General Overview and Highlights of the 2016 North American Consensus Document on Antithrombotic Therapy in the Atrial Fibrillation Patient Undergoing PCI Dominick J. Angiolillo, MD, PhD Professor of Medicine Medical Director - Cardiovascular Research Program Director – Interventional Cardiology Fellowship University of Florida College of Medicine - Jacksonville

AF + PCI: Dimension of the Problem AF is the most common cardiac arrhythmia occurring in 1- 2% of the general population, with a prevalence that increases with age. Among AF patients at moderate-to-high risk for cardioembolic events, the use of chronic OAC is the mainstay of stroke prevention. The prevalence of CAD also increases with age and coexists in 20- 30% of AF patients; ~ 5–7% of PCI patients, who are routinely treated with DAPT, also have AF or other indications for OAC. These estimates are expected to increase as the global burden of AF increases, driven in large part to the aging population. These observations raise an important clinical problem regarding the optimal antithrombotic management of patients undergoing PCI who also have AF. Currently, there are limited evidenced-based data on the optimal antithrombotic treatment regimen of PCI patients who also require OAC due to AF, and Guidelines provide limited insights on the management of these high-risk patients.

The 2011 North American Perspective Faxon DP et al. Circ Cardiovasc Interv. 2011;4:522-534

AF + PCI: A North American Perspective – 2016 Update

AF + PCI: A North American Perspective – 2016 Update The Challenge: Discerning the choice of antithrombotic therapy Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Triple therapy is associated with increased bleeding Bleeding risk in PCI patients (n=40,812) with AMI treated with different combination of aspirin, clopidogrel and VKA 40,812 patients from Denmark admitted to hospital with first-time MI Sorensen R, et al. Lancet. 2009;374:1967-74

AF + PCI: A North American Perspective – 2016 Update Consensus Document Objectives Provide current views on: embolic/stroke risk ischemic/thrombotic cardiac risk bleeding risk Describe the recent advances in antithrombotic (antiplatelets and anticoagulants) pharmacology, stent designs, and clinical trials relevant to the field. Provide expert consensus derived recommendations, using a pragmatic approach, on the management of patients with AF undergoing PCI. Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Defining the need for chronic OAC CHA2DS2-VASc Score CHF/LV dysfunction (LVEF ≤40%) 1 Stroke/TIA/TE 2 Hypertension 1 Vascular disease (prior MI, PAD, or aortic) 1 Age ≥75 years 2 Age 65–74 years 1 Diabetes mellitus 1 Sex category (ie, female sex) 1 Low risk (no antithrombotic therapy) defined as CHA2DS2-VASc of 0 in males (“age <65 and lone AF”) CHA2DS2-VASc of 1 in females (“age <65 and lone AF”) Lip GY, et al. Chest. 2010;137:263–272

AF + PCI: A North American Perspective – 2016 Update Defining the need for chronic OAC: Importance of Compliance Poorly controlled warfarin patients Connolly SJ, et al. Circulation 2008; 118: 2029-2037.

The North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI

AF + PCI: A North American Perspective – 2016 Update Pre-procedural Considerations 1. Define “Appropriateness” for PCI. - Consider Appropriateness Criteria for PCI - Nothing wrong with trying medical therapy first - Once stent is implanted: point of no return! A U I Patel M et al JACC 2009

AF + PCI: A North American Perspective – 2016 Update Pre-procedural Considerations 2. Ischemic/thrombotic & bleeding risk stratification Levine G et al. Circulation 2016

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI

The North American Perspective – 2016 Update Procedural Considerations 1. Vascular Access: Radial Consistently shown to be associated with less bleeding Mortality benefit 2. Stent choice: New generation DES - New generation DES: better safety even compared with BMS; typically AF patients also have more complex CAD - BMS: if considered, should only be for simple lesions (short length/ large diameter) - BVS: high early ST rates which increase with lesion complexity (some advocate more potent antithrombotic therapy) - Other new stent platforms: many not available in the US

Radial vs Femoral access Risk of mortality in 19 328 patients from 17 RCTs Andò G, Capodanno D. JACC Card Interv 2016

Definite Stent Thrombosis Through 3 Years In 18,334 Patients (28,739 Lesions) By Stent Type 3-Year Incidence of Stent Thrombosis 1-Year Landmark Analysis BMS 1G-DES 2G-DES BMS 1G-DES 2G-DES Stent thrombosis (%) Stent Thrombosis (%) When DES was first introduced, concerns regarding stent thrombosis arose as the addition of drug and polymer to a bare metal platform increased ST rates and thus the need for continued DAPT post-stenting. With polymer and drug science evolving, second generation DES has shown to be less apt for ST than both first generation DES and BMS. This shift has triggered debate about the recommendations for DAPT duration, especially considering the potential negative side effects of DAPT such as excessive bleeding and ischemia. Tada, Kastrati et al. JACC INTV 2013; 6:1267-74

ST Risk in EES Rates of Def/Prob ST at 1 Year Increasing complexity Xience CoCr EES Promus PtCr EES ABSORB BVS Increasing complexity All-Comers Patient Populations N: 751 897 1126 694 987 1862 905 1101 2503 101 660 171 74 135 *STEMI Population, **Indicates 6 month results EXAMINATION: Sabate, et al. Lancet 2012. COMPARE: Lancet 2010 Jan 16;375(9710):201-9., RESOLUTE All-Comers: Serruys et al N Engl J Med 2010; 363:136-146., TWENTE: Clemens von Birgelen at TCT 2011. , DUTCH PEERS: Clemens von Birgelen at TCT 2013; PE Prove: Raul Moreno, MD PCR 2013. HOST Assure: Hyo-Soo Kim, MD, PhD ACC 2013; ABSORB Cohort B: Serruys, PW, ACC 2013; ABSORB EXTEND: Chevalier B. , EuroPCR 2013; BVS EXPAND: Robert-jan van Guens. EuroPCR 2014. RAI: lelasi, A. EuroPCR 2014. Kraak, R. EuroPCR 2014. PLATINUM Plus, DUTCH PEERS, PE-PROVE and HOST ASSURE studied PROMUS Element stent (PtCr EES). Results from different studies are not directly comparable. Information provided for educational purposes only.

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI Whenever possible (i.e., elective / non-emergent procedures), a brief period of wash- out from the anticoagulant effect of OAC is preferable. For patients on a VKA: INR to be preferably ≤2.0 when using a radial approach (recommended) and ≤ 1.5 if femoral approach is used. Patients on a NOAC: withhold therapy for 24 hours (or 48 hours for patients with impaired renal function with dabigatran) irrespective of vascular access site. Although patients with stable CAD can forgo bridging with parenteral anticoagulation, this should be considered for patients presenting with an ACS.

AF + PCI: A North American Perspective – 2016 Update Suggested Timing of Interruption of NOACs before coronary angiography/percutaneous coronary intervention Day 0=day of the invasive procedure The suggested timings do not consider patients with severe renal insufficiency (CrCl or eGFR <30 ml/min). The last dose of these drugs should not be taken any later than the above recommended times. Bridging (e.g., with LMWH) is not recommended or necessary for these agents unless a longer period of interruption occurs. Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI Given the current controversies over the net benefits of bivalirudin over other antithrombotic treatment regimens as well as differences in practice patterns among interventionalists, this expert consensus does not recommend a specific parenteral antithrombin agent over another. However, bivalirudin appears to be a reasonable treatment option in patients at higher risk of bleeding, particularly in those presenting with ACS and if a femoral approach is being used.

Bleeding endpoints: BARC 3 or 5 2.5% 1.4% UFH Bivalirudin Valgimigli M et al. NEJM 2016

AF + PCI: A North American Perspective – 2016 Update The choice of OAC (VKA or NOAC) is at the discretion of the treating physician, with patients informed on the risk-benefit profiles of each agent based on available data. Continuing with the same OAC after PCI may be reasonable, particularly if the patient has been compliant and has not experienced complications. If a VKA is chosen, maintain an INR in the 2.0-3.0 range (ideally between 2.0–2.5). A NOAC at lowest therapeutic dose effective for stroke prevention should be preferred over a VKA in patients unable to have their INR routinely monitored or are unable to maintain INR in the therapeutic range. A recommendation on use of doses lower than the full anticoagulant dose of a specific NOAC cannot be provided until further data become available.

AF + PCI: A North American Perspective – 2016 Update Bleeding risk in PCI patients on DAPT + VKA % 100 95.1 % 95.1 % 90 80 Bleeding event free survival 70 † Dual therapy ‡ 66.7 % 60 Triple therapy (INR: 2.0-2.5) Triple therapy (INR > 2.5) 50 200 300 450 600 Days † Log Rank, p<0.0001 vs dual therapy ‡ Log Rank, p<0.0001 vs triple therapy (INR: 2.0-2.5) Rossini & Angiolillo, Am J Cardiol. 2008;102:1618-23

Use of Antiplatelets Drugs in AF Trials of NOACs Percentages refers to use of antiplatelet drugs at some time during the study period, including discontinuation at enrollment and non-consecutive use RE-LY Dabigatran ROCKET-AF Rivaroxaban ARISTOTLE Apixaban ENGAGE Edoxaban Concomitant use of aspirin alone 32% ≈37% ≈31% ≈29% Concomitant use of clopidogrel alone ≈2% <2% Concomitant use of DAPT ≈5% Excluded

AF + PCI: A North American Perspective – 2016 Update Summary of Randomized Trials of NOACs Compared With VKA in Patients With NVAF Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

The North American Perspective – 2016 Update This expert consensus recommends that the duration of DAPT in AF patients treated with stents also on OAC should not extend to a full 12 months and to consider SAPT starting within the first 6-months (0 to 6 months post-stenting depending on the ischemic/thrombotic and bleeding risk profile) for up to 12 months. This group consensus recommends that dropping aspirin rather than a P2Y12 receptor inhibitor should be considered (favoring the use of clopidogrel and avoiding prasugrel or ticagrelor).

AF + PCI: A North American Perspective – 2016 Update Bleeding reduction strategy: Minimize DAPT duration Minimize DAPT duration and start SAPT (timing based on thrombotic/bleeding risk profile of the individual patient) choosing clopidogrel over aspirin because: pivotal role of P2Y12-mediated signaling in thrombotic and inflammatory processes; established clinical efficacy of P2Y12 inhibitors to reduce stent thrombosis; although bleeding risk with OAC plus clopidogrel is higher than OAC plus aspirin, the combination of OAC plus clopidogrel is comparable to triple therapy in respect to the prevention of ischemic stroke, with a trend towards benefit of MI/coronary death; moreover, the risk of all-cause mortality is similar between OAC plus clopidogrel and triple therapy but markedly increased for OAC plus aspirin; superior efficacy of monotherapy with clopidogrel 75mg vs aspirin 325mg, with better gastrointestinal tolerability (discomfort and hemorrhage). Dropping clopidogrel may be a reasonable option, particularly if patients are “known” to be poor clopidogrel responders (or have HPR), or are at-risk for this condition due to CYP2C19 LOF allele carrier status. However, in the absence of data demonstrating a benefit of use of platelet function/genetic testing to tailor antiplatelet treatment regimens, this expert consensus recommends against the routine use of these tests. Moreover, switching to a more potent P2Y12 receptor inhibitor (prasugrel or ticagrelor) is strongly discouraged because of the increased the risk of bleeding complications.

AF + PCI: A North American Perspective – 2016 Update The WOEST Trial: First randomised trial comparing two regimens with and without aspirin in patients on OAC undergoing PCI treated with clopidogrel WOEST - 573 patients on oral anticoagulation undergoing PCI Dewilde WJ et al. Lancet. 2013;381(9872):1107-15

AF + PCI: A North American Perspective – 2016 Update ISAR-TRIPLE Short-term triple antithrombotic therapy is not superior than longer duration 6-week 6-month P value CV death 1.7% 3.0% 0.29 MI 2.0% 0.03 Definite ST 0.7% 0.50 Ischemic stroke 1.0% 1.3% 0.99 TIMI major bleeding 5.3% 4.0% 0.44 Death, MI, ST, stroke or TIMI major bleeding P=0.63 Fiedler et al. J Am Coll Cardiol. 2015;65:1619-29.

AF + PCI: A North American Perspective – 2016 Update Benefit and Safety With Triple Therapy Versus Dual Therapies Lamberts et al. JACC 2013; 62: 981 - 989

AF + PCI: A North American Perspective – 2016 Update Triple Therapy With Aspirin, Prasugrel, and VKA Kaplan-Meier analysis for the primary endpoint (cumulative incidence of TIMI major and minor bleeding) at 6 months. 377 DES treated pts of whom 21 switched to prasugrel because of HPR 6 [28.6%) vs. 24 [6.7%]; unadjusted HR: 4.6, 95% CI: 1.9-11.4, p 0.001; adjusted HR: 3.2, 95% CI: 1.1 to 9.1, p 0.03 Sarafoff N et al. J Am Coll Cardiol. 2013;61:2060-2066.

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI Discontinuation of one antiplatelet agent should be considered 1-3 months after PCI, this may occur sooner (including immediately after PCI) or later (but not beyond 6 months) according to the ischemic/thrombotic and bleeding risk profiles of the patient. Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Aspirin might be no longer needed after 12 months in AF patients with stable CAD on VKA Age ad gender adj. HR (95% CI) No difference In CV death/MI/CVA in patients treated with VKA + APT versus patients treated with VKA alone adj. HR: 1.15 95% CI 0.58-2.27 p=0.697 SAT Reference DAPT 1.58 [0.72-3.47] VKA+SAT 7.30 [3.91-13.64] VKA alone 1.69 [0.39-7.30] 0.1 1 100 CORONOR – 4,184 patients on oral anticoagulation with stable (>12 mo) CAD Hamon M, et al. J Am Coll Cardiol 2014;64:1430–6

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI Balanced thrombotic / bleeding risk Shorter (e.g., 1 month) and longer (e.g., 3 months) DAPT duration should be considered in patients treated with BMS and DES, respectively. Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI High bleeding / low thrombotic risk Discontinuation of one antiplatelet agent may be considered immediately after PCI if patients at very-high bleeding risk Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI High thrombotic / low bleeding risk Shorter (e.g., 3 month) and longer (e.g., 6 months) DAPT duration should be considered in patients treated with BMS and DES, respectively. Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Pragmatic algorithm for the management of AF patients requiring OAC undergoing PCI More frequent follow-up visits. Don’t leave in the exclusive care of PCP. Choice/duration of antithrombotic therapy may change over time depending on clinical evolution. At 1-year post-PCI need to evaluate need to continue with any antiplatelet agent based on bleeding/thrombotic risk.

AF + PCI: A North American Perspective – 2016 Update Peri- and post-procedural Considerations Angiolillo DJ et al. Circ Cardiovasc Interv. 2016

AF + PCI: A North American Perspective – 2016 Update Ongoing trials of NOACs in AF patients undergoing PCI Angiolillo DJ et al. Circ Cardiovasc Interv. 2016