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Letters to the Editor

Effect of ticagrelor-related dyspnea on compliance with therapy in acute coronary syndrome patients☆ Melanie Gaubert a, Marc Laine a, Toesca Richard b, Nathalie Fournier b, Christophe Gramond c, Jacques Bessereau b, Zaïr Mokrani d, Bruno Bultez e, Virginie Chelini f, Pierre Barnay g, Luc Maillard h, Franck Paganelli a, Laurent Bonello a,⁎ a

Département de Cardiologie Centre Hospitalo-Universitaire Nord, Aix-Marseille Univ., Marseille, France Pole RUSH, Assistance-Publique Hôpitaux de Marseille, Marseille, France c Service d'Urgences, Hôpital d'Instruction des Armées Robert Picque, Bordeaux, France d Service d'Urgences, Hôpital de Salon-de-Provence, Salon de Provence, France e Service d'Urgences, Hôpital de Sisteron, Sisteron, France f Service de Cardiologie, Hôpital de Martigues, Martigues, France g Service de Cardiologie, Hôpital d'Avignon, Avignon, France h Service de Cardiologie, Clinique Axium, Aix-en-Provence, France b

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Article history: Received 20 January 2014 Accepted 13 February 2014 Available online 22 February 2014 Keywords: Acute coronary syndrome Ticagrelor Side effects Compliance Dyspnea

Dual anti-platelet therapy is critical in preventing recurrent ischemic events in acute coronary syndrome (ACS) to prevent early stent thrombosis after percutaneous coronary intervention (PCI) [1,2]. Ticagrelor is a new P2Y12-receptor antagonist which overcomes most of the limitations of clopidogrel with a faster onset of action and a more intense and consistent platelet reactivity (PR) inhibition [3]. Accordingly, in the PLATO trial, ticagrelor was superior to clopidogrel in decreasing major adverse cardiac events (MACE) in the setting of ACS. In the PLATO trial, ticagrelor, which is issued from a new class of drug, was associated with a significantly higher incidence of dyspnea compared to clopidogrel. This original side effect may have contributed to the higher drug discontinuation rate observed in the ticagrelor group [3]. The impact of ticagrelor-related dyspnea on discontinuation and compliance in real world ACS patients has never been studied despite its potential impact on outcome. We therefore aimed to investigate in ACS patients undergoing PCI the impact of dyspnea on ticagrelor discontinuation and compliance during the first month following PCI. We performed a multicenter observational prospective study between February and August 2013. All consecutive patients admitted for ST-segment elevation myocardial infarction (STEMI) or an intermediate or high-risk non-ST segment elevation ACS and treated with a 180 mg ticagrelor (AstraZeneca, Wilmington, USA) loading dose were included. The protocol was approved by the local ethics committee and was in accordance with the Declaration of Helsinki as reflected in a priori approval by the institution's human research committee. Compliance with ticagrelor therapy was recorded during the one month follow-up. In addition, we collected all ischemic and bleeding events. Ischemic events included cardiovascular death, myocardial infarction, and urgent revascularization. Bleeding events were ☆ This work was supported by the Assistance Publique-Hopitaux de Marseille. ⁎ Corresponding author at: Hopital Universitaire Nord, Chemin des Bourrely, 13015 Marseille, France. Tel.: + 33 491968858; fax: +33 491968979. E-mail address: [email protected] (L. Bonello).

classified according to the BARC classification and nuisance bleeding was also captured. Discontinuation was defined as ticagrelor cessation following medical contact and non-compliance was defined as ticagrelor cessation related to patient's decision without medical contact. The present study included 164 patients. Most patients were males (75%) with a mean age of 61 ± 10 years. Clinical presentations were STEMI in 31.1%, NSTEMI in 48.4% and unstable angina in 20.5% of cases. During the one-month follow-up, 37 patients (22.6%) complained of dyspnea. Overall ticagrelor was withdrawn in 27 patients (16.7%). The reasons for ticagrelor withdrawal were dyspnea in 15 patients (55.6%), minor bleeding in 3 patients (11.1%), and renal failure requiring dialysis in 1 patient (3.7%) (Fig. 1). In 6 patients (22.2%) ticagrelor was stopped despite the lack of side effect. Ticagrelor was discontinued following medical contact in 26 patients (96.3%). Only one patient (3.7%) stopped ticagrelor without medical advice (non-compliance). In the vast majority of patients the physician decided to switch from ticagrelor to clopidogrel (81.6%). However 3 patients were left on aspirin alone (Fig. 2). The rate of MACE at one month was 4.2% which includes: 1 cardiovascular death, 1 NSTEMI and 5 unstable angina. Minor bleeding was observed in 3 patients (1.8%). Seven patients (4.2%) were emergently readmitted in the hospital during follow-up because of dyspnea. Among them, 3 (1.8%) had ticagrelor-related dyspnea. In the present study ticagrelor was withdrawn in 16.7% of patients during the first month following PCI for an ACS. The main reason for discontinuation was drug-related dyspnea (55.6%). The rate of bleeding including nuisance bleeds was low (1.8%) and was only the third reason for ticagrelor withdrawal (11.1%). The present study is the first to investigate the rate of ticagrelor-related dyspnea and its impact on drug use during the first month following PCI. We observed that the rate of drug withdrawal was high in real world ACS patients and could therefore have a clinical impact. In the present study, drug-related dyspnea was the main reason for ticagrelor withdrawal (55.6%). The mechanism of dyspnea related to ticagrelor remains undetermined and several hypotheses are being explored. Ticagrelor was not responsible for alteration in neither pulmonary nor cardiac function and drug-related dyspnea was not associated with an altered prognosis [4,5]. First, recent studies suggested an increase in adenosine level in patients receiving ticagrelor compared to those receiving clopidogrel [6]. Second, the expression of the P2Y12-receptor on sensory neurons could be responsible for dyspnea, particularly with reversible inhibitors such as ticagrelor [7]. Finally, the authors have postulated that dyspnea could be related to the reversible nature of ticagrelor binding on the receptor which could result in a syndrome similar to the “transfusionrelated acute lung injury” syndrome which is observed during transfusion [8]. In the present study although 22.6% of patients suffered from dyspnea, ticagrelor was responsible in only 16.7% of

Letters to the Editor

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Fig. 1. Reasons for ticagrelor withdrawal.

patients. In addition, drug-related dyspnea was responsible for emergent re-hospitalizations in 2% of the studied population. The second reason for ticagrelor withdrawal was physician preference for clopidogrel in 3.6% of patients. Such behavior may have various reasons. However, although it was not studied in the present study, in most cases it may be related to the lack of education on the benefit of ticagrelor over clopidogrel and the optimal duration

benefit of ticagrelor was obtained after the first month post-ACS in the PLATO trial. It may therefore be hypothesized that such switch from ticagrelor to clopidogrel could be associated with an altered long-term outcome in these patients. It has been well demonstrated that noncompliance with antiplatelet therapy within the first year post-ACS significantly increases the risk of major adverse cardiac events, cardiovascular death and stent thrombosis [10]. However, in the present study non-compliance was observed in only one patient in relation to dyspnea (0.7%). Improved education of patients and physician is warranted to reduce the rate of drug withdrawal. In fact in most cases ticagrelorrelated dyspnea was mild and sustained ticagrelor prescription for one year was shown to significantly reduce MACE in ACS patients compared to clopidogrel [4]. We would like to thank Olafa Helaf for data management.

References

Fig. 2. Antiplatelet therapy at one month.

of dual antiplatelet therapy after an ACS. Interestingly in the PARIS trial discontinuation of antiplatelet agent following medical contact was not associated with an increased risk of MACE [9]. In the present study most patients (81.6%) who had ticagrelor stopped were switched to clopidogrel and therefore kept on dual antiplatelet therapy. However the clinical consequences of a switch to clopidogrel have not been studied to date. It must be underlined that most of the

0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2014.02.028

[1] Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502. [2] Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33. [3] Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. [4] Storey RF, Becker RC, Harrington RA, et al. Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] pulmonary function substudy). Am J Cardiol 2011;108:1542–6. [5] Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J 2011;32:2945–53. [6] Bonello L, Laine M, Kipson N, et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 2014;63(9):872–7. [7] Cattaneo M, Faioni EM. Why does ticagrelor induce dyspnea? Thromb Haemost 2012;108:1031–6. [8] Serebruany VL. Viewpoint: reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and elinogrel. Thromb Haemost 2012;108:1024–7. [9] Mehran R, Baber U, Steg PG, et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013;382:1714–22. [10] Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–30.

Effect of ticagrelor-related dyspnea on compliance with therapy in acute coronary syndrome patients.

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