Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial

Abstract

Therapy with aspirin and/or adenosine diphosphate (ADP) receptor blockers is associated with better outcomes via inhibition of platelet activity, and subsequent reduction of ischemic vascular events. Non-compliance (NC) is a well-recognised hazard limiting the clinical utility of antiplatelet agents, and, probably worsening outcomes. However, comprehensive platelet characteristics of a confirmed NC patient after acute vascular event have never been reported within a major randomised trial with ADP-receptor antagonists. A 48-year-old male patient, well-educated, was among patients enrolled in the platelet sub-study for the JUMBO trial. He received 325 mg of aspirin daily for 9 months, presented with unstable angina for urgent coronary intervention, and was successfully reperfused with two intracoronary stents. The patient was randomised to a 60 mg prasugrel loading dose, and 10 mg of prasugrel daily for 30 days. Platelets were assessed at baseline, 4 and 24 h, and at 30 days after acute coronary event utilising ADP-, and collagen-induced conventional aggregometry, rapid cartridge-based analyser and flow cytometry. Loading with prasugrel resulted in significant inhibition of platelet activity during and after stenting. However, after assessing platelet biomarkers at 30 days, voluntary withdrawal from the antiplatelet agents was suspected. Based on the platelet activity characteristics, NC was later confirmed, and the patient admitted that he stopped taking both prasugrel and aspirin shortly after discharge due to minor bleeding episodes after shaving. Major platelet activity biomarkers of the index NC patient were compared with those from compliant prasugrel-, clopidogrel-treated patients, and healthy controls. The platelet tests uniformly revealed rebound activation by all platelet measures (at least twofold increase) while being especially high for ADP-, and collagen-induced aggregation, platelet/endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ib, GPIIb/IIIa activity, P-selectin, protease activated receptor (PAR)-1 thrombin receptor (activated and intact epitopes), and thrombospondin expression. The clinical benefits of antiplatelet agents are not only denied in NC outpatients, but may put them at additional risk for worsened vascular outcomes due to the rebound platelet activation. Proclaimed 'resistance' to antiplatelet agents may at least in part be a result of NC, especially in the chronic uncontrolled setting. Enforcing compliance will improve outcomes in the clinical trials, and save lives of patients really receiving antiplatelet therapy.

Impact of CYP2C19 Polymorphism on Antiplatelet Potency of Prasugrel 5 and 10 mg Daily Maintenance

“…These pharmacogenetic findings were in contrast to observations with clopidogrel, which might partly explain different pharmacological and clinical responses to these medications [23]. Many studies showed that CYP genetic variants had a significant influence on the pharmacokinetic and pharmacodynamic responses to clopidogrel, causing diminished antiplatelet response [24]. However, prasugrel is believed to be less affected by genotypic variability [25][26][27].…”

Adverse Events After Stopping Clopidogrel in Post–Acute Coronary Syndrome Patients

“…[1][2][3] Among patients taking clopidogrel and aspirin for 1 year after drug-eluting stent placement, there were significant increases in proinflammatory and prothrombotic markers after clopidogrel cessation. 1 This may be due to increased production of reticulated platelets, which have a higher thrombotic potential.…”

The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis

“…73 This patient was reported to have had at least a twofold increase in all platelet measures, with platelet activation biomarkers being higher than those observed at presentation of acute vascular event, suggesting a rebound effect in this patient. [97][98][99] ).…”

“…When the criteria were broadened to include patients with PCI, stroke, PAD and STEMI, most of the retrieved data were for patients who had undergone PCI. Of these: five RCTs, 50-54 two observational cohorts, 38,55 nine case series, 56-64 and 33 case reports across 17 publications [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] investigated clopidogrel and ticlopidine therapy. Only two case series 82,83 and two case reports in a single publication 84 were identified for patients who had not undergone PCI.…”

“…This rise in PCI use over 16 years is demonstrated in Figure 1, constructed from data from the British Cardiac Intervention Society (BCIS) audit reports. 101 According to the BCIS audit reports, 73 101 It is likely that many of the higherrisk patients included in the CURE trial would now undergo an early PCI rather than prolonged medical management or a late PCI procedure. Given this, it seems appropriate to determine the effectiveness of clopidogrel treatment in patients at intermediate risk of ACS, rather than in the entire ACS population.…”