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

Matthias K. Freynhofer; Ralph Hein-Rothweiler; Paul M. Haller; Daniel Aradi; Döme A. Dézsi; Lisa Gross; Martin Orban; Dietmar Trenk; Tobias Geisler; Zenon Huczek; Gabor G. Toth-Gayor; Steffen Massberg; Kurt Huber; Dirk Sibbing

doi:10.1055/s-0038-1677549

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2019; 119(04): 660-667
DOI: 10.1055/s-0038-1677549

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

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

Matthias K. Freynhofer^*

¹3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria

²Medical Faculty, Sigmund Freud University, Vienna, Austria

,

Ralph Hein-Rothweiler^*

³Department of Cardiology, LMU München, Munich, Germany

⁴DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

,

Paul M. Haller^*

¹3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria

⁵Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria

,

Daniel Aradi

⁶Balatonfüred State Cardiology Hospital, Balatonfüred, Hungary

,

Döme A. Dézsi

⁶Balatonfüred State Cardiology Hospital, Balatonfüred, Hungary

,

Lisa Gross

³Department of Cardiology, LMU München, Munich, Germany

⁴DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

,

Martin Orban

³Department of Cardiology, LMU München, Munich, Germany

⁴DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

,

Dietmar Trenk

⁷Department of Cardiology and Angiology II, University Heart Centre Freiburg, Bad Krozingen, Germany

,

Tobias Geisler

⁸Department of Cardiology and Cardiovascular Disease, University Hospital Tübingen, Tübingen, Germany

,

Zenon Huczek

⁹1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland

,

Gabor G. Toth-Gayor

¹⁰Department of Cardiology, University Heart Center Graz, Graz, Austria

,

Steffen Massberg

³Department of Cardiology, LMU München, Munich, Germany

⁴DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

,

Kurt Huber^**

¹3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Vienna, Austria

²Medical Faculty, Sigmund Freud University, Vienna, Austria

⁵Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria

,

Dirk Sibbing^**

³Department of Cardiology, LMU München, Munich, Germany

⁴DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

› Author Affiliations

Abstract

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.

Keywords

acute coronary syndrome - prasugrel - clopidogrel - diurnal variability - circadian variability

Full Text

References

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