경구용 항응고제와 항혈소판제의 병행치료에 대한 최신 지견 경구용 항응고제와 항혈소판제의 병행치료에 대한 최신 지견

who are we talking about today? Triple antithrombotic therapy: who are we talking about today? Scenario #1 A patient with AF presenting with an ACS Scenario #2 A patient with new onset AF and recent history of ACS (<1year) A patient with AF Undergoing elective PCI Scenario #3

Dual is not sufficient !

What are the options for Anticoagulation? None Warfarin (Target INR 2.0-2.5) Dabigatran 150 mg bid Dabigatran 110 mg bid Rivaroxaban 20 mg qd Rivaroxaban 2.5 mg bid (with DAPT) Apixaban 5 mg bid Edoxaban ? 2

Triple : Bleeding risk in patients with AMI Patients with AMI treated with different combination of aspirin, clopidogrel and VKA Sorensen R, et al. Lancet. 2009;374:1967-74

Bleeding risk in PCI patients on dual antiplatelet therapy requiring oral anticoagulation %100 95.1 % Bleeding event free survival 95.1 % 90 80 70 † Dual therapy Triple therapy (INR: 2.0-2.5) Triple therapy (INR > 2.5) ‡ 66.7 % 60 50 200 300 450 Days 600 † 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

Clinical data in PCI patients requiring oral anticoagulation Name/author Design n Mean F/U Comparison Efficacy endpoint OR/HR (95% CI) Bleeding endpoint  Riuz-Nodar Retrospective, single-centre 426 594 days DAPT vs. TT Mortality: 27.8 vs. 17.8% HR 3.43 (1.61–7.54); P = 0.002 Major bleeding: 14.9 vs. 9.0% Not reported MACE: 26.5 vs. 38.7% HR 4.90 (2.17–11.10); P = 0.001 Minor bleeding 12.6 vs. 9.0% Retrospective, 2 centres 604 693 days Mortality: % not reported HR 0.34 (0.17–0.68); P < 0.01 MACE: % not reported HR 0.40 (0.22–0.74); P < 0.01  Karjalainen Retrospective, 6 centres 478 12 months TT vs. DAPT Stent thrombosis: 1.9 vs. 5.9% Major bleeding: 6.6 vs. 11.8% Stroke: 2.8 vs. 8.8%  Sambola Prospective, 3 centres 405 6 months TT vs. VKA + single anti-platelet CV events: 7.9 vs. 15.2% Major bleeding: 4.3 vs. 6.5% Stent thrombosis 4.0 vs. 8.7% Minor bleeding: 11.2 vs. 6.5% TT vs. VKA + ASA Stent thrombosis: 1.9 vs. 15.2% Major bleeding: 6.6 vs. 6.1% MI: 8.5 vs. 18.2% TT vs. VKA + clopidogrel Stent thrombosis: 1.9 vs. 0.0% Major bleeding: 6.6 vs. 11.1% MI: 8.5 vs. 11.1%  Gao Meta-analysis (9 trials) 5181 1–18 months TT vs. non-TT Ischaemic stroke: % not reported OR 0.29 (0.15–0.58); P = 0.0004 Major bleeding: % not reported OR 2.00 (1.41 to 2.83); P = 0.0001 mortality: % not reported OR 1.20 (0.63–2.27); P = 0.56 MI: % not reported OR 0.84 (0.57–1.23); P = 0.38  Zhao 1996 >3 months MACE: 8.8% vs. 13.9 OR 0.60; (0.42–0.86); P = 0.005 Major bleeding: 4.1 vs. 1.9% OR 2.12 (1.05–4.29); P = 0.04 Mortality: 6.5 vs. 9.7% OR 0.59; (0.39–0.90); P = 0.01  Hensen Registry 118 606 3.3 years DAPT vs. VKA alone Stroke: % not reported HR 1.66 (1.34–2.04); P not reported TT vs. VKA alone Bleeding: 15.7 vs. 3.9% per Patient-year HR 3–70 (2.89–4.76); P not reported  Lamberts 11 480 288 days CV-death, MI, ischaemic stroke: 20.1 vs. 19.4% HR 1.15 (0.95;1.40); not significant early bleeding: % not reported HR 1.47 (CI: 1.04–2.08) delayed bleeding: % not reported HR 1.36 (0.95–1.95) Moser M, Eur Heart J. 2014;35:216-23.

Triple Therapy With Aspirin, Prasugrel, and VKA’s 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.

Case for and against shortening duration of triple therapy in AF patients with stents? For Most ST occurs early 1 year bleeding rates are unacceptably high Recommendations for ≥12m are based on low quality data No randomized evidence that shorter compromises efficacy Against Potential for harm (increased ST, MACE)

Meta-analysis of trials comparing different durations of DAPT in stented pts (n=8,274) Outcome 3-12 m ≥12 m Stent Thrombosis 0.6% 0.5% Myocardial Infarction 1.5% 1.4% Stroke 1.0% Death 2.1% 2.4% TIMI Major Bleeding* 0.2% 0.7% *Significant difference Cassese S, et al. Eur Heart J 2012; 33: 3078-87.

P2Y12 inhibitor is beneficial after stenting No evidence that addition of aspirin to P2Y12 inhibitor is beneficial after stenting Experimental ASA + Ticlopidine ASA + VKA clopidogrel Control ASA Trials STARS (n=1,103) ISAR (n=517) (n=1,096) MATTIS (n=350) FANTASTIC (n=485) TOPPS (n=1,016) Muller (n=700) CLASSICS (n=1,020) Superior treatment Clopidogrel (safety)

WOEST trial: Omission of aspirin reduces bleeding First randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting treated with clopidogrel Dewilde W, et al. Lancet 2013; 381: 1107-15.

WOEST trial: Omission of aspirin reduces bleeding Efficacy outcomes Dewilde W, et al. Lancet 2013; 381: 1107-15.

ISAR-TRIPLE

2012 ACC/AHA UA/NSTEMI Guidelines Antiplatelet Therapy IIa IIb III For UA/NSTEMI patients who have an indication for anticoagulation, the addition of warfarin‡ may be reasonable to maintain an INR of 2.0 to 3.0.§ I IIIIa IIIIb IIIIII Use of warfarin in conjunction with aspirin and/or P2Y12 receptor inhibitor therapy is associated with an increased risk of bleeding, and patients and clinicians should watch for bleeding, especially gastrointestinal, and seek medical evaluation for evidence of bleeding. Modified 2012 II IIa IIb III Targeting oral anticoagulant therapy to a lower INR (e.g., 2.0 to 2.5) might be reasonable in patients with UA/NSTEMI managed with aspirin and a P2Y12 inhibitor New 2012 Jneid, H. et al. JACC 2012:645–81 5

Other approaches to reduce bleeding without compromising efficacy Are there subgroups of patients who do not require oral anticoagulation?

Poorly controlled warfarin patients 12 12 TTR <65% TTR ≥65% 10 10 RR=0.93 (0.70–1.24) p=0.61 RR=2.14 (1.61–2.85) p<0.0001 8 8 Event rate (%) Event rate (%) 6 OAC C+A 6 C+A 4 4 OAC 2 2 0.0 0.5 1.0 1.5 0.0 0.5 1.0 Years 1.5 Years No. at risk No. at risk C+A 1598 1527 1156 439 C+A 1737 1625 1233 488 OAC 1600 1525 1152 417 OAC 1771 1697 1306 507 Connolly SJ et al. Circulation 2008;118:2029−2037 Connolly SJ, et al. Circulation 2008; 118: 2029-2037.

Patients at lower risk of stroke Annual risk of stroke less than 5% (CHADS2 0-2) Reduction in stroke with well-controlled warfarin vs. DAPT in lower stroke risk patients is likely outweighed by increased bleeding Connolly SJ, et al. Lancet 2006; 367: 1903-12.

ESC WG Thrombosis – EHRA – EAPCI Consensus Document Bleeding risk evaluation (HAS-BLED) Timing on triple therapy more limited as possible based on: indication to PCI (ACS, stable angina) stent type (DES and BMS) Limited use of triple therapy is associated with at least a 2-fold lower risk of major bleeding compared with prolonged use Lip G, et al. Eur Heart J 2010; 31, 1311–1318

Antithrombotic strategies following coronary artery stenting in patients with AF at moderate to high thrombo-embolic risk (in whom oral anticoagulation therapy is required): HAS-BLED 0-2 Elective BMS 1 month: triple therapy of VKA (INR 2.0–2.5) + aspirin ≤100 mg/day + clopidogrel 75 mg/day Lifelong: VKA (INR 2.0–3.0) alone DES 3 (-olimus group) to 6 (paclitaxel) months: triple therapy of VKA (INR 2.0–2.5) + aspirin ≤100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0–2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lifelong: VKA (INR 2.0–3.0) alone ACS BMS/DES 6 months: triple therapy of VKA (INR 2.0–2.5) + aspirin Lip G, et al. Eur Heart J 2010 / ESC Guidelines for AF 2010

Antithrombotic strategies following coronary artery stenting in patients with AF at moderate to high thrombo-embolic risk (in whom oral anticoagulation therapy is required): HAS-BLED ≥3 Elective BMS 2–4 weeks: triple therapy of VKA (INR 2.0–2.5) + aspirin ≤100 mg/day + clopidogrel 75 mg/day Lifelong: VKA (INR 2.0–3.0) alone ACS 4 weeks: triple therapy of VKA (INR 2.0–2.5) + aspirin ≤100 mg/day + clopidogrel 75 mg/day Up to 12th month: combination of VKA (INR 2.0– 2.5) + clopidogrel 75 mg/day (or aspirin 100 mg/day) Lip G, et al. Eur Heart J 2010; 31, 1311–1318 / ESC Guidelines for AF 2010

NOACs: Is there a role in ACS/PCI? Factor Xa antagonists Darexaban (RUBY-1) Rivaroxaban (ATLAS ACS 2) Apixaban (APPRAISE 2) Not Studied in ACS Edoxaban (only Afib, phase III ongoing) Betrixaban (only Afib, phase II completed) Factor IIa antagonists Ximelagatran (ESTEEM) Dabigatran (REDEEM) Angiolillo DJ et al. Am J Cardiovasc Drugs 2013

NOACs: the state of the evidence DABIGATRAN Data on dabigatran 150 bid plus aspirin in AF comes from the Phase II PETRO trial (increased bleeding with ASA 81- and 325-mg). In Phase II in the ACS setting (RE-DEEM), dabigatran in combination with aspirin and clopidogrel was associated with excessive bleeding, with no ischemic benefit (plans for phase III stopped). The only AF phase III trial where aspirin and clopidogrel use was not contraindicated was RE-LY with dabigatran, so data on triple therapy with a NOAC (when given at stroke prevention doses in AF patients) are limited.

RE-LY Antiplatelet Subgroup Anaysis Dabigatran 110mg Non-inferior Efficacy Superior safety Dans AL et al Circulation. 2013;127:634-640

RE-LY Antiplatelet Subgroup analysis Dabigatran 150mg Trend better Efficacy Non-inferior safety Dans AL et al Circulation. 2013;127:634-640

RE-LY Antiplatelet analysis Dans AL et al Circulation. 2013;127:634-640

RE-LY Antiplatelet analysis Dans AL et al Circulation. 2013;127:634-640 10

Limitations of the RE-LY subanalysis Use of antiplatelet agents was not randomized or stratified. At baseline, 40% of the patients were using an antiplatelet agent, and only 1 of 5 used it continuously throughout the study (median duration, 66% of the total study duration). This suggests that the bleeding rates reported here probably underestimate the true risk associated with prolonged continuous combination therapy. Most of these patients were taking aspirin, whereas the use of clopidogrel only (1.9%) or dual antiplatelet therapy (4.5%) was infrequent. Prasugrel or ticagrelor were not used. Dans Al et al. Circulation. 2013;127:634–640.

Do the results observed in RE-LY also apply to factor Xa antagonists?  Rivaroxaban Significantly lower mortality rates with very low doses (2.5 mg bid) on top of aspirin and clopidogrel compared with placebo in the ATLAS 2 trial in ACS (but ICH increased 4-fold), there are no data on ACS with the dose of rivaroxaban used for anticoagulation in AF (ROCKET-AF 20 mg od).  Apixaban Apixaban could have the best of both worlds (less stroke and less bleeding in the ARISTOTLE). However, any speculation on TAT with apixaban, at present, is not evidence-based. used at the stroke prevention dose (5 mg b.i.d.) in the ACS setting (APPRAISE II) in combination with aspirin plus clopidogrel, was associated with no reduction in cardiovascular events but an excess of major bleeding.

ATLAS ACS 2−TIMI 51 Trial design: Patients with recent ACS were randomized in a 1:1:1 fashion to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo, in addition to dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine in 93%. Patients were followed for 2 years. Results Primary endpoint: CV death/MI/stroke for rivaroxaba n vs. placebo: 8.9% vs.10.7%, p = 0.008. True for 2. 5 mg (9.1%) and 5 mg (8.8%) doses individually. Gr eatest efficacy for ischemic endpoints with the 2.5 m g daily dose, including mortality (2.9% vs. 4.5%, p = 0.002) Non-CABG TIMI major bleeding: placebo (0.6%), 2.5 mg (1.8%) and 5 mg (2.4%) p < 0.001 Conclusions Addition of very low dose rivaroxaban (2.5 mg twice daily) in patients with a recent ACS (most of whom were on DAPT) ↓ mortality, and ischemic events as compared with placebo. However, bleeding was sim ultaneously ↑ First successful large trial with an oral anti-Xa agent in patients with ACS taking antiplatelet agents; use will require assessment of ischemia/bleeding risks Mega JL, et al. N Engl J Med 2011;Nov 13:[Epub]

Clinical outcomes in patients with and without prior MI in ROCKET-AF

ARISTOTLE: Antiplatelet Analysis Alexander JH, et al. Eur Heart J 2013 (online)

Research on antithrombotic therapy in patients with NVAF undergoing PCI/post-ACS is ongoing Patients receiving OAC + antiplatelet Trial Design RE-DUAL PCI™1 (dabigatran) Parallel assignment N=2502 PIONEER AF-PCI2 (rivaroxaban) Parallel assignment N=2131 AUGUSTUS ACS/PCI3 (apixaban) 2x2 factorial N=2300 ENTRUST-AF-PCI4 (edoxaban) Parallel assignment N~1500 1. Cannon C et al. Clin Cardiol 2016; DOI 10.1002/clc.22572; 2. ClinicalTrials.gov Identifier: NCT01830543; 3. ClinicalTrials.gov Identifier: NCT02415400; 4. ClinicalTrials.gov Identifier: NCT02866175

ISTH major or CRNM bleeding RE-DUAL PCI™ investigates two new approaches to improving care for patients with AF undergoing PCI Patients with NVAF undergoing PCI with stenting randomized 1:1:1* Dual antithrombotic therapy with dabigatran Dual antithrombotic therapy with dabigatran Triple antithrombotic therapy with VKA Warfarin plus dual antiplatelets: ASA (for 1 month only after BMS or 3 months only after DES) plus P2Y12 inhibitor† 150 mg BID plus single antiplatelet (P2Y12 inhibitor†) 110 mg BID plus single antiplatelet (P2Y12 inhibitor†) Primary endpoint: ISTH major or CRNM bleeding *Patients aged ≥80 years outside of the USA will be assigned to 110 mg BID dabigatran etexilate or warfarin in a 1:1 ratio †Clopidogrel 75 mg OD or ticagrelor 90 mg BID; BMS, bare-metal stent; CRNM, clinically relevant non-major; DES, drug-eluting stent Cannon C et al. Clin Cardiol 2016; DOI 10.1002/clc.22572

XARELTO® (rivaroxaban) Use in Patients With AF Undergoing PCI: PIONEER AF-PCI End of eatment at 12 months XARELTO® 15 mg qd* Clopidogrel 75 mg qd† R A N D O After Sheath M removal I Z E  2100 patients with NVAF No prior s troke/TIA PCI with s tent place ment 1,6, or 12 months XARELTO® 2.5 mg bid Clopidogrel 75 mg qd† Aspirin 75-100 mg qd‡ ≤72 hours XARELTO® 15mg 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 VKA (target INR 2.0-3.0) Aspirin 75-100 mg qd 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 P2Y12 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.

Apixaban Versus Warfarin in Patients with AF and ACS or PCI: The AUGUSTUS Trial Randomize n =4,600 Patients Inclusion AF (prior, persistent, or >6 hrs duration) Physician decision that oral anticoag is indicated ACS and/or PCI with planned P2Y12 inhibitor for 6 months Exclusion Contraindication to DAPT Other reason for warfarin (prosthetic valve, mod/sev MS) Apixaban Warfarin P2Y12 inhibitor for all patients x 6 months Aspirin for all on the day of ACS or PCI Aspirin versus placebo after randomization ASA placebo ASA placebo Primary outcome: major/clinically relevant bleeding (through 6 months) Secondary objective: Death, MI, stroke, stent thrombosis

Elective PCI with newer generation DES or BMS ESC practical guidance 2015: long-term treatment of patients on a NOAC after revascularization or ACS Discharge 1 month Triple therapy NOAC+A+C 3 months 6 months 1 year Elective PCI with newer generation DES or BMS Double therapy NOAC + A or C NOAC monothera py Alternative: DAPT only, if CHA2DS2-VASc = 1 (men) or 2 (women) (only CAD) & elevated bleeding risk Acute coronary syndrome Triple therapy NOAC+A+C Double therapy NOAC + A or C NOAC monothera py Factors to shorten combination therapy - (Uncorrectable) high bleeding risk - Low atherothrombotic risk (by REACH or SYNTAX score if elective? - GRACE ≥118 if ACS?) Factors to lengthen combination therapy - First-generation DES - High atherothrombotic risk (scores as above; stenting of the left main, proximal left anterior descending, proximal bifurcation, recurrent MIs; etc) and low BMS, bare-metal stent; DES, drug-eluting stent; A, ASA 75–100 mg OD; C, clopidogrel 75 mg OD; Europace 2015; doi:10.1093/europace/euv309

What do I do in my practice? 1) Which stent? Define if PCI/stenting is “appropriate” BMS for simple lesions (rare), otherwise a 2nd generation DES (frequent) Preferential use of radial approach during PCI 2) Which antiplatelet agent? Clopidogrel (± low dose aspirin) Avoid prasugrel/ticagrelor; avoid/limit NSAIDs Add PPI (preferably non CYP2C19 interfering) 3) Which OAC? I prefer VKA (more data; antidote), targeting an INR 2.0-2.5 If already on a NOAC, continue with the same NOAC Limited data on NOACs (antidote; patients concerned) 4) For how long? Month 1 (may consider longer depending in high risk patient: Triple Rx After: Dual Rx with OAC + clopidogrel (stop aspirin) up to 12 month >1 year: Dual Rx with OAC ± aspirin (depending on patient risk)

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