Conversations in Cardiology: What to Do if Your Patient Can’t Take Aspirin After Stenting

The problem

My colleague, Sam Butman from Arizona, posed the following question to our cath lab experts: “I just put two drug-eluting stents into a native vessel and a distal graft anastomosis in a patient who is already on clopidogrel AND who has an aspirin allergy that cannot be touched or addressed. What additional drug, if any, would you give him, assuming that my stenting technique, short of IVUS [intravascular ultrasound], was okay?”

The answers

Mort Kern, Long Beach, California:  I’d switch to prasugrel or ticagrelor. Consider desensitization protocol for aspirin (ASA), but that might take some doing. I doubt dipyridamole would substitute for ASA. I do not envision 2 thienopyridines would be better than 1. At least be glad he didn’t fail a P2Y12 inhibitor yet. (NB: It’s off-topic, but really, no IVUS?)

Sam Butman, Cottonwood, Arizona:  Okay…A buck says at least 4 will say desensitize. I am thinking warfarin actually. Is that so bad? (Regarding the off-topic issue, I didn’t do IVUS because I did it through a 5 French catheter from the left radial and last time I did, it was essentially impossible to inject once IVUS was in it.)

Will Suh, Los Angeles, California:  Although rivaroxaban was not FDA approved for an acute coronary syndromes (ACS) indication (ATLAS ACS-2 TIMI 51), it could be useful in this situation for prevention of stent thrombosis, since only one antiplatelet can be given.

John Hirshfeld, Philadelphia, Pennsylvania:  I think it would be speculation to consider that adding a Xa inhibitor would provide equivalent stent thrombosis protection to an inhibitor of platelet activation. Recall ancient history that in STARS, wafarin had no benefit. This put the nail in the coffin of warfarin, which had been considered to be standard of care up to that time. I agree that the most valuable approach would be to switch to the most potent single oral platelet inhibitor. If you are really worried about short term (36-hour) stent thrombosis risk, you could use a IIb/IIIa short term. I would definitely investigate ASA desensitization. We have done that frequently, following a standard protocol with success and no adverse events. Unless this has been tried and failed previously, I would definitely consider that approach.

Gregg Stone, New York, New York: I agree, John. There are no core lab adjudicated data that factor Xa inhibitors meaningfully reduce stent thrombosis, although there are some clinical data in this regard with rivaroxaban. However, given the bleeding risk of rivaroxaban (which is not inconsequential), rivaroxaban would not be warranted. I fully agree that I would attempt to desensitize the patient, which is almost always successful. The patient needs aspirin for secondary prevention. That said, in contrast to the ADP antagonists, there is little evidence that aspirin is useful to prevent stent thrombosis. Aspirin resistance in ADAPT-DES and other series has not been associated with stent thrombosis, and dropping the aspirin in the WOEST trial (albeit under-powered) did not increase stent thrombosis. If you are really concerned about stent thrombosis on mono-clopidogrel, prior to switching to prasugrel or ticagrelor (off-label use unless the patient had ACS), this might be one situation where I would assess platelet reactivity on clopidogrel with VerifyNow [Accriva] or another point-of-care assay. If the patient is responsive, I would be comfortable on clopidogrel only.

Jeff Marshall, Atlanta, Georgia: ASA desensitization can be done in almost every patient, even those with anaphylaxis. Importantly, it can be done relatively quickly; over several hours. We use a protocol (Figure 1) that is based on studies from the allergy literature. We have adopted a policy (see ASA desensitization protocol in Figure 1) to desensitize all elective patients so they can receive dual antiplatelet therapy (DAPT). So far, we have not had an issue.

Mike Kutcher, Winston-Salem, North Carolina: At Wake Forest, we have used an ASA desensitization protocol with good success. It is important for the patient to know that they should stay on aspirin long term if at all possible, except for dire emergencies. If the aspirin is interrupted for more than 72 hours, the patient will recover their previous sensitivity within a few days.

Arnold Seto, Long Beach, California: With two fresh drug-eluting stents (DES), I would suspect that switching to prasugrel or ticagrelor alone would be the best (and most popular) choice. ASA desensitization is always an option, but may not be worth the effort, given the alternatives. The addition of vorapaxar (Zontivity) may also be helpful based on TRA 2°P-TIMI 50, albeit with concerns for intracranial bleeding.  There are many choices, even in this patient (dipyramidole, cilostazol, clopidogrel, ticagrelor, prasugrel, vorapaxar, and selected combinations [avoiding combinations of the three most potent drugs]). You could customize your approach based on the patient’s bleeding risk vs. stent thrombosis risk, which is difficult to estimate through the limited description given. With any choice that excludes ASA, you’re likely in an evidence-scarce zone, and probably won’t be wrong either way.

Barry Uretsky, Little Rock, Arkansas: I’d suggest immediate cilostazol loading, per our Asian colleagues, while ASA desensitization is started.

Sam Butman, Cottonwood, Arizona: I also agree about dipyridamole. He is 79, so I am a bit leery about putting him on a newer oral anticoagulant in combination with prasugrel, more so since absolutely no data, but am leaning towards warfarin. Right now, he is finishing up his eptifibatide (Integrilin) (used bivalirudin [Angiomax]) and is getting enoxaparin (Lovenox) bid. 

Dean Kereiakes, Cincinnati, Ohio: We have done both ASA desensitization as well as use of the most predictable, reliable P2Y12 inhibition, ticagrelor, in this type of case. I have a number of similar patients on ticagrelor mono therapy without problems to date, but ASA desensitization would be in the patient’s best interest. The other issue is how long to treat. Saphenous vein graft (SVG) percutaneous coronary intervention (PCI) is a situation where longer (2 years or more) looks better, regardless of stent type.¹ 

Gregg Stone, New York, New York: This [lack of rebound to P2Y12 drugs] has also been observed in ACS patients, whether or not they received a stent. The absence of a rebound phenomenon after clopidogrel discontinuation has been elegantly demonstrated in several double-blind trials.^2-3 In the clinical studies, the finding of an association is most likely explained by unmeasured confounders — lack of adequate understanding as to why the clopidogrel was discontinued in the first place, compared to patients in whom it was continued. 

Sam Butman, Cottonwood, Arizona: I printed out the ASA desensitization protocol, and shared it with our pharmacy and ICU nurses. The latter had a “conniption” and the patient prefers not to be desensitized. No good deed goes unpunished, or so the saying goes. Long story short, he is an alive 79-year-old man who now has a few bottles of ticagrelor and a few bottles of rivaroxaban while we ponder his future (translation: whether he has insurance that will cover the costs).

Aspirin allergy highlights

Before closing, I want to provide a quick review of ASA allergic responses. The prevalence of ASA sensitivity in cardiovascular patients is not well known. There are 3 types of hypersensitivity reactions to ASA: respiratory sensitivity (asthma and/or rhinitis), cutaneous sensitivity (urticaria and/or angioedema), and systemic sensitivity (anaphylactoid reaction).  

Respiratory sensitivity to aspirin is also part of a group of 3 findings: asthma, ASA sensitivity, and rhinitis/nasal polyps (also known as ASA-exacerbated respiratory disease [AERD]). AERD is the cause of 10% to 15% of all cases of asthma. The interruption of PGE2 by ASA and NSAIDs causes respiratory reactions in some patients, for reasons yet to be determined.

Cutaneous reactions to ASA and NSIDS include urticaria with or without simultaneous angioedema and may be accompanied by cough, dyspnea, hoarseness, wheezing, rhinorrhea, and/or tearing. This reaction occurs more often in adults, more in females, and patients with allergic history to other stimuli.

Anaphylactoid reactions after ingestion of ASA are characterized by hypotension, swelling, laryngeal edema, generalized pruritus, tachypnea, and loss of consciousness. Angioedema with hypotension is also considered an anaphylactoid reaction rather than a cutaneous reaction. Ramanuja et al provide a complete discussion of ASA allergy and its treatment.⁴

Bottom line

Alternatives to ASA are available but relatively unstudied to provide a definitive approach to the uncommon, but important, problem of an aspirin allergy. Desensitization, while appealing, is difficult and not commonly used, nor is it well understood even by pharmacists. I thank my colleagues for their insights and helpful comments, and hope that you learned something new, as I did.

References

1. Sachdeva A, Bavisetty S, Beckham G, Shen AY, Aharonian V, Mansukhani P, Stone GW, Leon M, Moses J, Moore N, Hyett R, Contreras R, Brar SS. Discontinuation of long-term clopidogrel therapy is associated with death and myocardial infarction after saphenous vein graft percutaneous coronary intervention. J Am Coll Cardiol. 2012 Dec 11; 60(23): 2357-2363. doi: 10.1016/j.jacc.2012.09.014.
2. Frelinger AL 3rd, Barnard MR, Fox ML, Michelson AD. The Platelet Activity After Clopidogrel Termination (PACT) study. Circ Cardiovasc Interv. 2010 Oct; 3(5): 442-449. doi: 10.1161/CIRCINTERVENTIONS.110.937961.
3. Sibbing D, Stegherr J, Braun S, Mehilli J, Schulz S, Seyfarth M, Kastrati A, von Beckerath N, Schömig A. A double-blind, randomized study on prevention and existence of a rebound phenomenon of platelets after cessation of clopidogrel treatment. J Am Coll Cardiol. 2010 Feb 9; 55(6): 558-565. doi: 10.1016/j.jacc.2009.09.038.
4. Ramanuja S, Breall JA, Kalaria VG. Approach to “aspirin allergy” in cardiovascular patients. Circulation. 2004 Jul 6; 110(1): e1-e4.