Capri Cardiovascular Conference 2.0 2015 Capri, 24-25 aprile 2015

Capri Cardiovascular Conference 2.0 2015 Capri, 24-25 aprile 2015 Web Lecture 25 aprile 2015 - ore 10:00-10:30 Le nuove frontiere dei nuovi anticoagulanti orali nella prevenzione tromboembolica nella fibrillazione atriale Raffaele De Caterina Università G. d Annunzio Chieti e Fondazione G. Monasterio Pisa, Italia 25 aprile 2015, 10:00-10:20 + 10 min. disc

Prof. Raffaele De Caterina Conflicts of Interest Co-author ESC Guidelines on Atrial Fibrillation 2010-2012 Steering Committee member, National Coordinator for Italy, and Co-author of APPRAISE-2, ARISTOTLE, AVERROES National Coordinator for Italy of ENGAGE-AF Fees, honoraria and research funding from Sanofi- Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi-Sankyo, Novartis, Merck

Le nuove frontiere con i NOACs nella FA NOACs peri-cardioversione NOACs peri-ablazione NOACs nella FA silente e nell ictus criptogenetico La FA nei pazienti che ricevano uno stent coronarico NOACs nella stenosi mitralica

Le nuove frontiere con i NOACs nella FA NOACs peri-cardioversione NOACs peri-ablazione NOACs nella FA silente e nell ictus criptogenetico La FA nei pazienti che ricevano uno stent coronarico NOACs nella stenosi mitralica

Stroke/systemic embolism (%) Rates of stroke/se within 30 days of cardioversion in RE-LY were similarly low for both dabigatran and warfarin 1.8 1.5 1.2 0.9 RR 1.28 (95% CI: 0.35 4.76) P=0.71 RR 0.49 (95% CI: 0.09 2.69) 0.6 0.3 0 0.77 Dabigatran 110 mg BID 0.30 P=0.40 Dabigatran 150 mg BID 0.60 Warfarin Events/number: 5/647 2/672 4/664 BID = twice daily; RR = relative risk; SE = systemic embolism Nagarakanti R et al. Circulation 2011;123:131 6

Cardioversion End of study treatment Cardioversion Design: randomized, open-label, parallel-group, active-controlled multicentre study Inclusion criteria: Age 18 years, non-valvular AF lasting >48 h or unknown duration, scheduled for cardioversion Rivaroxaban 20 mg od* Rivaroxaban 20 mg od* Early # R 1 5 days 42 days Cardioversion strategy 2:1 VKA Rivaroxaban 20 mg od* VKA Rivaroxaban 20 mg od* OAC 30-day follow-up Delayed R 2:1 21 days (max. 56 days) VKA 42 days VKA *15 mg if CrCl 30 49 ml/min; VKA with INR 2.0 3.0; # protocol recommended only if adequate anticoagulation or immediate TEE Ezekowitz MD et al. Am Heart J 2014;167:646 652; www.clinicaltrials.gov. NCT01674647

X-VeRT: primary efficacy endpoint by population Rivaroxaban % n*/n VKA % n*/n Risk ratio (95% CI) Favours rivaroxaban Favours VKA mitt population 0.51 5/978 1.02 5/492 0.50 (0.15 1.73) ITT population 0.50 5/1002 1.00 5/502 0.50 (0.15 1.72) Safety population (on-treatment) 0.51 5/988 0.80 4/499 0.63 (0.17 2.34) 0,1 1 10 The trend in risk ratio in favour of rivaroxaban was consistent for all populations analysed *Number of patients with events Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

X-VeRT: primary safety endpoints Rivaroxaban (N=988) VKA (N=499) % n* % n* Risk ratio (95% CI) Major bleeding 0.61 6 0.80 4 0.76 (0.21 2.67) Fatal 0.1 1 0.4 2 Critical-site bleeding 0.2 2 0.6 3 Intracranial haemorrhage 0.2 2 0.2 1 Hb decrease 2 g/dl 0.4 4 0.2 1 Transfusion of 2 units of packed RBCs or whole blood 0.3 3 0.2 1 *Number of patients with events; patients may have experienced more than one primary safety event Safety population Cappato R et al. Eur Heart J 2014: doi: 10.1093/eurheartj/ehu367

ENSURE-AF edoxaban peri-cardioversion Lip GWH et al. Am Heart J, in press 9

Le nuove frontiere con i NOACs nella FA NOACs peri-cardioversione NOACs peri-ablazione NOACs nella FA silente e nell ictus criptogenetico La FA nei pazienti che ricevano uno stent coronarico NOACs nella stenosi mitralica

Catheter ablation is associated with risk of thromboembolism and bleeding Major complications (%) Global survey of 20 825 catheter ablation procedures in 16 309 patients 1.4 1.2 1.31 1 0.8 0.6 0.71 0.4 0.2 0 Tamponade 0.23 Stroke TIA Anticoagulation before, during, and after ablation needs to be carefully managed to minimize stroke and bleeding risk TIA, transient ischaemic attack Cappato R et al. Circ Arrhythm Electrophysiol 2010;3:32 38; Calkins H et al. Europace 2012;14:528 606 11

ESC 2012 guidelines 1 recommend continuation of anticoagulation in patients undergoing catheter ablation For patients on OAC, guidelines recommend undertaking catheter ablation on continuous anticoagulation Anticoagulation should be kept at low therapeutic levels (e.g., INR 2.0 2.5) throughout ablation Continuation of long-term OAC post-ablation recommended in all patients with CHA 2 DS 2 -VASc score 2 Continuation of oral VKA therapy can be considered throughout the ablation procedure but robust data for NOACs are lacking 1. Camm AJ et al. Eur Heart J 2012;33:2719 47 12

RE-CIRCUIT : study design Target n=362 patients per arm (total N=724 patients) 1 endpoint ISTH major bleeding and stroke Patients with paroxysmal or persistent NVAF scheduled for catheter ablation, eligible for dabigatran 150 mg BID according to local label Dabigatran 150 mg BID Warfarin (INR 2.0 3.0) Randomization Day 0 (Ablation) Day 60 (End of treatment) Screening 0 2 weeks Pre-ablation 4 8 weeks Post-ablation 60 days Follow-up 1 week Notice: uninterrupted anticoagulation peri-ablation! Clinicaltrials.gov NCT02348723 Mar 2015

Le nuove frontiere con i NOACs nella FA NOACs peri-cardioversione NOACs peri-ablazione NOACs nella FA silente e nell ictus criptogenetico La FA nei pazienti che ricevano uno stent coronarico NOACs nella stenosi mitralica

Patients with ESUS* are a subset of patients with cryptogenic stroke Haemorrhagic (8%) 1 All strokes 25% large artery atherosclerotic stenosis 2,3 Ischaemic (92%) 1,2 5% unusual (e.g. dissections, arteritis) 2,3 25% small artery disease (lacunar stroke) 2,3 25% cryptogenic (no known cause) 2,3 20% major-risk source cardiogenic embolism 2,3 If clearly specified diagnostic criteria are fulfilled ESUS 2 *embolic stroke of undetermined source 1. Andersen K et al. Stroke 2009;40:2068 72; 2. Adams HP et al. Stroke 1993;24:35 41; 3. Hart RG et al. Lancet Neurol 2014;13:429 38 15

Criteria for diagnosis of ESUS Stroke detected by CT or MRI that is not lacunar Absence of extracranial or intracranial atherosclerosis causing 50% luminal stenosis in arteries supplying the area of ischaemia a No major-risk cardioembolic source of embolism b No other specific cause of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse) a Definition specific to RESPECT-ESUS trial; b For example, permanent, persistent, or paroxysmal AF CT = computed tomography; MRI = magnetic resonance imaging Hart RG et al. Lancet Neurol 2014;13:429 38 16

Current secondary prevention after cryptogenic stroke or ESUS Secondary stroke prevention is crucial High rate of morbidity and mortality 1 Routine use of anticoagulants not established Current guidelines recommend antiplatelets Cryptogenic stroke ACCP 2008 guidelines 2 Non-cardioembolic stroke AHA/ASA 2008 3, ESO 2008 4, ACCP 2012 5, AHA/ASA 2014 6 guidelines Recommendation [level of evidence] 6 ASA [A] ASA + dipyridamole [B] Clopidogrel [B] Limited knowledge and data to guide treatment decisions considerable unmet need 7 ASA = acetylsalicylic acid 1. Hankey GJ et al. Stroke 2002;33:1034 40; 2. Albers GW et al. Chest 2008;133:630S 669S; 3. Adams RJ et al. Stroke 2008;39:1647 52; 4. ESO Executive Committee. Cerebrovasc Dis 2008;25:457 507; 5. Lansberg MG. Chest 2012;141(suppl):e601S-e636S; 6. Kernan WN et al. Stroke 2014;45:2160 236; 7. Hart RG et al. Lancet Neurol 2014;13:429 38 17 Aug 2014

RE-SPECT ESUS : design Primary endpoint: stroke Index ischaemic stroke (ESUS)* Diagnostic pathway : assess with MRI/CT to rule out lacunae; vascular imaging and 24-hour rhythm monitoring to rule out AF R Dabigatran (150 or 110 mg BID) Placebo (matching ASA) ASA (100 mg OD) Placebo (matching dabigatran) End of treatment n=3000 n=3000 0 days 3 months 0.5 3 years Inclusion criteria ESUS within 3 months before randomization (6 months in patients 60 years + additional risk factors) No extra- or intra-cranial atherosclerosis with >50% luminal stenosis in artery supplying area of ischaemia No AF of >6 minutes duration/24 hour period No major risk of cardioembolic source of embolism Age 60 years or 50 59 years with 1 risk factor for recurrent stroke Eligible for treatment with antithrombotic therapy (i.e. dabigatran etexilate or ASA) 30-day follow-up ClinicalTrials.gov NCT02239120 Aug 2014

LCM Overview of upcoming studies* Study Indication Objective Secondary stroke prevention in patients with a recent Embolic Stroke of Undetermined Source (ESUS) To investigate the potential clinical value of rivaroxaban in preventing recurrence of stroke in patients with a recent ESUS (N~7,000) Peripheral artery disease (PAD) ACSsp To explore the potential benefits of rivaroxaban in reducing major thrombotic vascular events in patients with PAD undergoing peripheral artery interventions (N>5,000) To investigate rivaroxaban in combination with single antiplatelet treatment with either clopidogrel or ticagrelor for long-term secondary prevention in patients with recent ACS in a broader range of patients (N=2,000 3,000). If successful, this phase II study will be followed by a confirmatory, fully powered global phase III study. * Details on these studies will be made available once disclosed on www.clinicaltrials.gov

Le nuove frontiere con i NOACs nella FA NOACs peri-cardioversione NOACs peri-ablazione NOACs nella FA silente e nell ictus criptogenetico La FA nei pazienti che ricevano uno stent coronarico NOACs nella stenosi mitralica

What are the risks for patients with AF who undergo PCI? AF CAD/ACS PCI Increased risk of stroke Myocardial ischaemia Increased risk of stent thrombosis and bleeding Management of patients with AF who undergo PCI must balance the need for thromboprophylaxis with the risk of bleeding Lip GY et al. Thromb Haemost 2010;103:13 28 21

How should thromboprophylaxis be managed in these patients? Stroke prevention in AF Thrombosis prevention in PCI OACs DAPT (ASA + clopidogrel) PCI in patient with AF Triple therapy? (ASA + clopidogrel + OAC) Increased bleeding risk vs DAPT No robust data for efficacy and safety ASA = acetylsalicylic acid; DAPT = dual antiplatelet therapy Coppens M and Eikelboom JW. Circ Cardiovasc Interv 2012;5:454 5 22

ESC Working Group consensus Antithrombotic treatment following coronary artery stenting in AF patients at moderate to high risk of TE (in whom OAC is required) Short-term Triple therapy: warfarin + ASA + clopidogrel Duration varies from 2 4 weeks (high haemorrhagic risk, elective PCI and BMS) to 6 months (low/intermediate haemorrhagic risk, ACS, BMS/DES) Followed by warfarin + either clopidogrel or ASA for up to 12 months in some patient groups (ACS or DES) Lifelong Warfarin alone New antiplatelets such as prasugrel and ticagrelor have not yet been evaluated with OACs BMS = bare metal stent; DES = drug-eluting stent; ESC = European Society of Cardiology; RCT = randomized controlled trial; TE = thromboembolism 1. Lip GYH et al. Thromb Haemost 2010;103:13 28; 2. Heidbuchel H et al. Europace 2013;15:625 51 23

PIONEER AF-PCI 2100 patients with NVAF No prior stroke/tia PCI with stent placement 72 hours After Sheath removal R A N D O M I Z E 1,6, or 12 months Rivaroxaban 2.5 mg bid Clopidogrel 75 mg qd Aspirin 75-100 mg qd 1,6, or 12 months VKA (target INR 2.0-3.0) Clopidogrel 75 mg qd Aspirin 75-100 mg qd Rivaroxaban 15 mg qd* Clopidogrel 75 mg qd Rivaroxaban 15mg qd Aspirin 75-100 mg qd VKA (target INR 2.0-3.0) Aspirin 75-100 mg qd End of treatment at 12 months Primary endpoint: TIMI major, minor, and bleeding requiring medical attention Secondary endpoint: CV death, MI, stroke, and stent thrombosis *XARELTO dosed at 10 mg once daily in patients with CrCl of 30 to <50 ml/min. Alternative P2Y 12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor. Low-dose aspirin (75-100 mg/d). Data on File. Janssen Pharmaceuticals, Inc.

RE-DUAL PCI : design Dabigatran 150 mg BID + P2Y12 inhibitor Run-in period R n=2840 patients per arm Dabigatran 110 mg BID + P2Y12 inhibitor Warfarin (INR 2.0 3.0) + P2Y12 inhibitor + ASA 1 EP Follow-up visits at month 1, 3, 6, 9, 12, and 15; and 18, 24, and 30 post-randomization or end of trial Minimum treatment duration: 6 months DAT = dual antithrombotic therapy; EP = endpoint; INR = international normalized ratio Clinical Trial Protocol 1160.186 25

Le nuove frontiere con i NOACs nella FA NOACs peri-cardioversione NOACs peri-ablazione NOACs nella FA silente e nell ictus criptogenetico La FA nei pazienti che ricevano uno stent coronarico NOACs nella stenosi mitralica

«Valvular» AF always excluded from NOAC trials but definition of «valvular AF» has been variable Best definition: «Mechanical valve And Rheumatic Mitral stenosis AF» (MARM-AF) Yet, these two settings mechanical valve and rheumatic mitral stenosis are quite different

The ERA trial Design Flow Chart Key elements Open-label design, increasing feasibility Comparison with the standards of care for thromboembolic prophylaxis, which may consist of antiplatelet agents (aspirin in most cases); or VKAs, but in which case the quality of INR control is to be expected as being poor A superiority design, which we consider rational on the basis of the considerations highlighted above To be conducted in countries such as Mexico, South Africa, or China, where centers exist recruiting a large number of patients with rheumatic heart disease, and where a possibility exists of patient follow-up Ideally with a once-daily drug, considering the importance of practical aspects of long-term treatments in countries where difficulties in ensuring patients education to the importance of therapeutic adherence are higher than in developed countries

Grazie per l attenzione!