When should aspirin be dropped from triple therapy? Samir B. Pancholy, MD, FACC, FSCAI Scranton, PA

Disclosures Consultant, Honoraria Terumo Medical Speaker: Pfizer

When should aspirin be dropped from triple therapy? Short answer We don’t know for sure!! Longer answer Probably when the bleeding risk outweighs the ischemic benefit An even longer answer Once we can reliably separate bleeding risk from ischemic (MI, stent thrombosis, stroke, systemic embolism), then we will know in whom dual therapy with an anticoagulant and a P2Y12 inhibitor is preferred but RCTs are ongoing

When should we drop aspirin? Scope of the problem – how many patients are potentially candidates for triple therapy? Therapeutic goals of triple therapy Risks of triple therapy Data supporting OAC + P2Y12 (WOEST Trial) Recommendations – can we make any?

CAD (ACS, PCI/Stent, CABG) AF and CAD Overlapping Patient Populations Overlapping Indications for Antithrombotic Therapy Challenging Challenging Aspirin Clopidogrel New P2Y12s VKA? NOACs? VKA Antiplatelets NOACs CAD (ACS, PCI/Stent, CABG) Atrial Fibrillation Stroke risk Bleeding risk Renal function Subgroups Monitoring Reversal Cost Doses Duration Subgroups Genetics Cost 2.5 million patients are on chronic warfarin therapy – clarify afib is predominant cause >8% men over 65, >4% women over 65 Stroke risk: DVT/PE: anticoagulation assoc w absolute risk reduction of 7-26%/yr depending on underlying cause, incidence of thromboembolism between 0.6-2.1% per month AF: stroke rate <2-10% depending on CHADS2 score Annual risk of stroke 1.9% 2.8% 4.0% 5.9% 8.5% 12.5% 18.2% Valves: 8%/year if not anticoagulated The art of medicine Practice guidelines largely based on clinical trials that exclude patients with other diseases / indication

CHA2DS2-VASc Assessment of Thromboembolic Risk Score Annual stroke rate, % n 1084 73 538 0.78 1 1.3 2.01 2 2.2 3.71 3 3.2 5.92 4 4.0 9.27 5 6.7 15.26 6 9.8 19.78 7 9.6 21.50 8 22.38 9 15.2 23.64 CHF/ LV dysfunction 1 Hypertension 1 Age  75 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease 1 Age 65-74 1 Sex category (female) 1 Score 0 – 9 Validated in 1084 NVAF patients not on OAC with known TE status at 1 year in Euro Heart Survey Lip GYH, et al. Chest 2009 Olesen JB et al. BMJ 2011;342:124 6

CHA2DS2-VASc Assessment of Thromboembolic Risk Score Annual stroke rate, % n 1084 73 538 0.78 1 1.3 2.01 2 2.2 3.71 3 3.2 5.92 4 4.0 9.27 5 6.7 15.26 6 9.8 19.78 7 9.6 21.50 8 22.38 9 15.2 23.64 CHF/ LV dysfunction 1 Hypertension 1 Age  75 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease 1 Age 65-74 1 Sex category (female) 1 10-20% annual risk of stroke Score 0 – 9 Validated in 1084 NVAF patients not on OAC with known TE status at 1 year in Euro Heart Survey Lip GYH, et al. Chest 2009 Olesen JB et al. BMJ 2011;342:124 7

Coronary stenting in patient with AF and high risk of stroke: (The problem: You can not simultaneously prevent all three in all patients!) Stent thrombosis Stroke + DAPT OAC Major Bleeding

Registries from Denmark 2000-2005 Mean Follow-up 476 days Over 40,000 patients Registries from Denmark 2000-2005 Mean Follow-up 476 days 4.6% of patients were admitted to hospital with bleeding The Lancet. 2009;374(9706):1967-74

Yearly Incidence of Bleeding Aspirin 2.6% Clopidogrel 4.6% Warfarin 4.3% Aspirin plus clopidogrel 3.7% Aspirin plus Warfarin 5.1% Warfarin plus clopidogrel 12.3% Triple Therapy 12.0%

Hazard Ratios for Bleeding The Lancet. 2009;374(9706):1967-74

Why not ASA + Warfarin? Leon M et al, NEJM, 1998

Why not ASA + Warfarin? Leon M et al, NEJM, 1998

Why not ASA + Warfarin? AHJ 2007

What does the interventional community think? CRTonline.org poll November 23, 2011: For patients undergoing PCI with atrial fibrillation, what type of stent should be used?: Bare Metal Stent - 64.04% Drug Eluting Stent - 35.96% Fears of bleeding with triple therapy appear to drive therapeutic decisions in the cath lab

Study Design N=573 WOEST 1:1 Randomisation: Double therapy group: OAC + 75mg Clopidogrel qd 1 month minimum after BMS 1 year after DES Triple therapy group OAC + 75mg Clopidogrel qd + 80mg Aspirin qd 1 month minimum after BMS 1 year after DES Follow up: 1 year Primary Endpoint: The occurence of all bleeding events (TIMI criteria) Secondary Endpoints: Combination of stroke, death, myocardial infarction, stent thrombosis and target vessel revascularisation - All individual components of primary and secondary endpoints |

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

Secondary Endpoint (Death, MI,TVR, Stroke, ST) WOEST Secondary Endpoint (Death, MI,TVR, Stroke, ST) Days Cumulative incidence 30 60 90 120 180 270 365 0 % 5 % 10 % 15 % 20 % 284 272 266 261 252 242 223 n at risk: 279 276 273 263 258 234 Triple therapy group Double therapy group 17.7% 11.3% p=0.025 HR=0.60 95%CI[0.38-0.94]

All-Cause Mortality WOEST Triple therapy group Double therapy group 7.5 % Triple therapy group Double therapy group 6.4% HR=0.39 95%CI[0.16-0.93] p=0.027 5 % Cumulative incidence of death 2.6% 2.5 % Stent thrombosis rates nonsignificantly higher in the tripe therapy arm (1.5% vs. 3.2%) 0 % 30 60 90 120 180 270 365 Days n at risk: 284 281 280 280 279 277 270 252 279 278 276 276 276 275 274 256

Novel oral anticoagulants in patients with AF and ACS and/or coronary stents Trials examining triple therapy vs. NOAC + P2Y12: Rivaroxaban PIONEER Dabigatran RE-DUAL Apixaban AAA Edoxaban EVOLVE

ESC Recommendations in Patients with AF at Moderate to High Stroke Risk in Whom OAC is Required Low bleeding risk VKA (INR 2.0-3.0) Elective BMS* Elective DES (-olimus) VKA (INR 2.0-2.5) + Clopidogrel (or ASA) Elective DES (paclitaxel) ACS + BMS/DES 1 mo 6 mo 12 mo High bleeding risk** VKA (INR 2.0-2.5) + ASA + Clopidogrel Elective BMS ACS + BMS 1 mo 6 mo 12 mo *In the Consensus document of the ESC Working Group on Thrombosis (Lip et al. Eur Heart J 2010;31:1311-8.), warfarin alone (INR 2.0-3.0) is recommended after the first month. **DES should be avoided as far as possible, but if used, consideration of more prolonged (3 – 6 mo) triple antithrombotic therapy is necessary. Camm et al. Eur Heart J 2010;31:2369-429

Moser M. Eur Heart J 2014 35, 216–223

When to drop aspirin from triple therapy? Goals of therapy in patients requiring (N)OAC and DAPT: Reduce the risk for stroke and/or valve thrombosis Minimize bleeding risk WOEST trial suggests that with contemporary stents, aspirin can be dropped from therapy with no penalty and maybe decreased mortality RCTs with NOACs are ongoing Until these are available, consider dropping aspirin in patients at highest risk for bleeding Older age, anemia, known bleeding source

Thank you