Why does ticagrelor induce dyspnea?

Marco Cattaneo, MD, Medicina 3, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Via A. di Rudinì 8, 20142 Milano, Italy, Tel.: +39 02 503 23095, Fax: +39 02 503 23089, E-mail: .
Thrombosis and Haemostasis (Impact Factor: 5.76). 10/2012; 108(6). DOI: 10.1160/TH12-08-0547
Source: PubMed

ABSTRACT In studies that compared the reversible P2Y12 inhibitor ticagrelor with the irreversible inhibitor clopidogrel, dyspnea was observed more frequently among ticagrelor-treated patients than among clopidogrel-treated patients. Because dyspnea was not associated with acidosis, pulmonary or cardiac dysfunction, alterations in the mechanisms and pathways of the sensation of dyspnea may be involved in its pathogenesis. It has been hypothesised that the sensation of dyspnea in ticagrelor-treated patients is triggered by adenosine, because ticagrelor inhibits its clearance, thereby increasing its concentration in the circulation. However, dipyridamole, a much stronger inhibitor of adenosine clearance than ticagrelor, usually does not cause dyspnea. We hypothesise that inhibition of P2Y12 on sensory neurons increases the sensation of dyspnea, particularly when reversible inhibitors are used. We base our hypothesis on the following considerations: 1) cangrelor and elinogrel, which, like ticagrelor, are reversible P2Y12 inhibitors, also increase the incidence of dyspnea; 2) it is biologically plausible that inhibition of P2Y12 on sensory neurons increases the sensation of dyspnea; 3) inhibition of P2Y12 on platelets (which do not have a nucleus) by clopidogrel is permanent, despite the once daily administration and the short plasma half-life of the inhibitor; 4) in contrast, inhibition of P2Y12 on neurons by clopidogrel may be temporary and transient, because neurons have a nucleus and can therefore rapidly replace the inhibited receptors with newly synthetised ones; 5) inhibition of P2Y12 on neurons by reversible inhibitors is permanent, because the plasma drug concentration is maintained high by repeated dosing, in order to ensure permanent inhibition of platelet P2Y12.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dual antiplatelet therapy consisting of one of the P2Y12 receptor inhibitors in conjunction with aspirin is the mainstay of treatment for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary interventions (PCI). In recent years, multiple extra-platelet features of P2Y12 receptor antagonists have been reported in numerous clinical trials. The aim of this review is to summarise reported pleiotropic effects of clopidogrel, prasugrel, ticagrelor and other P2Y12 receptor blockers. We included observations made both in human and in animal models, together with proposed mechanisms of action for described features. If confirmed in randomised studies and properly applied to everyday practice, the observed extra-platelet actions could enable us to improve efficacy of ACS and post-PCI treatment, as well as to confine mortality and occurrence rate of cardiovascular events.
    Thrombosis and Haemostasis 04/2014; 112(2). · 5.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Objectives: To perform a systematic up-to-date review and critical discussion on potential clinical applications of cangrelor based on its pharmacologic properties and the main findings from randomized clinical studies. Methods: A database search (PubMed, CENTRAL and Google Scholar) by two independent investigators, including proceedings from scientific sessions of ACC, AHA, ESC, TCT and EuroPCR, from January 1998 through December 2013. Results: Cangrelor is a potent, intravenous, direct-acting P2Y12 antagonist with rapid-onset and quickly reversible action. In contrast to ticagrelor, cangrelor's interaction with thienopiridines requires termination of cangrelor infusion before switching to clopidogrel or prasugrel. According to randomized trials, cangrelor-clopidogrel combination is relatively safe and more effective than standard clopidogrel regimen in both urgent and elective percutaneous coronary intervention (PCI) setting, with the advantage of this drug combination fully evident when the universal definition of myocardial infarction is applied. In contrast to available antiplatelet drugs with delayed onset and offset of action, its favourable properties make cangrelor a desirable agent for ad hoc elective PCI, high risk acute coronary syndromes treated with immediate coronary stenting and for bridging those surgery patients who require periprocedural P2Y12 inhibition. Current evidence on cangrelor therapy is limited by the lack of adequately powered studies assessing cangrelor co-administration either with prasugrel or ticagrelor, suboptimal design of some of the trials favouring cangrelor, potentially attenuated benefits with modern stent design, and finally, by the lack of survival advantage. Conclusions: With its pharmacokinetic and pharmacodynamic advantages, allowing consistent and strong P2Y12 inhibition and with its rapid onset and swift reversal of action devoid of need for an antidote, cangrelor might improve clinical outcomes in clopidogrel-treated patients by reducing ischemic events, while maintaining a favourable safety profile. However, further studies, addressing the safety and efficacy of cangrelor on top of novel oral P2Y12 inhibitors, are warranted.
    Current Medical Research and Opinion 01/2014; · 2.37 Impact Factor
  • Expert Opinion on Pharmacotherapy 01/2013; · 2.86 Impact Factor