Triple Therapy After PCI in AF: A Quagmire Soon to be Drained

Triple Therapy After PCI in AF: A Quagmire Soon to be Drained Freek W.A. Verheugt Department of Cardiology, Onze Lieve Vrouwe Gasthuis (OLVG) Amsterdam, Netherlands

DISCLOSURES FOR FREEK W. A. VERHEUGT Research support/ principal investigator Consultant Speakers bureau Honoraria Scientific advisory board Bayer HealthCare, Boehringer Ingelheim, Eli Lilly and Roche Bayer Healthcare, Eli Lilly, Daiichi-Sankyo, and Merck none Bayer Healthcare, Eli Lilly, Daiichi-Sankyo and Merck AstraZeneca and Cardialysis B.V.

Triple Therapy in Stented Patients Benefit and risk in registries Benefit and risk in randomized controlled trials Guidelines Future perspectives

Triple Therapy in Stented Patients Benefit and risk in registries Benefit and risk in randomized controlled trials Guidelines Future perspectives

Risk of Triple Therapy on Bleeding in 82,854 Danish AF Patients (15%) Hansen ML. Arch Intern Med. 2010;170:1433-1441

Benefit of Triple Therapy on Stroke in 82,854 Danish AF Patients Hansen ML. Arch Intern Med 2010;170:1433-1441

40,812 MI patients in Denmark with a follow-up of 16 months Sorensen R. Lancet 2009; 374: 1967 1974

Bleeding in Stable Coronary Disease: CORONOR Registy Hamon M. J Am Coll Cardiol 2014;64:1430-1436

Ischemic Endpoints in Stable Coronary Disease: CORONOR Registy Hamon M. J Am Coll Cardiol 2014;64:1430-1436

Dual vs Triple Therapy after Stenting in AF (n = 67) (n = 162) (n = 679) Rubboli A. Clin Cardiol 2014;37:357-364

ASPIRIN USE IN ORBIT-AF Steinberg BA. Circulation 2013;128:721-728

Triple Therapy in Stented Patients Benefit and risk in registries Benefit and risk in randomized controlled trials Guidelines Future perspectives

Triple Therapy in AF and PCI for 6 wks vs 6 mos: ISAR-TRIPLE J Am Coll Cardiol 2015;65:1619 1629

Triple Therapy in AF and PCI for 6 wks vs 6 mos: ISAR-TRIPLE J Am Coll Cardiol 2015;65:1619 1629

Cumulative incidence of bleeding WOEST Lancet 2013:381:1107-1115 Primary Endpoint: Total number of bleeding events 50 % 40 % Triple therapy group Double therapy group 44.9% 30 % 20 % 19.5% 10 % 0 % p<0.001 HR=0.36 95%CI[0.26-0.50] NNT = 4 0 30 60 90 120 180 270 365 Days n at risk: 284 210 194 186 181 173 159 140 279 253 244 241 241 236 226 208

(n=) WOEST Locations of TIMI bleeding: Worst bleeding per patient 50 45 40 35 30 25 20 15 10 5 0 `p = NS 3 3 Intra- Cranial `p = NS 16 20 Acces site p<0.001 8 25 p<0.001 7 30 p<0.001 20 48 GI Skin Other Lancet 2013:381:1107-1115 Double therapy group Triple therapy group Lancet 2013:381:1107-1115

WOEST 9 8 7 6 5 p=0.027 6.4 Secondary Endpoint p=0.382 4.7 p=0.876 7.3 6.8 Lancet 2013:381:1107-1115 Double therapy group Triple therapy group 4 3 2.6 3.3 p=0.128 2.9 p=0.165 3.2 2 1.1 1.5 1 0 Death MI TVR Stroke ST Lancet 2013:381:1107-1115 MI=any myocardial infarction; TVR= target vessel revascularisation (PCI + CABG); ST= stent thrombosis

DUAL VS TRIPLE THERAPY IN AF AFTER PCI FOR MI n= 12,165 Lamberts M. J Am Coll Cardiol 2013;62:981-989

Triple therapy in Stented Patients Benefit and risk in registries Benefit and risk in randomized controlled trials Guidelines Future perspectives

Dual Therapy in AF and PCI ACC/AHA Guidelines on AF. Circulation 2014;130:2071-2104

Global Consensus: Antithrombotic Therapy for PCI in Patients with AF and Stable CAD STEP 1: stroke risk CHA 2 DS 2 -VASc = 1 CHA 2 DS 2 -VASc 2 STEP 2: bleeding risk Low to intermediate (e.g. HAS-BLED = 0 2) High (e.g. HAS-BLED 3) Low to intermediate (e.g. HAS-BLED = 0 2) High (e.g. HAS-BLED 3) STEP 3: antithrombotic therapy 4 weeks 6 months 12 months Lifelong Triple or dual therapy O A C or DAPT A C Dual therapy O A or C or DAPT A C Monotherapy O Dual therapy O C or DAPT A C Triple or dual therapy O A C Dual therapy O A or C Monotherapy O Triple or dual therapy O A C Dual therapy O A or C Time from PCI/ACS OAC ASA 75 100 mg daily Clopidogrel 75 mg daily O A C Lip GHY. Eur Heart J 2014;35:3155-3179 ESC Guidelines Revascularisation. Eur Heart J 2014;35:2541-2619

Antithrombotic Therapy in Patients with AF and ACS ESC Guidelines on NSTE-ACS. Eur Heart J 2016;37:267-315

Triple Therapy in Stented Patients Benefit and risk in registries Benefit and risk in randomized controlled trials Guidelines Future perspectives

Prospective trials of NOACs in NVAF patients with concomitant ACS or undergoing PCI are ongoing PIONEER AF-PCI (rivaroxaban) 2,100 NVAF patients with PCI RE-DUAL PCI (dabigatran) 2,500 NVAF patients with ACS or PCI AUGUSTUS (apixaban) 4,600 NVAF patients with ACS or PCI R Rivaroxaban 15 mg OD* + P2Y12 inhibitor Rivaroxaban 2.5 mg BD + DAPT (P2Y12 inh. + ASA) (for 1, 6 or 12 months) VKA + DAPT (for 1, 6 or 12 months) Rivaroxaban 15 mg OD + ASA VKA + ASA 12-month open-label treatment period *Rivaroxaban 10 mg OD in patients with CrCl 30-50 ml/min Primary objective: To assess the safety of two rivaroxaban treatment strategies vs the combination of VKA with DAPT Primary endpoint: TIMI major, minor bleeding or bleeding requiring medical attention (through 12 months) R Dabigatran 150 mg BD + clopidogrel/ticagrelor Dabigatran 110 mg BD + clopidogrel/ticagrelor VKA + clopidogrel/tic agrelor + ASA (for 1-3 m) # VKA + clopidogrel/ ticagrelor Open-label treatment period for up to 30m # ASA will be given for 1 month post-bms and 3 months post-des R Apixaban 5 mg BD + P2Y12 inhibitor VKA + P2Y12 inhibitor + ASA + placebo + ASA + placebo 6-month treatment period (ASA given doubleblinded) Apixaban 2.5 mg BD in selected patients. Primary objective: To show noninferiority Primary objective: To show non-inferiority of of two different doses of apixaban vs VKA in patients with concomitant dabigatran (150mg BD and 110 mg BD) + P2Y12 inhibitor therapy and To show single antiplatelet therapy (clopidogrel or superiority of anticoagulant (VKA or apixaban) ticagrelor) vs the combination of warfarin plus single antiplatelet therapy (P2Y12 + DAPT inhibitor) vs anticoagulant plus DAPT (P2Y12 Primary endpoint: ISTH major bleeding inhibitor + ASA) (even-driven) Primary endpoint: major/clinically relevant 1. Gibson et al. Am Heart J. 2015;169:472-478.e5; bleeding 2. Clinicaltrials.gov identifier: (through NCT02164864; 6 months) 3. RE-DUAL PCI. http://www.hcri.harvard.edu/research/trials/re-dual_pci; R R ASA for all on day of ACS/P CI

Triple Therapy in Stented Patients Take Home Messages 1. Triple therapy (OAC, clopidogrel and aspirin) for PCI in AF leads to unacceptable bleeding. Possibly, aspirin may be skipped 2. The most recent guidelines mandate for most AF patients undergoing PCI triple therapy for the shortest period as clinically acceptable. 3. For AF patients undergoing PCI the NOACs seem preferable because of their safety profile, but randomized trial data are necessary to support this