Author + information
- Bruno Revol, PharmD,
- Ingrid Jullian-Desayes, PharmD, PhD,
- Renaud Tamisier, MD, PhD,
- Vincent Puel, MD,
- Michel Mallaret, MD,
- Marie Joyeux-Faure, PharmD, PhD and
- Jean-Louis Pépin, MD, PhD∗ ()
- ↵∗Laboratoire Explorations fonctionnelles cardiorespiratoires, Thorax and Vessels, Grenoble Alpes University Hospital, CHU Grenoble Alpes, CS 10 217, 38043 Grenoble Cedex 09, France
Ticagrelor is a P2Y12 receptor antagonist used in first-line dual-antiplatelet therapy in coronary artery disease (1). Cheyne-Stokes respiration with central sleep apnea was reported in 4 patients after ticagrelor therapy was initiated and disappeared after ticagrelor withdrawal and switch to clopidogrel in 1 patient (2).
We analyzed reports of sleep apnea and dyspnea among ticagrelor users and compared the use of ticagrelor to the use of other antiplatelet agents by performing a disproportionality analysis in VigiBase, the World Health Organization global Individual Case Safety Reports (ICSRs) database, including >16 million ICSRs collected from 127 countries. Reports included reporters’ information (health professionals or pharmaceutical companies), patient characteristics (age, sex, and medical history), and a clinical description of adverse drug reactions (ADRs) and their seriousness and evolution.
Using VigiBase, we extracted all ICSRs by using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms “sleep apnea syndrome” and “dyspnea” in association with ticagrelor. The relationship between the use of ticagrelor and the occurrence of the ADR (sleep apnea or dyspnea) was assessed by calculating the reporting odds ratio (ROR) associated with their 95% confidence intervals (CI) in a case-noncase study compared to other drugs (3). A ROR value >2 with ≥5 cases was considered significant. Among the 13,636 ADRs reported with ticagrelor therapy, there were 28 cases of sleep apnea and 2,665 cases of dyspnea. In 9 of the 28 cases, sleep apnea and dyspnea were simultaneously reported. ROR values for ticagrelor were significant for sleep apnea (ROR: 4.16; 95% CI: 2.87 to 6.03) and for dyspnea (ROR: 8.26; 95% CI: 7.92 to 8.62), demonstrating a significant disproportionality signal (Figure 1A). This disproportionality was not found for other antiplatelet agents like clopidogrel (ROR: 0.55; 95% CI: 0.33 to 0.93; 14 apnea cases; and ROR: 0.67; 95% CI: 0.63 to 0.71; 988 dyspnea cases); or prasugrel (ROR: 1.08; 95% CI: 0.41 to 2.89; 4 apnea cases; and ROR: 1.12; 95% CI: 0.99 to 1.28; 239 dyspnea cases); or aspirin (ROR: 0.57; 95% CI: 0.41 to 0.80; 35 apnea cases; and ROR: 0.96; 95% CI: 0.92 to 0.99; 3,374 dyspnea cases).
Despite the well-known problem of under-reporting in pharmacovigilance, a significant disproportionality signal was found. Our result must be understood as a safety signal, confirming previous observations of dyspnea (2) and providing new insights regarding sleep apnea. This signal emerged before the case series publications, avoiding a notoriety bias, and a de-duplicated dataset was used to minimize information bias. However, our analysis is exposed to limitations, such as selective reporting. Another issue is the lack of information in VigiBase for appropriate adjustment of potential confounders. A prospective dataset with systematic sleep studies is needed to determine the prevalence of ADR, modulators of occurrence, and severity of ticagrelor-related sleep apnea.
Regarding underlying mechanisms (Figure 1B), ticagrelor may cause sleep apnea as a consequence of antagonism of microglial P2Y12 receptors, as previously hypothesized (2). However, ticagrelor is not known to cross the blood–brain barrier, and we found no impact of clopidogrel or prasugrel on the incidence of sleep apnea, despite the potential for active metabolites of these drugs to also block microglial P2Y12 receptors. The effects of ticagrelor on pulmonary C fibers may be a more likely mechanism for Cheyne-Stokes respiration, either as a consequence of ticagrelor’s inhibition of the type 1 equilibrative nucleoside transporter (ENT1) protein and its effects on tissue adenosine levels or due to the putative P2Y12 receptors on the pulmonary C-fibers (4).
A major concern is that both exaggerated chemosensitivity and central sleep apnea increase sympathetic activity, known to be deleterious in the long-term in patients with cardiac disease (5).
Even if data are under-reported, sleep apnea ADR appeared to be rare in VigiBase. Our results do not challenge the overall demonstrated effect of ticagrelor in reducing cardiovascular events. However, further studies should investigate the exact incidence, the sustainability, and the potential consequences of ticagrelor-induced central sleep apnea.
Please note: This work was supported by the French National Research Agency under the Investissements d’avenir program award ANR-15-IDEX-02. Results and conclusions are those of the authors and not those of the National Centers, Uppsala Monitoring Center, or World Health Organization. The authors have reported that they have no relationships with industry relevant to the contents of this paper to disclose. Drs. Revol and Julian-Desayes contributed equally to this work and are joint first authors. Drs. Joyeux-Faure and Pepin contributed equally to this work and are joint senior authors. The authors thank Alison Foote and Sebastien Bailly (Grenoble Alpes University Hospital, France) for critically editing the manuscript, and Uppsala Monitoring Center, which provided data and permission to use the data analyzed in the present study.
- 2018 American College of Cardiology Foundation
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