Diurnal Variability of On-Treatment Platelet Reactivity in Clopidogrel versus Prasugrel Treated Acute Coronary Syndrome Patients: A Pre-Specified TROPICAL-ACS Sub-Study.

Long-term evidence supports a clustering of cardiovascular events in the early morning and smaller mechanistic studies in aspirin-treated patients have shown increased platelet reactivity at the end of the dosing interval. Comparative pharmacodynamic analyses for different adenosine diphosphate (ADP) receptor inhibitors in percutaneous coronary intervention-treated acute coronary syndrome (ACS) patients are lacking and this pre-specified analysis from the randomized Testing Responsiveness To Platelet Inhibition On Chronic Antiplatelet Treatment For Acute Coronary Syndromes (TROPICAL-ACS) trial aimed for the first time at investigating diurnal variability of on-treatment platelet reactivity in clopidogrel versus prasugrel treated patients. TROPICAL-ACS randomized 2,610 ACS patients to either treatment with prasugrel (control group) or to a platelet function testing-guided de-escalation of anti-platelet treatment with a switch to clopidogrel (guided de-escalation group). This study design enabled a diurnal comparison of on-prasugrel versus on-clopidogrel treatment platelet reactivity under steady-state conditions. For 2,526 patients (97%), both the exact time of blood sampling and the ADP-induced platelet aggregation value (in units, Multiplate analyser) were available. Platelet reactivity in patients on clopidogrel (n = 1,265) was higher and subject to significant diurnal variability (p = 0.019) with a peaking of platelet reactivity in the early morning (5-10 a.m.). In prasugrel-treated patients (n = 1,261), there was no sign for diurnal variability (p = 0.174) or a peaking of platelet reactivity in the morning. The potent ADP receptor inhibitor prasugrel is not subject to diurnal variability while we observed a significant diurnal variability of on-clopidogrel platelet reactivity. The clinical impact of this observation may differ for patients with and without an adequate response to clopidogrel treatment and the issue of diurnal variability of platelet reactivity in ACS patients warrants further investigation.

Prolonging Ticagrelor Beyond a Year of Acute Coronary Syndrome: Worth or Harmful?

Platelet activation plays a central role in triggering and complicating acute coronary syndromes, especially in case of stent thrombosis and myocardial infarction. On top of aspirin, P2Y12- inhibitors are successfully used to treat and prevent these events for a duration of one year after an acute coronary episode or 6 months after drug-eluting stent implantation. However, patients with acute coronary syndromes remain at heightened risk for recurrent ischemic events after the recommended durations of P2Y12-inhibitors and therefore, prolonging treatment is often considered in clinical practice. However, the higher risk for bleeding limits the utility of such approach to a restricted group who is still poorly defined by available measures. This review aims to discuss potential benefits and highlight important pitfalls of prolonged treatment with P2Y12-inhibitors, with a focus on ticagrelor, an attractive reversible P2Y12-inhibitor in patients after myocardial infarction.

Impact of Test Conditions on ADP-Induced Platelet Function Results With the Multiplate Assay: Is Further Standardization Required?

BACKGROUND: Platelet function testing was suggested to help tailor P2Y12-inhibitor therapy; however, the lack of proper standardization is still a limitation. METHODS: In a prospective study, we enrolled clopidogrel-treated and P2Y12-inhibitor naive patients to investigate the influence of (1) time from blood collection, (2) stability of the stored Adenosine diphosphate (ADP) reagent, and (3) the use of enoxaparin on results of the Multiplate assay. Measurements were performed from samples kept for 0, 30, 60, 120, and 240 minutes at room temperature before processing. To determine the impact of the reagent stability, freshly thawed ADP was compared with ADP kept for 3 to 5 or 8 to 13 days at 2°C to 8°C. Finally, samples containing enoxaparin at therapeutic or prophylactic doses were compared with enoxaparin-free blood. RESULTS: A total of 180 measurements were performed. ADP-stimulated platelet reactivity values decreased significantly over time (67 ± 40 U to 68 ± 37 U to 58 ± 37 U to 45 ± 33 U to 35 ± 33 U; P < .0001). Consequently, a dramatic reduction was observed in the proportion of patients with high platelet reactivity ( P < .0001). A significant drop in platelet reactivity was observed with ADP stored for 8 to 13 days as compared to freshly thawed ADP ( P = .011). Enoxaparin triggered a slight, concentration-dependent increase in platelet reactivity ( P < .05). CONCLUSION: Test conditions may have profound impacts on the obtained results with the Multiplate assay. Our findings highlight the large influence of the time from sample collection until testing, suggesting that measurements should be performed within an hour of blood collection.

Antithrombotic treatment in anticoagulated atrial fibrillation patients undergoing percutaneous coronary intervention.

Coronary artery disease coexists in a clinically relevant number of patients with atrial fibrillation and it often requires percutaneous coronary intervention. These patients represent a particular challenge for clinicians in terms of antithrombotic management. They require combined antiplatelet-anticoagulant therapy to reduce the risk of recurrent ischemic cardiac events and stroke; however, this antithrombotic strategy is associated with an increased risk of bleeding complications. In the absence of randomized, controlled clinical trials, the majority of current recommendations rely on the results of cohort studies, meta-analyses, post-hoc analyses and subgroup analyses of large, phase III studies. Based on the available evidence, the present review discusses the optimal antithrombotic strategy for patients receiving chronic anticoagulant therapy due to atrial fibrillation who require antiplatelet treatment after acute coronary syndrome and/or percutaneous coronary intervention, and discusses the issue of dental procedures. The correct planning of therapy significantly reduces the risk of bleeding complications and thromboembolic events. KEY MESSAGES: In order to reduce the occurrence of recurrent cardiac ischemic events and stroke, anticoagulated patients with acute coronary syndrome and/or percutaneous coronary intervention require a combination of therapies including anticoagulants and antiplatelet drugs. Using the newest optimal combination of therapeutic strategies reduces the risk of haemorrhagic complications.

Eptifibatide-induced thrombocytopenia leading to acute stent thrombosis.

A 71-year old female patient with inferior ST-elevation myocardial infarction underwent primary percutaneous coronary intervention (PCI) within 3 h of symptom onset. She was preloaded with 300 mg aspirin and 600 mg clopidogrel before PCI. Coronary angiogram showed occlusion of the right coronary artery. During PCI, eptifibatide was initiated due to the large thrombus burden. Few hours after the procedure, on eptifibatide infusion, a severe drop in platelet count was observed (from 210,000/µl to 35,000/µl) and the infusion was discontinued. One hour later, still under eptifibatide effect and with severe thrombocytopenia, acute stent thrombosis developed. Lack of prior heparin exposure, quick onset of thrombocytopenia made heparin induced thrombocytopenia improbable that was later excluded by specific immunoassay. However, platelet function testing suggested that eptifibatide induced thrombocytopenia was mediated by activating autoantibodies since platelet reactivity was paradoxically very high at the time of stent thrombosis but decreased radically with eptifibatide washout. The patient was successfully managed without further complications on the basis of platelet function data obtained in the subsequent days. This rare subtype of thrombocytopenia highlights that not only platelet count but also platelet function should be closely monitored in case of severe thrombocytopenia to better balance bleeding and thrombosis.