Craig J. Beavers, PharmD, FAHA BCPS-AQ Cardiology, CACP; and Jayant Bagai, MD, FSCAI

Dual antiplatelet therapy (DAPT), consisting of aspirin and a P2Y12 inhibitor, is the standard of care post-percutaneous coronary intervention (PCI). However, patients who report allergic reactions to either agent in the DAPT regimen pose a clinical dilemma. Aspirin hypersensitivity can manifest itself as urticaria/angioedema in up to 0.2 percent of the general population and in 20–30 percent of patients with chronic idiopathic urticaria. Aspirin can also exacerbate respiratory disease by a nonallergic mechanism in 10 percent of the population.¹ For P2Y12 inhibitors, the rate of hypersensitivity has been reported to be up to 6 percent for clopidogrel, typically a pruritic erythematous maculopapular rash on the trunk or localized to extremities or face with a median onset of six days after exposure.^{2, 3} Allergic reactions to ticagrelor and prasugrel are rare (probably < 1 percent). There is a lack of clear understanding amongst cardiologists regarding management options for patients with allergies to these drugs. Based on a survey of 86 cardiologists, the majority (56 percent) preferred to manage aspirin hypersensitivity by changing the therapeutic regimen rather than attempt desensitization.⁴ There is insufficient data to support monotherapy with either aspirin or a P2Y12 inhibitor post-PCI. It is, therefore, important that cardiologists are aware of evidence-based strategies, including desensitization protocols, to manage patients with hypersensitivity to either component of DAPT.   

Management Strategies:

1. Obtaining an allergy history: It is important to determine if the purported “allergy” to the antiplatelet agent represents true hypersensitivity or simply intolerance due to the drug’s pharmacologic effect. A detailed history to ascertain the nature and severity of the reaction (urticaria, angioedema, wheezing, exfoliative skin reaction, or anaphylaxis) should be obtained.
2. Desensitization protocols: To manage patients with true allergies, desensitization protocols should be pre-emptively developed, in conjunction with dermatology, immunology/allergy specialists, and clinical pharmacists. General and interventional cardiologists, as well as referring providers, should be educated on these protocols. Institutional familiarity with such initiatives will help physicians become more comfortable using the protocols.
3. Aspirin hypersensitivity management: Types I, II, and III reactions are non-antibody-mediated reactions due to leukotrienes because of COX-1 inhibition of prostaglandin E2 production by aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). They manifest as skin or respiratory reactions with first exposure. Types IV and V reactions are IgE mediated and involve urticaria/angioedema and anaphylaxis respectively.⁵ Several aspirin-desensitization protocols have been described.^{4, 6, 7} Amongst 315 patients who underwent desensitization, success rate was 95 percent with no death or anaphylaxis reported.⁸ A total of 4–5 percent of patients developed minor reactions, which were successfully treated with steroids and/or antihistamines. The Wong protocol (Table 1) uses a starting dose of 0.1 mg and is associated with a low risk of adverse effects.⁷ While desensitization has been successfully and safely performed in patients with a history of anaphylaxis to aspirin, the risks must be weighed against the potential benefit.
4. P2Y12 inhibitor hypersensitivity management: The strategies for management of a P2Y12 inhibitor allergy are listed below.⁹

A. P2Y12 Inhibitor Sparing Approaches:

Desensitization (High Evidence):

Most of the desensitization protocols for P2Y12 inhibitors pertain to clopidogrel and have been described in a small number (less than 10) of patients in a nonacute scenario. During the acute phase of treatment, such as during acute coronary syndrome (ACS), the use of a glycoprotein IIb/IIIa inhibitor is recommended to allow performance of PCI. A protocol for clopidogrel desensitization is provided in Table 2.¹⁰

Steroid Therapy (Moderate Evidence):

The most basic approach is to maintain P2Y12 inhibitor therapy, by using corticosteroids, especially if the reactions are mainly dermatological. Commonly, patients are initially started on oral prednisone 30 mg twice daily for five days. The dose is then reduced by 5 mg per day every three days for a total of 20 days of therapy. The patient is provided antihistamines to treat pruritus. In the largest case series using this method, all patients were able to complete a full course of clopidogrel therapy, reaction free, with the longest treatment course being 576 days.³ If steroids are a concern, due to other comorbidities such as diabetes or fluid overload, an alternate approach should be utilized. 

B. P2Y12 Switching (Low Evidence):

In patients with a clopidogrel or prasugrel allergy, one could consider switching to ticagrelor, if there are no contraindications, given that ticagrelor is structurally different from clopidogrel. The risk of cross-reactivity is theorized to be low.¹¹ Switching from clopidogrel to prasugrel has been successful in some case reports; however, there are also reports of failures. This could be due to the similar structure of the agents (both are thienopyridines).

Points of Importance With Regards to Any Desensitization:

Desensitization should be performed prior to PCI in patients who require elective procedures and can be performed after PCI for patients who require emergent or urgent procedures due to ACS. Basic principles are the following:

1. The patient should be closely monitored during the entire protocol with vital signs and reactions documented every 15 minutes and prior to each dose.
2. A crash cart and medications such as epinephrine, diphenhydramine, and steroids should be immediately available.
3. Beta blockers should be held to allow efficacy of epinephrine.
4. Desensitization is contraindicated in patients with a history of Stevens-Johnson syndrome and toxic epidermal necrolysis.
5. After desensitization, the medication should be continued without interruption. Resensitization occurs after two to seven days off aspirin.
6. Close involvement of allergy specialists and cardiovascular clinical pharmacists is recommended during the protocol.

Conclusion

Hypersensitivity reactions to antiplatelet agents (aspirin and P2Y12 inhibitors) in DAPT occur not infrequently. Desensitization protocols offer the most successful, well-documented means of managing allergies to these agents. There is insufficient evidence to support monotherapy with antiplatelet agents or use of oral anticoagulation to prevent stent thrombosis for both bare-metal and drug-eluting stents. Care coordination amongst the team is critical for success and best outcomes for the patient.

References

1. Gollapudi RR, Teirstein PS, Stevenson DD, Simon RA. Aspirin sensitivity: implications for patients with coronary artery disease. JAMA. 2004 Dec 22;292(24):3017-23.
2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). The Lancet. 1996 Nov 16;348(9038):1329-39.
3. Cheema AN, Mohammad A, Hong T, et al. Characterization of clopidogrel hypersensitivity reactions and management with oral steroids without clopidogrel discontinuation. J Am Coll Cardiol. 2011 Sep 27;58(14): 1445-1454.
4. Bianco M, Bernardi A, D’Ascenzo F, et al. Efficacy and Safety of Available Protocols for Aspirin Hypersensitivity for Patients Undergoing Percutaneous Coronary Intervention: A Survey and Systemic Review. Circ Cardiovasc Interv. 2016 Jan;9(1): e002896.
5. Page NA, Schroeder WS. Rapid desensitization protocols for patients with cardiovascular disease and aspirin hypersensitivity in an era of dual antiplatelet therapy. Ann Pharmacother. 2007 Jan 4;41:61-67.
6. Silberman S, Neukirch-Stoop C, Steg PG. Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting. Am J Cardiol. 2005 Feb 15;95(4):509-10.
7. Wong JT, Nagy CS, Krinzman SJ, Maclean JA, Bloch KJ. Rapid oral challenge-desensitization for patients with aspirin-related urticaria-angioedema. J Allergy Clin Immunol. 2000 May;105(5):997-1001.
8. Rossini R, Iorio A, Pozzi R, et al. Aspirin Desensitization in Patients With Coronary Artery Disease: Results of the Multicenter ADAPTED Registry (Aspirin Desensitization in Patients With Coronary Artery Disease). Circ Cardiovasc Interv. 2017 Feb;10(2); pii:e004368.
9. Beavers CJ, Carris NW, Ruf KM. Management Strategies for Clopidogrel Hypersensitivity. Drugs. 2015 Jun; 75(9): 999-1007.
10. Walker NE, Fasano MB, Horwitz PA. Desensitization for the management of clopidogrel hypersensitivity: initial clinical experience. J Invasive Cardiol. 2006 Jul;18(7):341-4.
11. Harris JR, Coons JC. Ticagrelor Use in a Patient With a Documented Clopidogrel Hypersensitivity. Ann Pharmacother. 2014 Sep;48(9):1230-1233.

Table 1: Rapid Oral Aspirin Desensitization Protocol. The patient is started at the lowest dose and if tolerated, the dose is escalated every 20 minutes.⁷

Table 2: Rapid Oral Clopidogrel Desensitization Protocol. This is a two-hour protocol, with doses given every 15 minutes.¹⁰