10-16-2015 My approaches to the patients with AF for stroke prevention Seongwook Han, MD.PhD. Professor of Medicine, Keimyung University School of Medicine Arrhythmia Service, Cardiology, Dongsan Medical Center
CHA 2 DS 2 VASc Score Congestive heart failure 1 Hypertension 1 Age ( 75 years) 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease (MI, PAD, aortic plaque, etc) Age (65~74 years) 1 1 Sex category (female) 1 0 1 2 3 4 5 6 7 8 9 0 1.3 annual stroke risk (%) 2.2 3.2 4 6.7 9.8 9.6 6.7 15.2 Olesen JB, et al. BMJ 2011;342:d124 Lip GYH, et al, Chest 2010;137:263
2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation KUDMC I IIa IIb III CHA2DS2-VASc score recommended to assess stroke risk I IIa IIb III I IIa IIb III CHA2DS2-VASc score 2, oral anticoagulants recommended Warfarin Dabigatran, rivaroxaban, or apixaban January CT et al. JACC 2014;64:e1
Novel oral anticoagulant (NOAC) New oral anticoagulant (NOAC) Non-vitamin K antagonist oral anticoagulant (NOAC) Direct oral anticoagulant (DOAC)
Warfarin Rivaroxaban Apixaban,Edoxaban Dabigatran
Rivaroxaban versus warfarin in nonvalvular AF: ROCKET-AF Nonvalvular AF with 2 or 3 risk factors (CHADS 2 2) or stroke, TIA, or systemic embolism N=14,264: double blind 45 counties, 1178 sites Rivaroxaban 20mg OD or 15 mg (CCl 30-49 ml/min) Adjusted dose warfarin INR (2~3) Primary outcome: Stroke or systemic embolism Patel MR, et al. NEJM 2011;365:883
AF Patients in ROCKET AF had Higher Risk of Stroke than Patients in Other Phase III Trials ROCKET AF rivaroxaban RE-LY dabigatran ARISTOTLE apixaban ENGAGE AF edoxaban 13% 36% 32% 36% 34% 48% 87% 32% 30% 52% Mean: 3.5, Median 3.0 CHADS 2 score 1 2 3 6
Rivaroxaban versus warfarin in nonvalvular AF: ROCKET-AF Primary outcome: Stroke or systemic embolism HR 0.88 (0.75 1.03) <0.001 noninferiority; 0.12 superiority HR 0.79 (0.66 0.96) <0.001 noninferiority 2.4%/100-pt yr 2.2%/100-pt yr 2.2%/100-pt yr 1.7%/100-pt yr Intention-to-treat population Per protocol population Patel MR, et al. NEJM 2011;365:883
Rivaroxaban versus warfarin in nonvalvular AF: ROCKET-AF Secondary efficacy outcomes Patel MR, et al. NEJM 2011;365:883
Rivaroxaban versus warfarin in nonvalvular AF: ROCKET-AF Rates of Bleeding Events Patel MR, et al. NEJM 2011;365:883
Phase III studies Gold standard for evaluating efficacy and safety against the current standard of care Support marketing approval by regulatory authorities Strict protocols and inclusion/exclusion criteria may exclude some patients Event rates, patient characteristics (i.e. co-morbidities), & adherence/ persistence may not fully reflect real world settings Real world studies Unselected patient populations typical of those seen in routine clinical practice Observational design with little interference in patient management Provide additional information on rare safety events or routine clinical practice
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC To investigate the safety and efficacy of the Factor Xa inhibitor rivaroxaban in routine clinical use in the NVAF setting Primary outcome: Major adverse events (major bleeding, stroke, systemic embolism, TIA, MI) & all cause mortality Adult patients with NVAF receiving rivaroxaban for stroke/non-cns SE prevention Rivaroxaban; treatment duration and dose at physician s discretion Data collection at initial visit, hospital discharge (if applicable) and quarterly N=6,784* Final visit: 1 year Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF June 2012~December 2013: from 311 countries in Europe and Canada (Belgium, Canada, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Israel, Moldova, The Netherlands, Norway, Poland, Portugal, Russia, Slovakia, Slovenia, Sweden, Ukraine, UK) KUDMC Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC Major events, specifically major bleeding, stroke, SE, TIA and MI, adjudicated centrally by an independent CAC blinded to individual patient data Primary analysis population: defined as all patients who had taken at least one dose of rivaroxaban Screened (N=10,934) Enrolled (N=6785) Safety population (N=6784) 4149 patients excluded* Patient decision (n=1222) Administrative reason (n=456) Availability of drug (n=18) Medical guidelines (n=399) Price of drug (n=473) Medical reasons (n=442) Internal hospital guidelines (n=30) Type of health insurance (n=183) Other (n=1454) 1 patient Did not take any rivaroxaban (n=1) Rivaroxaban 20 mg od (n=5336) Rivaroxaban 15 mg od (n=1410) Another dose (n=35) # Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC Proportion of patients (%) 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 Mean: 2.0±1.3 Mean: 3.4±1.7 30.4 30.0 16.4 10.4 9.1 3.3 0.5 0 1 2 3 4 5 6 CHADS 2 score Proportion of patients (%) 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 23.3 20.7 19.4 12.3 11.6 10.1 2.6 0 1 2 3 4 5 6 9 CHA 2 DS 2 -VASc score Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC ----- All-cause death: 1.9/100 pt-yrs ----- Major bleeding: 2.1/100 pt-yrs ----- Stroke/SE 0.7/100 pt-yrs Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC In total, 6522 (96.1%) patients did not experience any of the outcomes of treatment-emergent all-cause death, major bleeding, or stroke/systemic embolism Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC Incidence proportion, n (%) Rivaroxaban (N=6784) Incidence rate, %/year (95% CI)* All-cause death 118 (1.7) 1.9 (1.6 2.3) Thromboembolic events 108 (1.6) 1.8 (1.5 2.1) Stroke/SE 51 (0.8) 0.8 (0.6 1.1) Stroke 43 (0.6) 0.7 (0.5 0.9) Primary haemorrhagic 11 (0.2) Primary ischaemic 32 (0.5) SE 8 (0.1) 0.1 (0.1 0.3) TIA 32 (0.5) 0.5 (0.4 0.7) MI 27 (0.4) 0.4 (0.3 0.6) Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC Rivaroxaban (N=6784) Incidence proportion, n (%) Incidence rate, %/year (95% CI)* Major bleeding 128 (1.9) 2.1 (1.8 2.5) Fatal 12 (0.2) 0.2 (0.1 0.3) Critical organ bleeding 43 (0.6) 0.7 (0.5 0.9) Intracranial haemorrhage 26 (0.4) 0.4 (0.3 0.6) Mucosal bleeding # 60 (0.9) 1.0 (0.7 1.3) Gastrointestinal 52 (0.8) 0.9 (0.6 1.1) Haemoglobin decrease 2 g/dl 52 (0.8) 0.9 (0.6 1.1) Transfusion of 2 units of packed RBCs or whole blood 53 (0.8) 0.9 (0.6 1.1) Non-major bleeding events 878 (12.9) 15.4 (14.4 16.5) Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC XANTUS versus ROCKET-AF CHADS 2 Prior stroke ROCKET AF 3.5 55% 4.0 3.5 ROCKET AF 3.6 XANTUS 2.0 19% 3.0 Incidence rate, %/year 2.5 2.0 1.5 1.0 0.5 0.8 XANTUS 0.7 1.9 2.1 0.4 0.9 2.5 2.0 1.5 1.0 0.5 1.7 1.7 1.9 0.5 2.0 0.0 Stroke/SE All strokes Death Major bleeding ICH GI bleeding 0.0 Stroke/SE All strokes Death Major bleeding ICH GI bleeding Camm AJ, et al. doi:10.1093/eurheartj/ehv466
XANTUS: A real-world, prospective, observational study of patients treated with rivaroxaban for SPAF KUDMC XANTUS is the first large, international, prospective study describing the use of rivaroxaban for stroke prevention in a broad NVAF patient population The rates of major bleeding and stroke with rivaroxaban were found to be low in routine clinical practice Over 96% patients receiving rivaroxaban did not experience any of the outcomes Treatment persistence and patient satisfaction were high 80% of patients remained on rivaroxaban 75% reported they were satisfied with their treatment at 1 year Camm AJ, et al. doi:10.1093/eurheartj/ehv466
Camm AJ et al. Eur Heart J. 2010;31:2369
Atrial Fibrillation Rapid ventricular response Loss of atrial contraction Loss of atrial kick Stasis of blood Tachycardia induced CM Cardiac output Congestive Heart failure Thromboembolism Rhythm control Rate control Anticoagulation
Atrial Fibrillation Rapid ventricular response Loss of atrial contraction Loss of atrial kick Stasis of blood Tachycardia induced CM Cardiac output Congestive Heart failure Thromboembolism Rhythm control Rate control Anticoagulation
~ Our Story ~ Chief complaints: easy fatigability Present illness: This 67 year-old gentleman presented with aggravation of easy fatigability. He had been diagnosed with paroxysmal AF 7 years ago. He had been treated with amiodarone for 4 years, which was stopped because of changing to persistent AF. He had no palpitation or DOE. However, he experiences easy fatigability and poor exercise capacity recently. Past History: Hypertension: (+), Diabetes: (-), CVA (-)
~ Our Story ~ Echocardiogram EF 54%, LA Volume 56.4 ml, concentric LVH, no valvular lesions Current medications Aspirin: 100mg Amlodipine 5mg Bisoprolol 2.5 mg
HR: 112 BPM ~ Our Story ~ ECG on the first day
Rivaroxaban Edoxaban Apixaban Dabigatran Mechanism of action Xa inhibitor Xa inhibitor Xa inhibitor thrombin inhibitor Dosing Once daily Once daily Twice daily Twice daily Pro-drug No No No Yes Oral bioavailability 80-100% >45% >50% 6.5% Food effect Yes (taken with food) No No No Renal clearance ~ 35% 50% ~27% 85% Dialysis Not expected Data NA Not expected Yes Mean half-life (t 1/2 ) 5-13 h 9-11 h ~12 h 12-14 h T max 2-4 h 1-3 h 3-4 h 0.5-2 h
Rivaroxaban 20mg QD Rivaroxaban 15mg QD 15 50 CrCl Rivaroxaban 20mg QD Rivaroxaban 15mg QD Avoid use in Child-Pugh B & C hepatic impairment or with any degree of hepatic impairment associated with coagulopathy
~ Our Story ~ CHADSVASc score: 2, (hypertension, age) CrCl: 68.94 ml/min LFT: WNL Medication changed Xarelto 20mg with morning meal Amlodipine 5mg OD Bisoprolol 5mg OD (increased dose)
Recommendations for Cardioversion in patients with AF 2014 AHA/ACC/HRS recommendations: Class Level AF/AFL 48 h or unknown, anticoagulation with warfarin (INR 2.0 to 3.0) is recommended for for 3 weeks before and for 4 weeks after cardioversion, regardless of the CHA2DS2-VASc score and the method AF/AFL 48 h or unknown that requires immediate cardioversion for hemodynamic instability, anticoagulation should be initiated as soon as possible and continued for at least 4 weeks after cardioversion unless contraindicated. AF/AFL < 48 h and high risk of stroke, intravenous heparin or LMWH, or administration of a factor Xa or direct thrombin inhibitor, is recommended as soon as possible before or immediately after cardioversion, followed by long-term anticoagulation therapy Following cardioversion for AF of any duration, the decision about long-term anticoagulation therapy should be based on the thromboembolic risk profile For NOACs, available data supporting similar use at cardioversion consist of subgroup analyses of RE-LY, ROCKET AF, and ARISTOTLE in patients who were receiving long-term anticoagulation (>3 weeks) around the time of cardioversion. I I I I B C C C January CT et al. J Am Coll Cardiol 2014 ;14:1740
~ Our Story ~ Transesophageal echocardiography 4 weeks later Dilated LA, no spontaneous echo or thrombi
Successful DC Cardioversion Presence of two or more P waves after shock delivery Immediate Recurrence of AF (IRAF) Re-initiation of AF within 1 min of successful CV Amiodarone Prevention of IRAF: better than sotalol, propafenone, ibutilide Conversion of persistent AF: ~ 25% Inhibits CYP3A, CYP2C9, P-glycoprotein increase the INR
Heidbuchel H, et al. DOI:10.1093/europace/euv309
Heidbuchel H, et al. DOI:10.1093/europace/euv309
Contraindicated/not recommended Reduce dose Consider dose reduction if 2 yellow factors are present Heidbuchel H, et al. DOI:10.1093/europace/euv309
~ Our Story ~ Medication changed after TEE Amiodarone loading and maintained for 4 weeks Xarelto 20mg OD with the meal Norvasc 5mg OD D/C bisoprolol
HR: 76 BPM ~ Our Story ~ ECG on the day of cardioversion
HR: 56 BPM ~ Our Story ~ DCCV was successful with 100 J
~ Our Story ~ The patient was discharged after DCCV with Amiodarone 200mg OD Xarelto 20mg OD Amlodipine 5mg OD The sinus rhythm was maintained for 6 days The patients felt the recurrence of AF with severe weakness and dizziness
HR: 99 BPM ~ Our Story ~ ECG 7 days after DCCV
~ Our Story ~ Previous medication had been kept for 2 more months Amiodarone 200mg OD Xarelto 20mg OD with meal Amlodipine 5mg OD The patient had been weaker as time goes by. However, the surface ECG showed sinus rhythm
~ Our Story ~
Longitudinal Cohort study from Stroke prevention in AF (SPAF) intermittent AF:sustained AF=460:1552 treated with aspirin 2 Year-FU similar risk of stroke between paroxysmal & persistent annualized rate of ischemic stroke 3.2% 3.3% Paroxysmal Persistent Hart RG, et al. J Am Coll Cardiol. 2000;35:183
ACTIVE-A study 7554 Patients unsuitable to OAC with AF Aspirin + placebo (n=3782) vs Aspirin + clopidogrel (n=3772) AVERROES study 5599 patients unsuitable to OAC with AF Aspirin (n=2791) vs Apixaban (n=2808) Analyze the Aspirin only arms to identify the AF type as a risk factor Vanassche T, et al. Eur Heart J 2015;36:281
6% annual stroke rate 4% 3.0% 4.2% 2% 2.1% 0% PAF PeAF LSPeAF Vanassche T, et al. Eur Heart J 2015;36:281
ROCKET-AF: 14,264 = PAF (2,514=18%):PeAF (11,548=82%) % 80 Rivaroxaban P=NS % 80 TTR P=NS 8 CHADS P=NS 8 CHADSVASc P=NS 60 60 6 40 50 50 40 57 58 4 4 4.9 4.9 20 20 2 3.5 3.5 0 PAF PeAF 0 PAF PeAF 0 PAF PeAF 0 PAF PeAF Steinburg BA, et al. Eur Heart J 2015:36;288
Rate Rate of of all-cause mortality Persistent AF Paroxysmal AF Adjusted HR:0.79 (95% CI: 0.67~0.94, P=0.0061) Steinburg BA, et al. Eur Heart J 2015:36;288
ROCKET-AF: 14,264 = PAF (2,514=18%):PeAF (11,548=82%) 6 All Cause Mortality Stroke/SE Major bleeding 6 6 P=0.0061 P=0.0048 P=0.77 Events/100 person-year 4 2 3.52 4.78 4 2 1.73 2.18 4 2 3.31 3.55 0 PAF PeAF 0 PAF PeAF 0 PAF PeAF Steinburg BA, et al. Eur Heart J 2015:36;288
65% 37% 37% Roy D, et al. NEJM 2000;342:913
Ablation in Patients with NVAF The main clinical benefit of the procedure is an improvement in quality of life owing to elimination of the arrhythmia-related symptoms Ablation is increasingly being offered to patients with NVAF and comorbidities
Meta analysis of randomized controlled trials; 11 studies; 1481 patients Recurrence 65% Recurrence RR (95% CI) P value 0.4 (0.31-0.52) 0.00001 28% 1 st line Tx 0.52 (0.30-0.91) 0.02 2 nd line Tx 0.37 (0.29-0.48) <0.00001 CA AAA (222/785) (451/696) Favor CA Favor AAA Khan AR, et al. Circ AE 2014;7:853
2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation KUDMC I IIa IIb III I IIa IIb III AF catheter ablation is useful for symptomatic paroxysmal AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication when a rhythm-control strategy is desired Before consideration of AF catheter ablation, assessment of the procedural risks and outcomes relevant to the individual patient is recommended
~ Our Story ~ Discuss with the patient about the risks and benefits of RFCA Patient wanted to proceed the procedure Stop amiodarone 4 weeks ago Stop Xarelto 1 day ago
Initiation of AF by focal trigger KUDMC I avf V 1 HRA-p HRA-d His-p His-d CS-p CS-d 2015-06-09 NJS: PeAF to PAF
Biantral ablation 2015-06-09 NJS: PeAF to PAF
~ Our Story ~ Holter monitor 3 months after RFCA Meds: Carvedilol SR 16mg OD, Xarelto 20mg OD
HR: 71 BPM ~ Our Story ~ ECG 4 months after RFCA
Anticoagulation should be based on CHA 2 DS 2 VASc score and risk & benefit of efficacy and safety Minimizing AF burden may be helpful to reduce the risk of stroke in NVAF Rhythm control should be tried as possible as you can considering risks and benefit
Thank You for Your Attention! Seongwook Han, MD.PhD. Professor of Medicine, Keimyung University School of Medicine Arrhythmia Service, Cardiology, Dongsan Medical Center