title: Dyspnea and reversibility of antiplatelet agents: ticagrelor, elinogrel, cangrelor, and beyond.
abstract: BACKGROUND
  Oral reversible platelet P2Y12 receptor inhibitors (ticagrelor and elinogrel) cause double-digit rates of dyspnea, while irreversible oral antiplatelet drugs (aspirin, ticlopidoine, clopidogrel, and prasugrel) or intravenous glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, or tirofiban) do not increase the incidence of dyspnea in randomized trials. Dyspnea after oral reversible antiplatelet agents remains unexplained. A transfusion-related acute lung injury (TRALI) hypothesis has been proposed. The dyspnea risks after cangrelor, an intravenous reversible antiplatelet agent, are not well defined but may offer a universal mechanism linking TRALI, dyspnea, and reversible platelet inhibition.
  
  
  OBJECTIVE
  We analyzed safety data from recent head-to-head randomized trials with reversible antiplatelet agents (ticagrelor, elinogrel, and cangrelor) compared to irreversible (clopidogrel/placebo) comparators.
  
  
  RESULTS
  All three reversible antiplatelet agents cause excess dyspnea. In contrast to the high double-digit rates after oral ticagrelor or elinogrel, the dyspnea risks after intravenous cangrelor were smaller (<2%) but still consistently and significantly higher than in the corresponding control arms.
  
  
  CONCLUSIONS
  The clinical utility of reversible antiplatelet strategies has been challenged. Despite a potential advantage of fewer bleeding events during heart surgery, reversible antiplatelet agents carry the risk of potential autoimmune reactions manifesting as dyspnea. Repeated binding and unbinding cycles, impaired platelet turnover, and lung sequestration or apoptosis of overloaded destructive platelets are among the potential mechanism(s) responsible for dyspnea after reversible antiplatelet agents.
authors.affiliation: HeartDrug™ Research Laboratories, Johns Hopkins University, Towson, Md., USA.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Serebruany
authors.forename: Dirk
authors.initials: D
authors.lastname: Sibbing
authors.forename: James J
authors.initials: JJ
authors.lastname: DiNicolantonio
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology; D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D000284:Administration, Oral; D000077144:Clopidogrel; D004417:Dyspnea / Q000139:chemically induced*; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D052999:Quinazolinones / Q000008:administration & dosage / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects; D000077486:Ticagrelor; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D065227:Transfusion Reaction
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D052999:Quinazolinones; D013449:Sulfonamides; D000249:Adenosine Monophosphate; C117446:cangrelor; C549473:elinogrel; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine