Stent thrombosis in a patient with high on-treatment platelet reactivity despite ticagrelor treatment

Abstract

We describe, to the best of our knowledge, the first incidence of stent thrombosis in a patient treated with ticagrelor, who exhibited high on-treatment platelet reactivity (HTPR) according to platelet reactivity testing. He was on clopidrogel and tested for platelet reactivity using the VerifyNow P2Y12 assay. The test showed a PRU of 249 and only 12% platelet inhibition. The patient was then switched to ticagrelor, with a loading dose of 180 mg given. The patient had stent thrombosis three weeks later with an acute myocardial infarction (MI). The patient had good platelet inhibition when started on Ticagrelor treatment (PRU=33), but had HTPR when the stent thrombosis occurred three weeks later (PRU=339).

Introduction

In patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), high on-treatment platelet reactivity (HTPR) while on clopidogrel treatment is associated with adverse cardiovascular events.^1,2 Compared to clopidogrel, the new antiplatelet medications – prasugrel and ticagrelor –have better pharmacodynamic properties, with more effective inhibition of platelet reactivity, and with very low rates of HTPR during maintenance treatment.³ In the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38) and PLATelet inhibition and patient Outcomes (PLATO) trials, these drugs were associated with a reduction in ischemic events, though with increased risk of bleeding.² Both new antiplatelet medications were also associated with a significantly lower rate of stent thrombosis, compared to clopidrogel. We present a patient treated with ticagrelor who experienced stent thrombosis with exhibited HTPR.

Case report

A 72-year-old male with risk factors of diabetes, hypertension and hyperlipidemia was admitted with ST elevation myocardial infarction three weeks after stenting of the left anterior descending (LAD). His ischemic heart disease was firstly diagnosed 15 years ago when, due to stable angina pectoris, he underwent coronary angiography which revealed one vessel disease of the mid LAD. Three bare metal stents were implanted. He was symptom free for almost 15 years. Due to pancreatic cancer, the patient underwent pancreaticoduodenectomy (Whipple procedure) eight months prior and was with no evidence of a residual disease.

Two months earlier, coronary angiography was performed due to stable angina. Two-vessel disease was found: a significant narrowing of 90% in the mid-right coronary artery (RCA) and in the LAD a 75% narrowing in the proximal portion and an 80% in the mid-distal area. The LAD stents were patent with mild irregularities. A drug-eluting stent was deployed in the mid RCA with a good final angiographic result. The patient’s medications at discharge included aspirin, clopidogrel, beta blocker, angiotensin converting enzyme (ACE) inhibitor, calcium channel blocker and a statin.

One month later, the patient was electively admitted for a planned follow-up coronary angiogram and angioplasty to the LAD. He was tested for platelet reactivity using the VerifyNow P2Y12 assay. The test showed a P2Y12 Reaction Units (PRU) of 249 and only 12% platelet inhibition. The patient was then switched to ticagrelor, with a loading dose of 180 mg given two hours before the procedure. The angiogram showed a narrowings in the LAD with a patent stent at the mid-RCA. A Nobori drug eluting stent (Biodegradable polymer biolimus-eluting stent, Terumo, Tokyo, Japan) was deployed in the proximal LAD and balloon inflations were done in the mid-LAD with a good final angiographic result and a TIMI-3 flow. The next day, the VerifyNow P2Y12 assay test showed a PRU of 33 and 88% of platelet inhibition. The patient was discharged home. He took all his medications every day including ticagrelor 90 mg twice daily. For the next several weeks there were no special events.

Three weeks later, he was admitted urgently with an acute anterior ST-elevation myocardial infarction (MI) with cardiogenic shock. Immediately after achieving arterial access, before giving any medication, bloods were drawn for different tests including platelet reactivity. There was an acute occlusion of the proximal LAD due to stent thrombosis. PCI was performed using thrombus aspiration followed by multiple balloon inflations at the proximal and middle LAD. A TIMI-3 flow was achieved in the LAD.

The VerifyNow P2Y12 assay test from blood sample taken at the beginning of the procedure showed a PRU of 339 and 0% of platelet inhibition. The patient was treated during and after the procedure with IIb\IIIa inhibitor. An intra-aortic balloon pump was inserted during the procedure. High dosages of cathecholamines were needed to stabilize the patient in the first hours after admission. A 60 mg Prasugrel loading was given following the PCI. The VerifyNow P2Y12 assay test, performed 72 h following the PCI with treatment with prasugrel 10 mg daily, showed a PRU of 127 and 56% of platelet inhibition.

Discussion

To the best of our knowledge this is the first report of stent thrombosis in a patient treated with ticagrelor, who exhibited HTPR according to platelet reactivity testing. A recent analysis of the PLATO trial showed that treatment with ticagrelor resulted in a lower risk of stent thrombosis when compared with clopidogrel in the setting of ACS.⁴ The benefit of ticagrelor in reducing definite stent thrombosis appeared independent of baseline variables, such as type of ACS, diabetes, geographic region of enrollment, CYP2C19 genotype, prerandomization dose of aspirin and clopidogrel, and stent type (bare metal or drug eluting). Among 11,289 (61% of 18,624 patients hospitalized with ACS in PLATO) who had a previous stent implanted or received one during the trial, definite stent thrombosis occurred in 177 patients (1.6%), and all but one had the event within one year. Definite stent thrombosis occurred in 1.37% (n=71) of patients treated with ticagrelor and 1.93% (n=105) of those treated with clopidogrel, a difference that translated into a 33% lower risk with ticagrelor (hazard ratio (HR) 0.67, 95% confidence interval (CI) (0.50–0.90), p=0.0091). Overall, in the PLATO trial, stent thrombosis rarely occurred in ticagrelor-treated patients, with a rate of 1:400 patients in the first 24 h and in 2:300 (0.66%) in the next 30 days.⁴

In patients with STEMI, prasugrel and ticagrelor provide effective platelet inhibition two hours after the loading dose in only a half of patients, and at least four hours are required to achieve effective platelet inhibition in the majority of patients.⁴ However, during maintenance ticagrelor treatment HTPR is rare – about 5% in the study by Alexopoulos et al.,⁵ and 3.5% in the study by Laine et al.,⁶ the rate of HTPR in the latter study defined as a vasodilator-stimulated phosphoprotein (VASP) index ≥50%.

It is interesting to note that our patient had good platelet inhibition when started on ticagrelor treatment (PRU=33), but had HTPR when the stent thrombosis occurred three weeks later (PRU=339). Several mechanisms can be thought of. It is possible that the acute setting, with the stent thrombosis, was associated with platelet hyper-reactivity, affecting the test result. However, presumably a certain degree of HTPR was present before the acute stent thrombosis event. Ticagrelor is a direct-acting medication and needs no known enzymes in order to work, thus post-absorption etiologies are less likely. Yet, possibly the changes in platelet reactivity during ticagrelor treatment may have been also due to the fact that the patient underwent major abdominal surgery that may have affected drug absorption. The patient brought and showed the ticagrelor empty blister pack. He denied any transient problem leading to a reduced reabsorption of the drug such as gastrointestinal infection or diarrhea.

In conclusion, despite the pharmacodynamic and clinical advantages of ticagrelor over clopidrogel, there are rare cases of HTPR during ticagrelor treatment that may lead to stent thrombosis.

Conflicts of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References