelet Therapy
Design

Case report

Case Presentation

A 75-year-old white woman was admitted after a positive stress test indicating inferolateral ischemia. The patient's past medical history includes seasonal allergies, hypothyroidism, hypertension, cardiac arrest, myocardial infarction, and coronary artery disease. 

The patient was on ticlopidine but stopped taking it due to a national drug shortage. Prior to that, the patient was admitted to the emergency department (ED) for acute coronary syndrome and was given clopidogrel during the visit; however, she experienced clopidogrel-induced angioedema within 24 hours of its initiation. The patient was prescribed ticlopidine since then and had no adverse effects.

Before the patient's cardiac catheterization procedure, prasugrel was recommended as dual antiplatelet therapy with aspirin in place of the thienopyridine. During the cardiac catheterization procedure, two drug-eluting stents were placed, bivalirudin was used, and a 60-mg oral loading dose of prasugrel was given. The patient showed no signs of an allergic reaction to prasugrel. 

The patient was discharged home 24 hours later with a prescription of prasugrel 10 mg orally daily for at least one year along with lifelong aspirin 325 mg oral daily. A follow-up call three-month later revealed the patient was doing well on prasugrel with no adverse effects. 

Study Author Conclusions

A shortage of ticlopidine prompted the use of prasugrel in a clopidogrel-allergic patient requiring dual antiplatelet therapy. Prasugrel therapy was well tolerated, with no evidence of allergic reaction.

Treatment options for patients with a clopidogrel allergy include a clopidogrel rechallenge with corticosteroids and antihistamines, desensitization to clopidogrel, or administration of an alternative antiplatelet agent.

In this case, prasugrel was chosen as an alternative antiplatelet. Prasugrel is a third-generation thienopyridine that has the thiophene and pyridine ring structures also seen in clopidogrel and ticlopidine. Although these agents share structural similarities, it is unknown whether the etiology of hypersensitivity is to clopidogrel a metabolite. Clinical trials of prasugrel excluded patients with an allergy to clopidogrel or ticlopidine. As such, the degree of risk of cross-reactivity between the thienopyridines is unknown.

An additional option, ticagrelor (a nonthienopyridine P2Y12 inhibitor), was not explored even though its structural dissimilarity from other thienopyridines suggests that the drug may have a role in patients with a clopidogrel allergy. Ticagrelor was indicated for acute coronary syndrome (ACS), and the patient in this case did not have ACS. Additionally, ticagrelor was not on the hospital formulary at the time. 

 

References:

Felix-Getzik E, Sylvia LM. Prasugrel use in a patient allergic to clopidogrel: effect of a drug shortage on selection of dual antiplatelet therapy. Am J Health Syst Pharm. 2013;70(6):511-513. doi:10.2146/ajhp120529

 

Oral Antiplatelet Agent Hypersensitivity and Cross-Reactivity Managed by Successful Desensitasation
Design

Case report

Case Presentation

A 57-year-old man with a history of ischemic heart disease had an elective percutaneous coronary intervention to his proximal left anterior descending artery and an insertion of two drug-eluting stents. He was started on dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. After eleven days of clopidogrel, the patient experienced an urticarial rash on his scalp and palms and also peripheral paresthesia. He was subsequently treated with antihistamines and was switched to ticagrelor.

Following the 36 hours of ticagrelor initiation, he experienced angioedema of the face and dysphagia. The symptoms were relieved with the use of intravenous (IV) corticosteroids and intramuscular (IM) adrenaline, and the patient was later discharged home. 

The patient was then put on prasugrel, but again he experienced urticarial reactions on his hands, groin, and feet after 2 hours. The symptoms subsided after administration of IM adrenaline, IV antihistamines, and IV fluids.

A fourth antiplatelet, ticlopidine, was considered but was later disregarded due to previous reactions from the other three antiplatelets and the similarity of structure between clopidogrel and ticlopidine. The patient was ultimately treated with clopidogrel desensitization with prednisolone. Four months after the desensitization, he continues clopidogrel with no reported adverse effects.

Study Author Conclusions

This case describes the first documented cross-reactive hypersensitivity of clopidogrel towards both its fellow thienopyridine, prasugrel, as well as the structurally dissimilar ticagrelor, and its subsequent successful desensitization.

Normally, a patient reporting a clopidogrel allergy would be switched to an alternative antiplatelet. There have been reports of cross-reactivity between clopidogrel and ticlopidine but not between prasugrel and ticagrelor. Ticagrelor, a nonthienopyridine, was used as a substitute for clopidogrel in this case. Despite structural dissimilarity, features of drug hypersensitivity with angioedema occurred within 72 hours of exposure. The suspected etiology of this angioedema is a delayed mast cell activation or bradykinin release. Subsequent challenge with prasugrel, a thienopyridine, led to a reaction within two hours.

Since there were allergic reactions with agents that are structurally dissimilar, the authors hypothesize the reaction may be due to a common mechanism of action, such as P2Y12 platelet receptor inhibition. This is similar to the hypersensitivity reactions seen in susceptible individuals towards structurally dissimilar aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) due to the common mechanism of cyclooxygenase-1 enzyme inhibition. 

 

References:

Chin N, Rangamuwa K, Mariasoosai R, et al. Oral antiplatelet agent hypersensitivity and cross-reactivity managed by successful desensitisation. Asia Pac Allergy. 2015;5(1):51-54. doi: 10.5415/apallergy.2015.5.1.51.

 

Acute Coronary Syndrome Antiplatelet Alternatives in Clopidogrel Allergy

Design

Case report 

Case 1 

A 65-year-old white woman with a history of chronic kidney disease, systemic lupus erythematosus, paroxysmal atrial fibrillation, hypertension, adrenal insufficiency, anxiety, gastrointestinal reflux disease, and gout presented to the hospital with acute myocardial infarction (MI). She was treated via percutaneous coronary intervention (PCI) with the implementation of two bare-metal stents. After a loading dose of aspirin 325 mg and clopidogrel 300 mg by mouth, the patient was started on aspirin 81 mg by mouth daily, clopidogrel 150 mg by mouth daily, as well as her home medications including warfarin. After 7 days, the clopidogrel dose was decreased to 75 mg/day PO for 6 months.

Approximately 9 months after her first acute MI patient had a second MI and a new stent was placed at one of the previously treated vessels. The patient was then given a loading dose of 600 mg of clopidogrel followed by a regimen of clopidogrel 75 mg/day for 28 days.

After 16 days, the patient complained of a very severe itch all over her body including her face and scalp. No visible rash was present. After a careful investigation, the team determined clopidogrel to be the cause. The patient has then treated with oral and topical steroids as well as an antihistamine for the completion of the last 12 days of clopidogrel.

One year later, the patient experienced another MI. Due to suspicion of clopidogrel allergy and/or intolerance, the patient was loaded with a single dose of ticagrelor 180 mg followed by 90 mg by mouth BID for five days. Then the patient was discharged on ticagrelor 90 mg BID and aspirin 81 mg daily without reported incident.

Case 2 

A 38-year-old man with a history of depression, anxiety, and frequent tobacco use had PCI with two drug-eluding stets implemented following ST-segment elevation MI (STEMI). The patient was loaded with clopidogrel 600 mg and aspirin 325 mg by mouth daily, followed by clopidogrel 75 mg/day and aspirin 81 mg/day.

On a follow-up visit 8-months later, he reported a chronic rash on his arm and torso that appeared shortly after his PCI and worsened through time was documented by his cardiologist. Four months later, the rash had spread and increased in severity, requiring topical steroids. At this point (one year after his treatment), the clopidogrel was discontinued and the rash resolved.

The patient experienced another acute MI in 2014. He underwent another PCI and implantation of a bare-metal stent. Based on his history of clopidogrel allergy, he was given a loading dose of aspirin 325 mg and ticagrelor 180 mg followed by initiation of ticagrelor 90 mg daily and aspirin 81 mg daily. The patient was discharged with this regimen without a reported incident.

Study Author Conclusion 

Clopidogrel lymphocyte-mediated delayed hypersensitivity reaction carries a 27% crossreactivity with prasugrel and ticlopidine that may be avoided with ticagrelor. The unique structure of ticagrelor compared with other available oral ADP antagonists seems to make it a viable alternative in patients requiring dual antiplatelet therapy who have a clopidogrel allergy

This documentation of two cases of patients with clopidogrel hypersensitivity who were later successfully initiated on ticagrelor suggests that this approach is acceptable. Further investigation across a larger population of thienopyridine intolerant patients is warranted.

 

References:

Manchette AM, Drucker AG, Januzzi JL. Acute coronary syndrome antiplatelet alternatives in clopidogrel allergy. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2014;34(8):e152-e156.

 

Rash with both clopidogrel and ticlopidine in two patients following percutaneous coronary intervention with drug-eluting stents

Design

 Case report
Case 1

A 60-year-old man with a medical history of type 2 diabetes mellitus and coronary artery bypass graft surgery presented to an outside hospital with ischemic chest pain. Medications taken at the time of presentation included aspirin, atenolol, atorvastatin, fosinopril, glimepiride, metformin, and docusate sodium (doses not known). The patient underwent percutaneous transluminal coronary balloon angioplasty (PTCA). Just prior to PTCA, an oral loading dose of clopidogrel 300 mg was administered, and eptifibatide was initiated. Following angioplasty, the clopidogrel dosage was decreased to 75 mg daily. Eptifibatide was discontinued prematurely secondary to an abrupt decrease in platelet count.

Within 24 hours following PTCA, the patient developed recurrent ischemic chest pain. Eptifibatide was restarted, and the patient’s symptoms resolved. Repeat angiography revealed thrombotic occlusion of the distal left circumflex artery, and elevated cardiac enzymes indicated a myocardial infarction. Repeat PTCA of the left circumflex coronary artery was performed, and the patient was transferred to another hospital for further medical management.

Medications at time of transfer included oral aspirin 325 mg daily, metoprolol, and clopidogrel 75 mg daily; intravenous therapy included nitroglycerin and eptifibatide 2 µg/kg/min. His physical examination was significant for a maculopapular, pruritic rash on the abdomen, back, and neck. The rash was treated with hydrocortisone 1% cream and oral hydroxyzine 50 mg 4 times daily.

On hospital day 5, the patient was discharged; however, the rash remained unchanged. On the day of discharge, clopidogrel was discontinued secondary to rash, and ticlopidine 250 mg twice daily was initiated.

Three days following discharge, the patient presented to the emergency department with substernal chest pain; a resolving rash on his abdomen, back, and neck; and a new maculopapular rash on his legs and arms. The new rash worsened thereafter. 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 placed in each of the left circumflex and the superior obtuse marginal branch coronary arteries. The patient was discharged on hospital day 7. At the time of discharge, the rash was not pruritic; therefore, prednisone and hydrocortisone cream were discontinued. The rash on the lower extremities subsided after 10 days, but the rash on the back persisted for up to 2 months following hospital discharge. The patient remains on cilostazol. No additional episodes of acute coronary syndrome or rash occurred during that time.
Case 2

A 57-year-old man with dilated cardiomyopathy (ejection fraction 35%), Class I heart failure, and chronic atrial fibrillation was admitted for elective angiography after evidence of a small inferior reperfusion defect suggestive of myocardial ischemia. His medication regimen included warfarin, aspirin, and extended-release metoprolol.

Angiography revealed luminal irregularities in the left main, left anterior descending, and right coronary arteries as well as 80-90% proximal right coronary artery stenosis. Eptifibatide, intravenous unfractionated heparin, and clopidogrel 600 mg were administered. The patient underwent uncomplicated PCI, and a paclitaxel drug-eluting stent was placed. The patient was discharged the following morning on aspirin 162 mg daily, clopidogrel 75 mg daily, ramipril 5 mg daily, extended-release metoprolol 100 mg daily, and atorvastatin 40 mg daily.

Two days following discharge, the patient reported that a pruritic rash had developed on his posterior thorax the afternoon of discharge and spread to his stomach and anterior thorax that evening and to his face and neck the next day. He also reported eyelid swelling but denied throat swelling, wheezing, or difficulty breathing. The patient was prescribed diphenhydramine and advised to discontinue ramipril secondary to possible angioedema. The next morning, he reported that the swelling had subsided and the pruritus had diminished, but the rash was still extensive. The patient continued taking diphenhydramine for the next 2 days without relief. On day 5 following discharge, clopidogrel was discontinued and oral ticlopidine 250 mg twice daily was administered.

Ten days following discharge and 5 days following initiation of ticlopidine, the rash worsened. Ticlopidine was discontinued and oral cilostazol 100 mg twice daily was initiated. The rash resolved 3 days following discontinuation of ticlopidine. The patient self-discontinued cilostazol and restarted clopidogrel approximately 4 weeks after discharge. The rash reappeared and he discontinued clopidogrel and restarted cilostazol. At the time of this report, the patient had continued on warfarin, cilostazol, aspirin, atorvastatin, and ramipril and remained symptom-free 3 months following hospitalization.
Study author conclusion

In both cases, patients who had a prior rash with clopidogrel also saw a rash with ticlopidine. According to the Naranjo probability scale, the occurrence of the rash in the first patient was "probable" with both clopidogrel and ticlopidine. As for the second patient, the occurrence of rash was classified as definite with clopidogrel and probable with ticlopidine.

Based on these two cases and previous reports regarding rashes with clopidogrel and ticlopidine, patients who develop rash from both clopidogrel and ticlopidine and do not have a contraindication to cilostazol or anticoagulation may be treated with aspirin, cilostazol, and enoxaparin or warfarin for 2-6 months after drug-eluting stent placement. Certain patients may also undergo clopidogrel desensitization several months or years after the occurence of the rash with close monitoring to prevent allergic reactions.

 

References:

Makkar K, Wilensky RL, Julien MB, Herrmann HC, Spinler SA. Rash with both clopidogrel and ticlopidine in two patients following percutaneous coronary intervention with drug-eluting stents. Ann Pharmacother. 2006;40(6):1204-1207. doi:10.1345/aph.1g587

 

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes (PLATO)

Design

Randomized, double-blind, double-dummy, multicenter, phase 3 trial

N=18,624

Objective

To compare ticagrelor and clopidogrel for the prevention of cardiovascular events in patients admitted to the hospital with an acute coronary syndrome (ACS), with or without ST-segment elevation

Study Groups

Ticagrelor (n=9,333)

Clopidogrel (n=9,291)

Inclusion Criteria

Hospitalized for an ACS, with or without ST-segment elevation, with an onset of symptoms during the previous 24 hours.

Exclusion Criteria

Any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours before randomization, a need for oral anticoagulation therapy, an increased risk of bradycardia, and concomitant therapy with a strong cytochrome P450 3A inhibitor or inducer.

Methods

Eligible patients were randomized to receive either ticagrelor (a loading dose of 180 mg followed by a dose of 90 mg twice daily or clopidogrel) or clopidogrel (a loading dose of 300 mg followed by a dose of 75 mg daily). Others in the clopidogrel group continued to receive a maintenance dose of 75 mg daily.

Patients undergoing percutaneous coronary intervention (PCI) after randomization received an additional dose of their study drug at the time of PCI. In patients undergoing CABG, the study drugs were withheld (for 5 days in the clopidogrel group, and 24-48 hours in the ticagrelor group).

All patients received 75 to 100 mg of aspirin daily unless could not tolerate it. For those who had not previously been receiving aspirin, 325 mg was the preferred loading dose; 325 mg was also permitted as the daily dose for 6 months after stent placement.

Duration

Treatment: 12 months

Outcome Measures

Primary outcome: a composite of death from vascular causes, myocardial infarction (MI), or stroke

Secondary outcome: composite of death from any cause, myocardial infarction, or stroke; the composite of death from vascular causes, myocardial infarction, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, transient ischemic attack, or other arterial thrombotic events; myocardial infarction alone; death from cardiovascular causes alone; stroke alone; and death from any cause

Baseline Characteristics

  

Ticagrelor

(n=9,333)

Clopidogrel

(n=9,291)

 p-value

Median age

 62.0 62.0 --

Female

2,655 (28.4%) 2,633 (28.3%) --

White

8,566 (91.8%) 8,511 (91.6%) --

Final diagnosis of ACS

STEMI

NSTEMI

Unstable Angina

Other/missing data

 

3,496 (37.5%)

4,005 (42.9%)

1,549 (16.6%)

283 (3.0%)

 

3,530 (38.0%)

3,950 (42.5%)

1,563 (16.8%)

248 (2.7%)

 --

Invasive procedure conducted

PCI

Stenting

Bare-metal only

Drug-eluting

CABG

 

5,978 (64.1%)

5,640 (60.4%)

33,921 (42.0%)

1,719 (18.4%)

931 (10.0%)

 

5,999 (64.6%)

5,649 (60.8%)

3,892 (41.9%)

1,757 (18.9%)

968 (10.4%)

 

0.46

0.61

0.87

0.40

0.32

Results

  

Ticagrelor

(n=9,333)

Clopidogrel

(n=9,291)

p-value

Death from vascular causes, MI, or stroke

864 (9.8%) 1,014 (11.7%) <0.001

Death from any cause, MI, or stroke

901 (10.2%) 1,065 (12.3%) <0.001

Death from vascular causes, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic events

 1,290 (14.6%) 1,456 (16.7%) <0.001
MI 504 (5.8%) 593 (6.9%) 0.005
Death from vascular causes 353 (4.0%) 442 (5.1%) 0.001
Stroke 125 (1.5%)  106 (1.3%) 0.22
All cause mortality 399 (4.5%) 506 (5.9%) <0.001

Major bleeding

CABG-related major bleeding

Fatal bleeding

961/9,235 (11.6%)

619/9,235 (7.4%)

20/9,235 (0.3%)

929/9,186 (11.2%)

654/9,186 (7.9%)

23/9,186 (0.3%)

0.43

0.32

0.66

Adverse Events

Common Adverse Events: dyspnea was more common in the ticagrelor group than in the clopidogrel group (13.8% vs 7.8%)

Serious Adverse Events: ticagrelor and clopidogrel groups did not differ significantly with regard to the rates of major bleeding as defined in the trial (11.6% vs 11.2%, respectively; p=0.43).

Discontinuation of the study drug due to adverse events: occurred more frequently with ticagrelor than with clopidogrel (7.4% vs 6.0%; p<0.001) 

Study Author Conclusions

In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding.

InpharmD Researcher Critique

The study used a composite endpoint which can be misleading. Though the two treatment groups did not differ significantly in the rates of CABG-related major bleeding, there was a higher rate of non–CABG-related major bleeding in the ticagrelor group. 

 

References:

Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. doi: 10.1056/NEJMoa0904327.

 

Frequency of Allergic or Hematologic Adverse Reactions to Ticlopidine Among Patients with Allergic or Hematologic Adverse Reactions to Clopidogrel

Design

Retrospective, observational chart review

N=76

Objective

To evaluate the frequency and severity of allergic cross-reactivity between clopidogrel and ticlopidine

Study Groups

Patients with an allergic or hematologic reaction to both thienopyridines; patients with an allergic or hematologic reaction to clopidogrel but who tolerated ticlopidine; patients with an allergic or hematologic reaction to ticlopidine but who tolerated clopidogrel

Inclusion Criteria

Adult patients with adverse reactions of allergic or hematologic adverse reactions to a thienopyridine in their medical record who received both clopidogrel and ticlopidine in their lifetime

Exclusion Criteria

Adult patients with adverse reactions of allergic or hematologic adverse reactions to a thienopyridine and only tried one agent from the class.

Methods

Medical charts were reviewed to identify patients with an allergic reaction to thienopyridines (clopidogrel, ticlopidine, and/or both) and to assess adverse reaction details. Since there are no assays to confirm the allergy, allergic reactions assessed were anaphylaxis, angioedema, and rash.

Duration

January 1995 to June 2007

Outcome Measures

 Frequency of cross-reactivity between clopidogrel and ticlopidine.

Baseline Characteristics

  

Study population (n=76)

Mean age, years

 69

Male 

 70%

Comorbidities

Hypertension

Hyperlipidemia 

Diabetes

 

82%

84%

20%

Peripheral arterial disease 

Previous myocardial infarction 

Previous percutaneous coronary intervention 

Previous coronary artery bypass grafting 

26%

49%

76%

20%

Results

  

Study population (n=76)

Allergic reaction to

Clopidogrel only

Ticlopidine only

Both agents

 

38 (50%)

24 (32%)

14 (18%)

Type of allergic reaction 

Rash

Angioedema

Thrombocytopenia

Neutropenia

 

71 (93%)

4 (5%)

3 (4%)

2 (3%)

Of the 52 patients with allergic reactions to clopidogrel 14 (27%) had similar reactions to ticlopidine. Thirty-six of the other 38 patients (95%) were able to tolerate ticlopidine.

Of the 38 patients with allergic reactions to ticlopidine, 14 (37%) had similar reactions to clopidogrel.

Adverse Events

N/A 

Study Author Conclusions

Patients who develop an allergic or hematologic adverse reaction to clopidogrel may be safely treated with ticlopidine without fear of a life-threatening allergic reaction to ticlopidine. However, our data suggest that 24% of patients will develop an allergic or hematologic adverse reaction to ticlopidine as well.

InpharmD Researcher Critique

The study is subject to the limitations inherent to a retrospective analysis. The absence of immunologic testing creates uncertainty on whether the reported allergies are true allergies or not. 

 

References:

Lokhandwala JO, Best PJM, Butterfield JH, et al. Frequency of allergic or hematologic adverse reactions to ticlopidine among patients with allergic or hematologic adverse reactions to clopidogrel. Circ Cardiovasc Interv. 2009;2(4):348-351. doi: 10.1161/CIRCINTERVENTIONS.108.832964.108.832964.