Ticagrelor and central sleep apnea: analysis of VigiBase, the WHO pharmacovigilance database

Background: Ticagrelor is a P2Y12-receptor antagonist frequently used for dual antiplatelet therapy in coronary artery disease. Cheyne–Stokes respiration with central sleep apnea has been previously reported in 4 patients following ticagrelor introduction. Objective: To analyze in VigiBase, the reported cases of sleep apnea syndrome (SAS) among ticagrelor users compared to other antiplatelet agents. Methods: All cases of SAS and dyspnea associated to ticagrelor were extracted from VigiBase. A disproportionality analysis was performed by calculating the reporting odds ratio (ROR) in a case-noncase study to confirm the relationship between the use of ticagrelor and SAS or dyspnea compared to other drugs. A ROR>2 with a number of cases ≥5 is considered significant. Results: 28 cases of SAS and 2 665 of dyspnea were reported with ticagrelor. The RORs for ticagrelor were significant for SAS (ROR [95%CI] = 4.16 [2.87-6.03]) and for dyspnea (8.26 [7.92-8.62]). This relationship was not found for the other antiplatelet agents: clopidogrel, prasugrel or aspirin. Conclusion: The P2Y12 receptor is expressed in the central nervous system including in the respiratory centers. Ticagrelor by P2Y12 antagonism induces respiratory drive deregulations that might explain the occurrence of dyspnea and SAS. Further studies should investigate the exact incidence, the sustainability and consequences of ticagrelor-induced central sleep apnea.