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1 Current status of antiarrhythmic and antithrombotic therapy for AF in Korea 온영근삼성서울병원성균관의대

2 심방세동 (Atrial Fibrillation) 심장부정맥중에서가장흔한부정맥 뇌졸중의위험이약 5배증가 매년뇌졸중의발생률약 5% 혈색전증에의한뇌졸중중에서심방세동에의한뇌졸중이약 20% 심방세동의치료에있어뇌졸중의예방이매우중요

3 Prevalence of atrial fibrillation in Korean by age and gender 14,540 adults (mean age 54.6 years, range 40~92 yr, 45.2% males) who received screening tests for general health in 8 cities/counties in Gyeongsang-nam-do April, 2000 ~ Dec, 2000 Jeong JH. J Korean Med Sci. 2005; 20(1): 26

4 Incidence of atrial fibrillation per 1000 person-year by age and gender 16,568 adults (median age 49 years,range 20~89 yr, 64.5% males) who had repeatedly received screening tests for general health at the Health Promotion Center, Samsung Medical Center March, 2001 ~ June, 2006 mean follow up duration: 44 months Kim HJ, et al. Korean Circ J. 2007;37:609

5 Recurrence of atrial fibrillation in Korean patients after DC cardioversion Kim SK, et al. Europace 2009;11:1632

6 심방세동의치료 Rhythm control Rate control Prevention of thromboembolism : Antithrombotic therapy

7 AADs in AF Rhythm control Rate control β Na+ K+ receptor Ca++ Class I Class III Class II Class IV Digoxin Class Ia Quinidine Disopyramide Class Ic Flecainide Propafenone Amiodarone Sotalol Dofetilide Ibutilide Betablockers* Metoprolol Bisoprolol Carvedilol Calcium channel blockers (Nondihydropyridine calcium channel antagonists ) Verapamil Dilitazem * Betablockers can also be used as rhythm control agents

8 Antiarrhythmic drug to maintain sinus rhythm in recurrent paroxysmal or persistent AF

Class Ia: Disopyramide, Procainamide, Quinidine, Mexiletine Class Ic: Flecainide, Propafenone, Pilsicainide Class III: Amiodarone,

9 항부정맥약제 (Korea) 항부정맥약제시장의크기 (Korea): 6.8 billion 원 (2009 년 4 분기 ~ 2010 년 3 분기, 1 년간의자료 ) 성장율 Annual Growth : 7.4% 성장 ( 금액 ) 9.4% 성장 (tablet 수 ) (2009 년 3 분기대비 2010 년 3 분기성장율 ) 항부정맥약제 : For Rhythm control: Oral Anti-arrhythmic market (Class Ia/c, class III) Class Ia: Disopyramide, Procainamide, Quinidine, Mexiletine Class Ic: Flecainide, Propafenone, Pilsicainide Class III: Amiodarone, Sotalol, Dronedarone 1 st Propafenone, 2 nd Flecanide, 3 rd Amiodarone 시장의크기 ( 금액, million 원 ) 7.7% (CAGR) 시장의크기 (tab 수, million) 7.6% (CAGR) 자료 : IMS 제공시장자료

10 주요항부정맥약제 (Korea) 대표성분용법용량적응증대표약품명제약사명 Daily Price (average) Amiodarone 400mg bid (8~10 days) 200 mg qd~bid 1. 심방성부정맥, 심실성부정맥, 기타다른부정맥용제로치료되지않는재발성중증부정맥 2. 협심증등기초심질환을수반하는부정맥 코다론 사노피 - 아벤티스 319 원 1. 심실성부정빈맥, 심실성기외수축 Flecainide 50~100mg bid (max 400mg/d) 2. 발작성심실성빈맥, WPW 증후군 3. 다른수단에의해회복된정상리듬의유지 탬보코정중외신약 240~480 원 4. 발작성심방세동 Propafenone 150mg tid or 300mg bid 300 mg tid 증후성상실성부정빈맥 (WPW 증후군또는발작성심방세동을수반한상실성빈맥, 방실접합부빈맥 ), 생명을위협하거나의사의판단에의해치료가필요한심한증후성심실성부정빈맥 리트모놈정 일성신약 1,392~1,512 원 Sotalol 40-80mg/d (max mg/d) 증후성상실성부정빈맥 ( 방실결절빈맥, WPW 증후군또는발작성심방세동을수반하는상실성빈맥 ), 중증의증후성심실성부정빈맥의치료및예방 소타론정비티오제약 240~480 원

11 심방세동에서의혈전색전증예방 와파린약물복용 (61% 혈전색전증예방효과 ) 문제점 : 와파린의개인차가너무크다. 정기적인혈액검사여러가지음식물및약제의제한출혈위험성증가 아스피린약물복용 (19% 혈전색전증예방효과 ) 문제점 : 와파린에비해예방효과적다. 위장장애

12 Warfarin is widely used as an oral anticoagulant for AF Warfarin has a narrow therapeutic index and may be associated with adverse events. : thromboembolic complications or bleeding. Life-threatening bleeding episodes after initiation of warfarin therapy have been reported in approximately 12%. (Levine MN, et al. Chest 2001;119:S108-21) During maintenance therapy, only 50-60% of patients can be expected to achieve their target INR range. Marked within- and between-individual variability in warfarin dose requirements Monitoring the safety and efficacy of warfarin treatment.

13 105 patients with atrial fibrillation, and who were receiving warfarin for more than 1 yr in SMC. 96 patients (91%) were receiving concurrent medications, antiarrhythmics (n=43), diuretics (n=31), aspirin (n=16), antilipidemic agents (n=9), oral diabetic agents (n=6), allopurinol (n=4), beta-adrenergic blockers (n=2), steroids (n=2), antidepressants (n=2), NSAIDs (n=2), antihistamines (n=1). 26 patients (25%) were taking drugs that could potentially increase their INR (aspirin, simvastatin, allopurinol, or NSAIDs) Over 69% of the patients had underlying comorbid conditions, diabetes mellitus (n=19), hypertension (n=17), valvular heart disease (n=10), asthma (n=5), lung disease (n=5), thyroid disease (n=3), arthritis (n=3), chronic hepatitis (n=2), and other diseases (n=9). Kwon MJ, et al. Korean J Lab Med 2009;29:515

14 49.5% (52/105) of patients experienced a variety of bleeding complications, including epistaxis, gum bleeding, melena, and hematuria. 5.7% (6/105) of patients experienced thrombotic complications during warfarin treatment, including cerebral infarction and mesenteric infarction. mean maintenance dose of warfarin in 105 patients : 4.1±1.3 mg/day (range, mg/day) mean plasma warfarin concentration : 1.3±0.5 mg/l. 74 patients (70%) showing INR within target range despite of constant INRs within the target range (2.0~3.0) over at least 3 consecutive monthly clinic visits just before the index visit. Kwon MJ, et al. Korean J Lab Med 2009;29:515

15 INR level in warfarin-treated patients with non-valvular AF 129 patients, men (71.3%), with NVAF, Average age : 63.6 years (range 34~86 years) 36.4% were less than 60 years old. The median duration of follow up was 2.03 years. Correlation between weekly warfarin dose and age. p < % Kim JH, et al. Yonsei Med J. 2009;50:83

16 Mode of Action of New Anticoagulants A: Tissue factor/ factor VIIa inhibitors B: Factor Xa inhibitors C: Direct thrombin inhibitors

17 Anticoagulants in development Garcia D, et al. Blood. 2010;115:15

18 Rivaroxaban (Xarelto) Direct factor Xa inhibitor 10 mg qd 하지의주요정형외과수술 ( 슬관절또는고관절전치환술 ) 을받은성인환자의정맥혈전색전증예방 Dabigatran Direct thrombin inhibitor

19 항응고제 (Korea) Korea Anti-Coagulant market is 13.8 Bn Krw in Q Anticoagulant Market Value 10 4Q Anticoagulant Market Volume VKA + 4.8% LMWH VKA VKA 45% 13% 11% 31% UFH LMWH VKA UFH FXa & DTI LMWH 1% 1% 73% 25% UFH LMWH VKA UFH FXa & DTI FXa & DTI FXa & DTI LMWH(Low molecule weigh heparin) : Enoxaparin UFH(Unfractured heparin) VKA(Vitamin K antagonist) DTI(Direct Thrombin inhibitor) Fxa(Fxa inhibitor) : Rivaroxaban(Direct Fxa inhibitor), Fondaparinux(Indirect Fxa inhibitor) Source : Q IMS MAT

20 Rivaroxaban 적응증 : 하지의주요정형외과수술을받은성인환자의정맥혈전색전증예방 용법용량 1 일 1 회 1 정 가격 10mg 정당 6,030 원 급여범위 고관절, 슬관절전치환술환자중 아래의 1 가지이상위험군 급여기간 슬관절전치환술 : 최대 14 일 고관절전치환술 : 최대 35 일

21 Enoxaparin 적응증 1. 외과영역의수술후발생하는정맥의혈전 / 색전질환예방 2. 혈액투석시체외혈액순환회로에서의혈액응고방지 3. 폐색전증유무와상관없이, 심재성정맥혈전증의치료 4. 아스피린과의병용투여 : 불안정협심증과비 Q 파심근경색증 (NQMI) 의치료 5. 다음의급성내과질환으로활동부적상태환자에서의심재성정맥혈전색전질환예방 1) 심부전 (NYHA class Ⅲ or Ⅳ) 2) 급성호흡부전 3) 아래의한가지이상정맥혈전색전의위험인자가동반된급성감염혹은급성류마티스질환 -75 세이상 - 암 - 정맥혈전색전질환의병력 - 비만 - 호르몬치료 - 심부전 - 만성호흡부전 6. 급성 ST 분절상승심근경색증 (STEMI) 의치료, 경피적관상동맥중재술시행여부와관계없이혈전용해제와병용가능용법용량

22 Enoxaparin 용법용량 1. 외과영역의수술후발생하는정맥의혈전색전질환예방 ( 피하주사 ) 1) 혈전색전의우려가적은환자의경우혈전색전의효과적인예방을위해서는 1 일 1 회 20mg 의에녹사파린 (0.2ml) 을투여한다. 일반외과수술시에는수술약 2 시간전에초회주사하여야한다. 2) 혈전색전의위험률이높은환자, 특히정형외과수술환자의경우에는 1 일 1 회 40mg 의에녹사파린 (0.4ml) 을주사한다. 정형외과수술시에는 12 시간전에초회주사하여야한다. 3) 혈전색전의우려가남아있는한일반적으로환자가보행할수있게될때까지는투약을계속해야한다. ( 수술후평균 7 또는 10 일 ) 2. 폐색전증유무와상관없이, 심재성정맥혈전증의치료 ( 피하주사 ) 1) 1 일 2 회, 12 시간의간격을두고 1mg/kg 의용량으로주사한다. 2) 경구용항응고제와체내평형상태에도달하는데걸리는시간을포함하여 10 일이상사용하지않도록한다 3. 급성내과질환으로입원한환자에의정맥혈전색전질환예방 ( 피하주사 ) 1) 1 일 1 회 4000anti-Xa IU(40mg/0.4mL) 의에녹사파린을주사한다. 2) 6-14 일간투여하는것이바람직하다. 약가 : 7,004 원 / 40mg 보험급여기간 : 수술후 7 일 ~10 일

23 Warfarin 적응증 1. 정맥혈전증의예방및치료 2. 색전성심방세동의치료 3. 폐동맥색전증의예방및치료 4. 관상동맥폐색의보조제 용법용량 PT/INR 및 CYP2C9, VKORC1 유전자의특정유전형에따라개인별로차이가있음보통초기용량은와파린나트륨으로서 1일 2~5 mg, 유지용량은 1일 2~10mg 고령자나쇠약환자는적은용량이권장 약가 30원 / 2mg, 63원 /5mg 23

24 Nonpharmacological device (Watchman device : LAA closure) Watchman device Schwartz RS, et al, J Am Coll Cardiol Intv 2010;3:870

26 SMC Experience of Watchman device for LAA closure

27 Conclusions 한국인의심방세동의유병률 65 세이상에서약 2.2%, 심방세동의발생률이 45 세미만에비해 65 세이상에서 10 배증가. 항부정맥약제의사용이최근 5 년간평균연 7.6%, 작년 9.4% 증가, 새로운항부정맥약제 : Dronedarone 와파린사용중출혈경험약 50%, 와파린사용중 INR 2~3 : 61% 새로운항혈전제 Dabigatran: direct thrombin inhibitor Apixaban and Rivaroxaban: factor Xa inhibitors 비약물적요법 : Watchman device (LAA closure) another option for prevention of stroke in AF patients.

Table 1. Common medication dosage for rate control of atrial fibrillation 약물 정주 경구상용용량 s Metoprolol tartrate 2분에걸쳐 mg 투여, 3회까지 mg BID M

Table 1. Common medication dosage for rate control of atrial fibrillation 약물 정주 경구상용용량 s Metoprolol tartrate 2분에걸쳐 mg 투여, 3회까지 mg BID M 심방세동의약물치료 원광대학교의과대학내과학교실김남호 Nam-Ho Kim, MD Department of Internal Medicine, Wonkwang University Medical School, Iksan, Korea ABSTRACT Management of AF patients is aimed at reducing symptoms and at preventing