1

Introduction

Recent American College of Cardiology and European Society of Cardiology Guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and one of the P2Y ₁₂ inhibitors as a standard regimen after percutaneous coronary intervention (PCI) with or without stenting. These recommendations are based on clinical trials demonstrating that DAPT reduces stent thrombosis (ST) and other major adverse cardiac events after PCI. However, of late, the safety and duration of guideline directed DAPT strategy has been challenged .

The three cases of aspirin hypersensitivity reported here, provide important insight in the management of antiplatelet therapy in patients with coronary artery disease, where it is not possible to introduce aspirin therapy.

2

Case 1

A 51-year-old male presented with acute inferior ST-elevation myocardial infarction (STEMI). He was subjected to rescue PCI for failed thrombolytic therapy. Coronary angiogram showed significant triple vessel disease. PCI was done to right coronary artery (culprit lesion) with an everolimus-eluting stent (EES). The patient reported that he is allergic to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). In the hospital, he developed eye swelling after receiving paracetamol. A history of aspirin hypersensitivity and an allergic response to paracetamol precluded aspirin therapy in this patient. He had received clopidogrel 300-mg with tenecteplase. Clopidogrel was discontinued after PCI and replaced with ticagrelor 90 mg twice daily. His pre-discharge platelet reaction unit (PRU) on ticagrelor therapy, assessed by VerifyNow P2Y ₁₂ assay was 112 units. He was discharged for a 3-week observation period on single antiplatelet therapy (SAPT). During this period, he had no adverse cardiovascular event and was tolerating ticagrelor without any of its known side effects. Three weeks later, elective PCI to proximal to mid-left anterior descending artery (LAD) and obtuse marginal artery was done with two EESs. He was discharged on ticagrelor, atorvastatin, bisoprolol and perindopril. The post-procedure 16 months follow-up has been uneventful.

2

Case 1

A 51-year-old male presented with acute inferior ST-elevation myocardial infarction (STEMI). He was subjected to rescue PCI for failed thrombolytic therapy. Coronary angiogram showed significant triple vessel disease. PCI was done to right coronary artery (culprit lesion) with an everolimus-eluting stent (EES). The patient reported that he is allergic to aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). In the hospital, he developed eye swelling after receiving paracetamol. A history of aspirin hypersensitivity and an allergic response to paracetamol precluded aspirin therapy in this patient. He had received clopidogrel 300-mg with tenecteplase. Clopidogrel was discontinued after PCI and replaced with ticagrelor 90 mg twice daily. His pre-discharge platelet reaction unit (PRU) on ticagrelor therapy, assessed by VerifyNow P2Y ₁₂ assay was 112 units. He was discharged for a 3-week observation period on single antiplatelet therapy (SAPT). During this period, he had no adverse cardiovascular event and was tolerating ticagrelor without any of its known side effects. Three weeks later, elective PCI to proximal to mid-left anterior descending artery (LAD) and obtuse marginal artery was done with two EESs. He was discharged on ticagrelor, atorvastatin, bisoprolol and perindopril. The post-procedure 16 months follow-up has been uneventful.

3

Case 2

A 60-year-old female patient presented to emergency room with symptoms of recent onset angina. There was no history of hypertension, diabetes mellitus and tobacco abuse. Electrocardiogram showed QS-complex and inverted T-waves in V1 to V3. Her cardiac markers (troponin-T and CK-MB) were elevated, and echocardiography detected left ventricular regional wall motion abnormality in antero-lateral left ventricular segments. She was diagnosed as non ST-elevation myocardial infarction. She gave history of aspirin hypersensitivity, and with a trial dose developed rashes and itching requiring antihistamine therapy. She was treated with clopidogrel 300 mg loading dose followed by 150 mg once daily. The PRU by VerifyNow P2Y ₁₂ was 166 units. Coronary angiography revealed severe disease of mid LAD. PCI was done with a 3 mm × 38 mm EES. Patient was discharged with an advice to continue clopidogrel 150 mg daily for 3 months, followed by 75 mg daily. Fifteen months post-PCI, she remains well without any cardiac symptom, on medical therapy.

4

Case 3

A 54-year-old female with a past medical history of dyslipidemia, hypertension and uncontrolled diabetes mellitus presented with recurrent episodes of angina. She had anterior STEMI, 2 days before admission, and received thrombolytic therapy in a different hospital. Her antiplatelet treatment included clopidogrel only, as she was allergic to aspirin. Her coronary angiography was delayed due to uncontrolled blood sugar and electrolyte derangements. In the meantime, her platelet function assessment by the VerifyNow test was 248 PRU. Clopidogrel was switched to ticagrelor 180 mg loading dose and 90 mg twice daily maintenance dose. The patient had a tight proximal LAD stenosis that was managed using a bare metal stent. The post procedure follow-up has been uneventful.

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Discussion

An optimal regimen of antiplatelet therapy in an individual patient after PCI is still evolving. Evidence for the intensity and duration of DAPT has been challenged recently . Several factors are responsible for this debate: risk of bleeding, poor tolerance of aspirin, availability of potent antiplatelet agents, and changes in stent technology. DAPT predisposes a patient to the risk of major bleeding , and bleeding adversely affects the outcomes after PCI . Aspirin therapy is associated with 2–3% risk of gastrointestinal bleeding . In SYMPHONY trials, 17.5% of patients discontinued aspirin prematurely, and about 10% of these high-risk acute coronary syndrome patients did not take it, in-spite of a careful follow-up . Major bleeding was seen in 4.4% patients. Allergic reactions were seen in 2.3% patients. In the CHARISMA trial , the rate of severe bleeding on DAPT (including fatal bleeding and intracranial hemorrhage) was 1.7%, which exceeds most of estimates of ST over a similar time interval. None of our patient on SAPT developed minor or major bleeding episode.

Recommendations for aspirin use during and following PCI are based on placebo controlled trials of eighties . After ticlopidine became available, aspirin use continued as a historical precedent. No trial has been done with clopidogrel or newer antiplatelet agents alone in PCI patients in the same way as the MATCH trial for high risk patients with ischaemic stroke or transient ischaemic attack, where the addition of aspirin on top of clopidogrel did not prove useful and increased major bleeding . On the contrary, adding clopidogrel to a background of aspirin therapy has been successful. Even the studies on ST have analysed the data of DAPT or clopidogrel stoppage only and rarely looked into the discontinuation of aspirin alone. In a systematic review of 84 articles for reported cases of late and very late ST, 161 cases were identified . Thienopyridine discontinuation was a common factor for ST in 142(88.2%) patients. On the contrary, none of the patients, who continued on a thienopyridine after they stopped aspirin, developed late ST. Similarly, in the recently reported ADAPT-DES trial, the rate of ST was related to the level of platelet responsiveness to clopidogrel but not to aspirin . In ADAPT-DES, 478 patients had high on-treatment platelet reactivity (HTPR) on aspirin. Aspirin nonresponsiveness was not associated with ST, myocardial infarction or death but was found to be protective against major bleeding events. In the Dutch stent thrombosis registry, lack of clopidogrel therapy at the time of ST was identified as the most important independent predictor of ST . It takes us to the fact that post PCI; P2Y12 antagonists are the mainstay of antiplatelet regimen.

Novel antiplatelet agent ticagrelor has been shown to have a greater inhibition of platelet aggregation compared with clopidogrel and was used in two of the patients in this series. In the second patient, a higher than conventional maintenance dose of clopidogrel was used. A high-dose of 150 mg/day clopidogrel causes more intense platelet inhibition and significantly reduces incidence of ST . Doubling the maintenance dose of clopidogrel was not associated with the reduction of ischaemic events, or ST in GRAVITAS and RECLOSE 2-ACS trials . The possible reason for negative clinical outcomes in these two trials was due to a different patient population with HTPR on clopidogrel. However, PRU in the second case on clopidogrel was lower than the defined limit of ≥ 230 for HTPR. The last patient had HTPR on clopidogrel and was started on ticagrelor. Though the clinical utility of switching drugs on the basis of PRU result is not established, it was considered appropriate in this patient as she was without concomitant aspirin therapy.

In the last one decade, stent technology has morphed significantly, impacting the post PCI management. There is reduced requirement of antiplatelet drugs with current generation of drug eluting stents having thinner struts, bio-degradable polymer or no polymer, and better implantation techniques using intravascular imaging. In a meta-analysis by Palmerini et al. , fluoropolymer-coated cobalt-chromium EES was associated with lower rates of definite ST than the other drug eluting stents, and even lower than bare metal stent. The biocompatible phosphorylcholine and fluoropolymer coatings incorporated into ZES (zotarolimus-eluting stent) and EES respectively, have in vitro resistance to fibrinogen adsorption. Two of the patients in this series received EES, and a bare metal stent was used in the third patient.

Several randomized trials have focused recently on reducing the duration of DAPT after PCI. A three month regimen of DAPT was found to be safe and noninferior to standard 12 month DAPT in RESET Trial . Clinical safety and efficacy of shorter duration DAPT with aspirin and ticagrelor for one month only, followed by ticagrelor monotherapy will be tested in GLOBAL LEADERS trial , after BioMatrix family of stent implantation. In the ARGENTO trial, DAPT duration of ≤ 15 days was reported to be safe after treatment with Genous Bio-engineered R stent . An early and complete endothelialization of implanted stent with a bio-compatible polymer is the key factor in reducing ST and may reduce the need for DAPT. In ENDEAVOR OCT trial, mean percentage of neointima covered stent struts at 3 month was 99.9 ± 0.4% compared with 64% prevalence at 6 months in sirolimus eluting stent trial . These newer generation of stents combined with potent P2Y ₁₂ antagonists may provide a safer alternative to the currently recommended dual antiplatelet regimen.

Interestingly, some evidence on the safety of SAPT in post-PCI patients is available from WOEST trial of triple antithrombotic therapy . The WOEST was the first trial to look into the use of clopidogrel without aspirin in the patients taking oral anticoagulants and undergoing PCI. Use of clopidogrel alone resulted in significantly less bleeding complications without an increase in thrombotic events in the patients with stents compared with triple therapy group. Thus, the first propose from WOEST data is that the aspirin use may not be necessary in patients with stents. The target international normalization ratio (INR) in WOEST was 2.0, and perhaps a mean of only 70% of patients were in the therapeutic range at any given time. Thus it can be reasonably presumed that many patients in clopidogrel only arm might have sub-therapeutic INR during the follow-up period of 1 year; still, there was a trend for fewer ST in clopidogrel only group (1.4%) compared with triple-therapy group (3.2%). Thus there may be a rationale for using P2Y ₁₂ antagonists alone without oral anticoagulants, though this hypothesis has not been tested in randomized clinical trials.