Dyspnoea after antiplatelet agents: the AZD6140 controversy

Abstract

Recent randomised studies suggest that experimental oral reversible platelet P2Y12 receptor inhibitor, AZD6140, causes dyspnoea. This also raises similar concerns about the parent compound, and another adenosine triphosphate (ATP) analogue (AR-69931MX or cangrelor), which is currently in Phase 3 trial in patients undergoing coronary interventions. We analysed package inserts, and available clinical trials safety data for antiplatelet agents with regard to the incidence of dyspnoea. We found that dyspnoea is a very rare complication of the presently approved platelet inhibitors, mostly caused by underlying disease, rather than antiplatelet therapy per se. The main reasons for respiratory distress after oral (AZD6140), and intravenous (cangrelor) agents may be the development of mild asymptomatic thrombotic thrombocytopenic purpura, fluid retention and dyspnoea because of the reversible nature of these drugs. Also, these agents are ATP analogues, which rapidly metabolise to adenosine, a well-known bronchoprovocator causing dyspnoea as well. In summary, dyspnoea is seldom considered, there are no treatment algorithms when it does occur, plausible mechanisms exist and despite these plausible mechanisms, the true cause of dyspnoea in these exposed individuals is unknown. Additional pulmonary function testing, immunological investigations and platelet receptor studies are urgently needed to determine the cause of dyspnoea after AZD6140, and to point out how such serious adverse reactions can be prevented, or at least minimised, raising potential concerns about this drug.

Why does ticagrelor induce dyspnea?

“…We are aware that we are purporting a hypothesis that is difficult to test for at least two reasons: i) the definition of the precise physical stimulus that causes dyspnea is problematic (32); ii) dyspnea is a sensation that can only be properly assessed in collaborating human beings (16) (these difficulties likely explain why previous pathogenic hypotheses that have been published [33] have not been successfully tested yet). Due to these difficulties, and considering that C fibers can react to various stimuli, which may be thermal, mechanical or chemical in nature (34), we are planning to test our hypothesis in preliminary experiments, in which the effects of different P2Y 12 inhibiting drugs on surrogate end-points, such as thermal and tactile sensations, will be measured.…”

New P2Y 12 Inhibitors

“…The pathogenesis of dyspnea during ticagrelor treatment is unclear, although it has been hypothesized that it may be mediated by adenosine. 42 A substudy of DISPERSE-2 showed that ticagrelor inhibited platelet aggregation in a dose-dependent fashion and that both doses achieved greater levels of inhibition than clopidogrel. 43 In addition, ticagrelor produced further suppression of platelet aggregation in patients who were currently receiving clopidogrel.…”

Dyspnea and Reversibility of Antiplatelet Agents: Ticagrelor, Elinogrel, Cangrelor, and Beyond

“…In the USA, dyspnea is not only considered a serious adverse event but it also represents a heavy economic burden, with an average cost of USD 6,958 per single outpatient visit [2]. Historically, dyspnea did not appear to represent a safety concern for any of the antiplatelet agents [3], until the introduction of ticagrelor in 2011. Few anecdotal observations suggested that aspirin [4], hirudin [5], or eptifibatide [6] may be associated with dyspnea.…”