Ticagrelor-related dyspnea: An underestimated and poorly managed event?

Dear Editor, We read with great interest the paper ‘Effect of ticagrelor-related dyspnea on compliance with therapy in acute coronary syndrome patients’ by Gaubert et al. [1], a multicenter observational prospective study aimed at investigating the impact of dyspnea on ticagrelor discontinuation during the first month following percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). Discontinuation was defined by the authors as ticagrelor cessation following medical contact. This study is probably the first to investigate the rate of ticagrelor-related dyspnea and its impact on drug use. The authors observed that the rate of drug withdrawal was high in real world ACS patients and could therefore have a significant clinical impact. According to the study, ticagrelor was withdrawn in 16.7% of patients (n = 164) during the first month following PCI for an ACS and the main reason for discontinuation was drug-related dyspnea (55.6%). The authors conclude that improving the education of patients and physicians is warranted to reduce the rate of ticagrelor discontinuation. In addition, they assert that in most cases ticagrelor-related dyspnea was mild and sustained ticagrelor prescription for one year was shown to significantly reduce cardiovascular events in ACS patients compared to other antiplatelet agents. While on the one hand we agree with the authors about the possibility of improving the management of ticagrelor-related dyspnea by educating both patients and prescribers, on the other hand we believe that the ticagrelor-related dyspnea is not always an event as “mild” as authors affirmed, especially in the case of frail population such as ACS patients. Furthermore, the choice and duration of antiplatelet therapy for secondary prevention of coronary artery disease (CAD) should be determined by the clinical framework and treatment strategy [2]. In this context, we suggest that continuing ticagrelor treatment should not be justified only by his best efficacy profile in the reduction of one-year cardiovascular events compared with other antiplatelet drugs [3], since in ACS patients the continuation of ticagrelor treatment in the presence of dyspnea might have a negative clinical impact on patient's general conditions and quality of life. This is also suggested by the paper recently published in your journal “First report of stent thrombosis after a switch therapy resulting from ticagrelor-related dyspnea” by Wu H. et al. [4], an interesting case report in which dyspnea contributed to the ticagrelor discontinuation. In their conclusion the authors suggest that ticagrelor should be discontinued in certain clinical situations and the management of switching therapy should be well-conducted to confer ischemic protection. During our activities of intensive pharmacovigilance monitoring in emergency departments (ED) in Florence (Italy) we encountered a case (the first described, at the best of our knowledge) of severe paroxysmal nocturnal dyspnea developed in a post-stenting ACS elderly 90-year-old man associated to the first use of ticagrelor (90 mg/die plus acetylsalicylic acid 100 mg/die). The event caused an ED admission and several days of hospitalization at the cardiologic intensive care unit (ICU). During hospitalization all cardio-respiratory and metabolic causes of dyspnea were excluded and ticagrelor treatment was discontinued only after that a pulmonologist consultant recommended the replacement of ticagrelor with clopidogrel, maintaining acetylsalicylic acid assumption. Drug discontinuation has led to a reduction in the frequency of nocturnal dyspnea episodes, with a gradual improvement of patient's general condition. Dyspnea is a relative frequent adverse event observed during ticagrelor therapy [3]. It has been hypothesized that the sensation of dyspnea in ticagrelor-treated patients is triggered by adenosine, because ticagrelor inhibits its clearance, thereby increasing its concentration in the circulation [5]. Since pulmonary, cardiac and metabolic diseases that are associated with dyspnea may be common among patients with ACS, it is critical to identify those cases of dyspnea that are not attributable to these conditions [6]. It is our opinion that to date both ED physicians and cardiologists are not yet sufficiently aware of the recognition and management of this adverse drug reaction (ADR). Herein we would like to emphasize the possibility of a real world underestimation and mismanagement of ticagrelor-related dyspnea also caused by the difficulty to fully ascertain its causality assessment, especially in ACS elderly patients treated with several drugs. We believe that physicians should consider this potential association in daily clinical practice to reduce time of diagnosis especially when this event occurs early after ticagrelor administration. In conclusion, in order to better manage ACS patients who present at ED with respiratory distress and no other cardio-respiratory and metabolic conditions, it is necessary for prescribing healthcare professionals to consider ticagrelor replacement in order to maintain in this group of patients (1) antiplatelet therapy compliance and (2) a high quality of life without compromising their cardiovascular safety. Since the clinical impact of dyspnea resulting from ticagrelor is an unresolved issue [4], we believe that additional studies are needed to identify the optimal strategy to manage ticagrelor-related dyspnea and its possible consequent replacement therapy.