Edoxaban therapy in non-valvular atrial fibrillation patients: Paradoxical effect on mean platelet volume

Öz

Introduction: New generation oral anticoagulants (NOACs), which selectively and reversibly block the activity of clotting factor Xa, are now preferred as first-line therapy for preventing ischemic stroke in the treatment of atrial fibrillation (AF). Edoxaban, one of these NOACs, has been shown to be as effective as warfarin in preventing stroke or systemic embolism, while carrying a lower risk of bleeding and cardiovascular death. Mean platelet volume (MPV), as an indicator of platelet activity, is associated with an increased risk of ischemic stroke in patients with AF. Therefore, medical therapies that reduce MPV may play an important role in preventing unwanted ischemic events. Objective: The aim of this study is to determine whether edoxaban has an effect on platelet volume and other platelet indices, in addition to its protective anticoagulant effect against ischemic stroke. Materials and Methods: The study was designed as a retrospective cross-sectional study. Two hundred non-valvular AF patients without a history of oral anticoagulant use were included in the study. Complete blood count (CBC) and basic biochemical parameters (urea, creatinine, electrolytes, etc.) were recorded from the hospital registration system before edoxaban treatment was started, along with basic demographic data. The CBCs of the patients were reevaluated an average of 6 months (184 ± 9 days) after edoxaban treatment initiation, and platelet indices after edoxaban treatment were compared. Results were presented as mean ± standard deviation and percentage. Data were compared using Student's t-test and Wilcoxon test, and p<0.05 was considered statistically significant. Results: The mean age of the patients was 74±9 years. The majority of the patients in the study were female (52.5%). A significant increase in MPV value was observed after treatment [10.0 fL (6.0-13.8) vs. 10.2 fL (7.1-14.9), p=0.023], considering the change in MPV values of the patients. This increase in MPV was not observed in the group using 30mg/day edoxaban (p=0.333), while a significant increase was observed in the group using 60mg/day (p=0.041). In addition, no gender-related change was observed in MPV. No significant changes were observed in platelet count (PLT) (p=0.863), platelet distribution width (PDW) (p=0.085), or plateletcrit (PCT) (p=0.127) values during the six-month period of edoxaban use. Conclusion: The observed increase in mean platelet volume suggests that edoxaban may have unknown pleiotropic effects on platelet indices, and further studies are needed to determine whether this increase in MPV has any clinical significance.

Anahtar Kelimeler

• edoxaban
• mean platelet volume
• atrial fibrillation

Non-valvüler atriyal fibrilasyon hastalarında edoksaban tedavisi: Ortalama trombosit hacmi üzerinde paradoksal etki

Öz

Araştırmanın konusu: Atriyal fibrilasyon (AF) tedavisinde iskemik inmenin önlenmesi için artık yeni nesil oral antikoagülanlar (NOAK'lar) birinci basamak tedavi olarak tercih edilmektedir. Seçici ve geri dönüşümlü olarak pıhtılaşma faktörü Xa'nın aktivitesini bloke eden yeni nesil oral antikoagülanlardan biri olan edoxabanın, felç veya sistemik embolizmi önlemede varfarin kadar etkili olduğu, kanama ve kardiyovasküler nedenlerden ölüm oranları açısından daha düşük risk taşıdığı gösterilmiştir. Ortalama trombosit hacmi (OTH), trombosit aktivitesinin bir göstergesi olarak, AF'li hastalarda artmış iskemik inme riski ile ilişkilidir. Bu nedenle OTH'yi düşüren medikal tedaviler, iskemik istenmeyen olayları önlemede önemli bir rol oynuyor olabilir. Amaç: Bu çalışmanın amacı, edoksabanın iskemik inmeye karşı koruyucu antikoagülan etkisinin yanı sıra trombosit hacmi ve diğer platelet indeksleri üzerine etkisinin olup olmadığını belirlemektir. Gereç ve Yöntem: Çalışma retrospektif kesitsel çalışma olarak tasarlandı. Çalışmaya daha önce oral antikoagülan ilaç kullanım öyküsü olmayan 200 non-valvüler AF hastası dahil edildi. Hastane kayıt sisteminden edoksaban tedavisi başlanmadan önce çalışılan tam kan sayımı (TKS) ve temel biyokimya parametreleri (üre, kreatinin, kan elektrolitleri vb.) ile temel demografik veriler kayıt altına alındı. Hastaların ortalama 6 ay (184 ± 9 gün) sonra tekrarlanan TKS'leri incelenerek edoksaban tedavisi ve sonrası platelet indeksleri karşılaştırıldı. Bulgular ortalama ± standart sapma ve % oranıyla gösterildi. Veriler Student's t testi ve Wilcoxon testleri kullanılarak karşılaştırıldı. p<0.05 istatistiksel olarak anlamlı kabul edildi. Bulgular: Hastaların ortalama yaşı 74±9 yıldı. Çalışmaya katılan hastalarımızın çoğunluğu kadınlardan oluşmaktaydı (%52,5). Hastaların OTH değerlerindeki değişimi göz önünde bulundurarak, tedavi sonrası OTH değerinde anlamlı artış gözlendi [10,0 fL (6,0-13,8) vs. 10,2 fL (7,1-14,9), p=0,023]. OTH'de görülen bu artış 30mg/gün edoksaban kullanan grupta görülmezken (p=0,333), 60mg/gün kullanan grupta anlamlı artış izlendi (p=0.041). Ek olarak, OTH'de cinsiyetle ilgili bir değişiklik gözlenmedi. Edoxaban kullanımının altı aylık sürecinde kan trombosit sayısı (PLT) (p=0,863), trombosit dağılım genişliği (PDW) (p=0,085) veya trombokrit (PCT) (p=0,127) değerlerinde anlamlı değişiklikler gözlenmedİ. Sonuç: Ortalama trombosit hacminde saptanan bu artış, edoksabanın trombosit indeksleri üzerinde bilinmeyen pleiotropik etkilere sahip olabileceğini ve OTH'deki bu artışın herhangi bir klinik sonucu olup olmadığını belirlemek için ileri çalışmaların gerektiğini düşündürmektedir.

Anahtar Kelimeler

• edoksaban
• atriyal fibrilasyon
• ortalama trombosit hacmi

Kaynakça

1. 1. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine. 2011;365(10):883-91.
2. 2. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New England journal of medicine. 2009;361(12):1139-51.
3. 3. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2011;365(11):981-92.
4. 4. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. The Lancet. 2014;383(9921):955-62.
5. 5. Furie KL, Goldstein LB, Albers GW, Khatri P, Neyens R, Turakhia MP, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: a science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(12):3442-53.
6. 6. Wen M-S, Lee MTM. Warfarin pharmacogenetics: new life for an old drug. Acta Cardiologica Sinica. 2013;29(3):235.
7. 7. Larsen TB, Skjøth F, Nielsen PB, Kjældgaard JN, Lip GY. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. bmj. 2016;353.
8. 8. Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 2003;23(12):2131-7.

9. 9. Park Y, Schoene N, Harris W. Mean platelet volume as an indicator of platelet activation: methodological issues. Platelets. 2002;13(5-6):301-6.
10. 10. O’brien J, Jamieson S. A relationship between platelet volume and platelet number. Thrombosis and Haemostasis. 1974;31(02):363-5.
11. 11. Bath P, Algert C, Chapman N, Neal B. Association of mean platelet volume with risk of stroke among 3134 individuals with history of cerebrovascular disease. Stroke. 2004;35(3):622-6.
12. 12. Greisenegger S, Endler G, Hsieh K, Tentschert S, Mannhalter C, Lalouschek W. Is elevated mean platelet volume associated with a worse outcome in patients with acute ischemic cerebrovascular events? Stroke. 2004;35(7):1688-91.
13. 13. Yuce M, Cakici M, Davutoglu V, Ozer O, Sari I, Ercan S, et al. Relationship between mean platelet volume and atrial thrombus in patients with atrial fibrillation. Blood coagulation & fibrinolysis. 2010;21(8):722-5.
14. 14. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2013;369(22):2093-104.
15. 15. Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: Design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation–Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF–TIMI 48). American heart journal. 2010;160(4):635-41. e2.
16. 16. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström- Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS) The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European heart journal. 2021;42(5):373-498.
17. 17. Cameron H, Phillips R, Ibbotson R, Carson P. Platelet size in myocardial infarction. Br Med J (Clin Res Ed). 1983;287(6390):449-51.
18. 18. Thompson CB, Love DG, Quinn PG, Valeri CR. Platelet size does not correlate with platelet age. Blood. 1983;62(2):487-94.
19. 19. Pathansali R, Smith N, Bath P. Altered megakaryocyte– platelet haemostatic axis in hypercholesterolaemia. Platelets. 2001;12(5):292-7.
20. 20. De Luca G, Secco GG, Iorio S, Verdoia M, Bellomo G, Marino P. Short-term effects of aspirin and clopidogrel on mean platelet volume among patients with acute coronary syndromes. A single-center prospective study. Blood coagulation & fibrinolysis. 2012;23(8):756-9. ERBAY et al. The effect of edoxaban treatment on platelet indices
21. 21. Kei A, Elisaf M. Nicotinic acid/laropiprant reduces platelet count but increases mean platelet volume in patients with primary dyslipidemia. Archives of Medical Science. 2014;10(3):439-44.
22. 22. Duzen IV, Oguz E, Cekici Y, Yavuz F, Vuruskan E, Sincer I, et al. Effect of new oral anticoagulants on platelet indices in non- valvular atrial fibrillation patients. Herz. 2021;46(1):76-81.
23. 23. McCabe DJ, Harrison P, Sidhu PS, Brown MM, Machin SJ. Circulating reticulated platelets in the early and late phases after ischaemic stroke and transient ischaemic attack. British journal of haematology. 2004;126(6):861-9.
24. 24. Smith NM, Pathansali R, Bath PM. Altered megakaryocyte- platelet-haemostatic axis in patients with acute stroke. Platelets. 2002;13(2):113-20.
25. 25. Chandrashekar V. Plateletcrit as a screening tool for detection of platelet quantitative disorders. Journal of Hematology. 2013;2(1):22-6.
26. 26. Jindal S, Gupta S, Gupta R, Kakkar A, Singh HV, Gupta K, et al. Platelet indices in diabetes mellitus: indicators of diabetic microvascular complications. Hematology. 2011;16(2):86-9.
27. 27. Lyu Q-s, Liu B, Huang C, Huang Y-q. The association between platelet distribution width and stroke in atrial fibrillation patients. Annals of Clinical & Laboratory Science. 2019;49(1):143-7.