Dyspnoea after AZD6140: safety first?

Husted et al.1 published dose-finding Phase 2 randomized study comparing novel oral reversible platelet P2Y12 antagonist, AZD6140, with conventional clopidogrel on top of low-dose aspirin. The authors should be acknowledged for the thoughtful design, detailed analysis, well-balanced opinions, and perfect timing for such work to appear. Indeed, the era of expanding antiplatelet regimens and indications may require new agents as the substitutes or additions to the available strategies. However, the alarming frequency of dyspnoea reported in the paper1 (Table 5) was not mentioned in the abstract or tried to be explained in the discussion. In fact, at least 10% for the lower doses and up to 20% of patients treated with the highest dose of AZD6140 experienced dyspnoea. The association between treatment with antithrombotic agents and dyspnoea is not new. Few anecdotal observations suggested that aspirin,2 hirudin,3 or eptifibatide4 might cause dyspnoea, although such side effects are extremely rare. It seems that the immune conflict between the hostile platelet receptors subjected to the reversible blockade by the antiplatelet agent(s) may lead to the mild episodes of thrombotic thrombocytopenic purpura and consequent fluid retention contributing to dyspnoea. Being the first ever oral cyclopentyltriazolopirimidine to be tested in the clinical trials as an antiplatelet agent, and especially because of its reversible nature, AZD6140 may appear to be safe for the intact platelets in the pre-clinical studies, but hurt already activated platelets during the unbinding from the cell surface in patients with vascular disease, as was previously documented for the oral platelet glycoprotein IIb/IIIa inhibitors.5 Lack of dyspnoea episodes after clopidogrel or prasugrel, which are irreversible P2Y12 receptor inhibitors also indirectly supports this hypothesis. Additional pulmonary function tests, immunological and platelet receptor studies are needed to determine the cause of dyspnoea after AZD6140 and to figure out how such serious adverse reaction can be prevented or at least minimized. Last but not least is the fact that clopidogrel replaced ticlopidine based not on the superior efficacy, or more potent platelet inhibition, but because of the better safety profile. In conclusion, although the initial clinical results with AZD6140 are promising, the unusually high incidence of dyspnoea is not an artefact. Such serious adverse reaction requires straightforward acknowledgement, much better understanding, and possible prevention plan, especially in the chronic long-term setting.