《美國心血管藥物雜誌》：中國學者最新研究——地高辛顯著增加房顫患者不良結局，臨牀上應謹慎使用！

房顫是最常見的心律不齊疾病，但危險性不容小覷。由於心房的收縮功能喪失，引起心臟節律紊亂，同時會形成血栓，誘發室顫，對患者的健康有極大影響，嚴重時可危及生命。房顫的治療主要有兩大方面：控制心室率和預防血栓形成。作爲心血管內科應用最久的藥物之一，地高辛一直作爲控制房顫心室率的一線用藥，在臨牀上應用廣泛。

但是，中國學者2019年5月11日發表在《美國心血管藥物雜誌》（American Journal of Cardiovascular Drugs）上的一項旨在評估地高辛與中國房顫患者不良結局之間關係的研究，結果卻令人瞠目結舌：在未接受消融治療的房顫患者中，地高辛的使用與不良結局的顯著增加相關，臨牀上應謹慎使用地高辛！

Association Between Digoxin Use and Adverse Outcomes Among Patients in the Chinese Atrial Fibrillation Registry

Am J Cardiovasc DrugsOriginal Research Article

Early Recent, May 11, 2019

10.1007/s40256-019-00350-8

Introduction

地高辛廣泛應用於房顫（AF）患者，但其與不良結局的關係仍有爭議。

研究目的

我們旨在評估地高辛與中國房顫患者不良結局之間的關係。

研究方法

我們使用來自中國房顫登記處的數據，進行了一項涉及31家醫院的前瞻性、多中心、基於醫院的登記研究。從2011年8月到2016年12月，共有10472名符合條件的房顫患者被納入本研究。使用Cox比例風險模型研究地高辛的使用與全因死亡率、心血管死亡和心血管住院的關係。

研究結果

總共1152（11%）名患者在基線時接受地高辛治療。接受地高辛治療的患者年齡較大（平均年齡69.7歲vs.66.5歲），心率較快（92.4 vs.79.7次/min）。接受地高辛治療的患者有心力衰竭（62.5 vs.15.6%）、糖尿病（34.4 vs.24.4%）和持續性房顫（67.9 vs.38.4%）病史的比例較高。地高辛的使用與全因死亡率（校正危險比（aHR）1.21；95%CI 1.02-1.43； P＝0.031）、心血管死亡（aHR 1.25；95%CI 1.01-1.55； P＝0.043）和心血管住院（aHR 1.21；95%CI 1.05-1.39； P＝0.007）的增加獨立相關。除腎功能不全和無腎功能不全的患者外，不同亞組間的相關性也相同（相互作用 P=0.029）。

討論

在這組中國房顫患者中，未接受消融治療的患者，地高辛的使用與不良結局的顯著增加相關。雖然可能存在殘餘混雜因素，也沒有地高辛的血清濃度，但地高辛在臨牀實踐中應謹慎使用，其療效需要在隨機試驗中進行嚴格評價。

引用文獻

1. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation. 2006;113:2556–64.CrossRefGoogle Scholar2. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW, College American, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;2014(64):e1–76.CrossRefGoogle Scholar3. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Authors/Task Force Members; Document Reviewers. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the Task Force for the 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. Endorsed by the European Stroke Organisation (ESO). Eur Heart J. 2016;37:2893–962.CrossRefGoogle Scholar4. Hallberg P, Lindback J, Lindahl B, Stenestrand U, Melhus H. Digoxin and mortality in atrial fibrillation: a prospective cohort study. Eur J Clin Pharmacol. 2007;63:959–71.CrossRefGoogle Scholar5. Whitbeck MG, Charnigo RJ, Khairy P, Ziada K, Bailey AL, Zegarra MM, Shah J, Morales G, Macaulay T, Sorrell VL, Campbell CL, Gurley J, Anaya P, Nasr H, Bai R, Di Biase L, Booth DC, Jondeau G, Natale A, Roy D, Smyth S, Moliterno DJ, Elayi CS. Increased mortality among patients taking digoxin—analysis from the AFFIRM study. Eur Heart J. 2013;34:1481–8.CrossRefGoogle Scholar6. Turakhia MP, Santangeli P, Winkelmayer WC, Xu X, Ullal AJ, Than CT, Schmitt S, Holmes TH, Frayne SM, Phibbs CS, Yang F, Hoang DD, Ho PM, Heidenreich PA. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol. 2014;64(7):660–8.CrossRefGoogle Scholar7. Freeman JV, Reynolds K, Fang M, Udaltsova N, Steimle A, Pomernacki NK, Borowsky LH, Harrison TN, Singer DE, Go AS. Digoxin and risk of death in adults with atrial fibrillation: the ATRIA-CVRN study. Circ Arrhythm Electrophysiol. 2015;8(1):49–58.CrossRefGoogle Scholar8. Shah M, Avgil Tsadok M, Jackevicius CA, Essebag V, Behlouli H, Pilote L. Relation of digoxin use in atrial fibrillation and the risk of all-cause mortality in patients ≥ 65 years of age with versus without heart failure. Am J Cardiol. 2014;114:401–46.CrossRefGoogle Scholar9. Chao TF, Liu CJ, Tuan TC, Chen SJ, Wang KL, Lin YJ, Chang SL, Lo LW, Hu YF, Chen TJ, Chiang CE, Chen SA. Rate-control treatment and mortality in atrial fibrillation. Circulation. 2015;132:1604–12.CrossRefGoogle Scholar10. Adedinsewo D, Xu J, Agasthi P, Oderinde A, Adekeye O, Sachdeva R, Rust G, Onwuanyi A. Effect of digoxin use among medicaid enrollees with atrial fibrillation. Circ Arrhythm Electrophysiol. 2017;10(5):e004573.CrossRefGoogle Scholar11. Gjesdal K, Feyzi J, Olsson SB. Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data. Heart. 2008;94(2):191–6.CrossRefGoogle Scholar12. Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR, ROCKET AF Steering Committee and Investigators. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Lancet. 2015;385:2363–70.CrossRefGoogle Scholar13. Eisen A, Ruff CT, Braunwald E, Hamershock RA, Lewis BS, Hassager C, Chao TF, Le Heuzey JY, Mercuri M, Rutman H, Antman EM, Giugliano RP. digoxin use and subsequent clinical outcomes in patients with atrial fibrillation with or without heart failure in the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2017;6(7):e006035.CrossRefGoogle Scholar14. Vamos M, Erath JW, Benz AP, Lopes RD, Hohnloser SH. Meta-analysis of effects of digoxin on survival in patients with atrial fibrillation or heart failure: an update. Am J Cardiol. 2019;123(1):69–74.CrossRefGoogle Scholar15. Friberg L, Hammar N, Rosenqvist M. Digoxin in atrial fibrillation: report from the Stockholm Cohort study of Atrial Fibrillation (SCAF). Heart. 2010;96:275–80.CrossRefGoogle Scholar16. Gheorghiade M, Fonarow GC, van Veldhuisen DJ, Cleland JG, Butler J, Epstein AE, Patel K, Aban IB, Aronow WS, Anker SD, Ahmed A. Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial. Eur Heart J. 2013;34:1489–97.CrossRefGoogle Scholar17. Allen LA, Fonarow GC, Simon DN, Thomas LE, Marzec LN, Pokorney SD, Gersh BJ, Go AS, Hylek EM, Kowey PR, Mahaffey KW, Chang P, Peterson ED, Piccini JP, ORBIT-AF Investigators. Digoxin use and subsequent outcomes among patients in a contemporary atrial fibrillation cohort. J Am Coll Cardiol. 2015;65:2691–8.CrossRefGoogle Scholar18. Mulder BA, Van Veldhuisen DJ, Crijns HJ, Tijssen JG, Hillege HL, Alings M, Rienstra M, Van den Berg MP, Van Gelder IC, RACE Investigators II. Digoxin in patients with permanent atrial fibrillation: data from the RACE II study. Heart Rhythm. 2014;11:1543–50.CrossRefGoogle Scholar19. Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, Steeds RP, Townend J, Kotecha D. Safety and efficacy of digoxin: systematic review and metaanalysis of observational and controlled trial data. BMJ. 2015;351:h4451.CrossRefGoogle Scholar20. Du X, Ma C, Wu J, Li S, Ning M, Tang R, Guo X, Long D, Yu R, Sang C, Jiang C, Zhang T, Pan J, Liu X, Dong J, Lip GY, CAFR Investigators. Rationale and design of the Chinese Atrial Fibrillation Registry Study. BMC Cardiovasc Disord. 2016;7(16):130.CrossRefGoogle Scholar21. Chang SS, Dong JZ, Ma CS, Du X, Wu JH, Tang RB, Xia SJ, Guo XY, Yu RH, Long DY, Bai R, Liu N, Sang CH, Jiang CX, Liu XH, Pan JH, Lip GY. Current status and time trends of oral anticoagulation use among chinese patients with nonvalvular atrial fibrillation: the Chinese Atrial Fibrillation Registry Study. Stroke. 2016;47(7):1803–10.CrossRefGoogle Scholar22. Goldberger ZD, Alexander GC. Digitalis use in contemporary clinical practice: re-fitting the foxglove. JAMA Intern Med. 2014;174:151–4.CrossRefGoogle Scholar23. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.CrossRefGoogle Scholar24. Darby AE, Dimarco JP. Management of atrial fibrillation in patients with structural heart disease. Circulation. 2012;125(7):945–57.CrossRefGoogle Scholar25. Al-Zakwani I, Panduranga P, Zubaid M, Sulaiman K, Rashed WA, Alsheikh-Ali AA, AlMahmeed W, Shehab A, Al Qudaimi A, Asaad N, Amin H. Impact of digoxin on mortality in patients with atrial fibrillation stratified by heart failure: findings from gulf survey of atrial fibrillation events in the Middle East. J Cardiovasc Pharmacol Ther. 2016;21:273–9.CrossRefGoogle Scholar26. Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, See LC, Kuo CF. Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA. 2017;318:1250–9.CrossRefGoogle Scholar27. Ziff OJ, Kotecha D. Digoxin: the good and the bad. Trends Cardiovasc Med. 2016;26(7):585–95.CrossRefGoogle Scholar28. Murphy SA. When ‘digoxin use’ is not the same as ‘digoxin use’: lessons from the AFFIRM trial. Eur Heart J. 2013;34:1465–7.CrossRefGoogle Scholar29. Eisen A, Ruff CT, Braunwald E, Nordio F, Corbalán R, Dalby A, Dorobantu M, Mercuri M, Lanz H, Rutman H, Wiviott SD, Antman EM, Giugliano RP. Sudden cardiac death in patients with atrial fibrillation: insights from the ENGAGE AF-TIMI 48 Trial. J Am Heart Assoc. 2016;5(7):e003735.CrossRefGoogle Scholar30. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871–8.CrossRefGoogle Scholar31. Boriani G, Savelieva I, Dan GA, Deharo JC, Ferro C, Israel CW, Lane DA, La Manna G, Morton J, Mitjans AM, Vos MA, Turakhia MP, Lip GY, Document reviewers. Chronic kidney disease in patients with cardiac rhythm disturbances or implantable electrical devices: clinical significance and implications for decision making—a position paper of the European Heart Rhythm Association endorsed by the Heart Rhythm Society and the Asia Pacific Heart Rhythm Society. Europace. 2015;17(8):1169–96.CrossRefGoogle Scholar32. Lopes RD, Rordorf R, De Ferrari GM, Leonardi S, Thomas L, Wojdyla DM, Ridefelt P, Lawrence JH, De Caterina R, Vinereanu D, Hanna M, Flaker G, Al-Khatib SM, Hohnloser SH, Alexander JH, Granger CB, Wallentin L, ARISTOTLE Committees and Investigators. Digoxin and mortality in patients with atrial fibrillation. J Am Coll Cardiol. 2018;71(10):1063–74.CrossRefGoogle Scholar33. Shin JH, Kang KW, Kim JG, Lee SJ. Concurrent renal dysfunction with ischemic heart disease is an important determinant for cardiac and cerebrovascular mortality in patients on chronic digoxin therapy for atrial fibrillation. Kidney Res Clin Pract. 2018;37(2):130–7.CrossRefGoogle Scholar34. Le Quan-Sang KH, David-Dufilho M, Kerth P, Pernollet MG, Frisk-Holmbert M, Meyer P, Devynck MA. Changes in platelet free Ca2+ concentration after chronic digoxin treatment. Fundam Clin Pharmacol. 1987;1:125–34.CrossRefGoogle Scholar35. Chirinos JA, Castrellon A, Zambrano JP, Jimenez JJ, Jy W, Horstman LL, Willens HJ, Castellanos A, Myerburg RJ, Ahn YS. Digoxin use is associated with increased platelet and endothelial cell activation in patients with nonvalvular atrial fibrillation. Heart Rhythm. 2005;2:525–9.CrossRefGoogle Scholar36. Pastori D, Carnevale R, Nocella C, Bartimoccia S, Novo M, Cammisotto V, Piconese S, Santulli M, Vasaturo F, Violi F, Pignatelli P. Digoxin and platelet activation in patients with atrial fibrillation: in vivo and in vitro study. J Am Heart Assoc. 2018;7(22):e009509. https://doi.org/10.1161/jaha.118.009509.CrossRefGoogle Scholar