1. 경구용 항응고제와 항혈소판제의 병행치료에 대한 최신 지견
경구용 항응고제와 항혈소판제의 병행치료에 대한 최신 지견

2. 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

3. Dual is not sufficient !

4. What are the options for Anticoagulation?
None
Warfarin (Target INR )
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

5. 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:

6. 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: )
Triple therapy (INR > 2.5) ‡
66.7 % 60 50
200
Days
600
† Log Rank, p< vs dual therapy
‡ Log Rank, p< vs triple therapy (INR: )
Rossini & Angiolillo, Am J Cardiol. 2008;102:

7. 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 =
Major bleeding: % not reported
OR 2.00 (1.41 to 2.83); P =
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
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:

8. 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: , p ;
adjusted HR: 3.2,
95% CI: 1.1 to 9.1, p 0.03
Sarafoff N et al. J Am Coll Cardiol. 2013;61:

9. 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)

10. 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:

11. 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)

12. 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:

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

14. ISAR-TRIPLE

18. 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

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

20. Poorly controlled warfarin patients12 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 C+A
OAC OAC
Connolly SJ et al. Circulation 2008;118:2029−2037
Connolly SJ, et al. Circulation 2008; 118:

21. 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:

22. 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

23. 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

24. 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

25. 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

26. 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.

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

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

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

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

31. 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.

32. 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.

33. 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 = 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 = )
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]

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

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

38. 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 /clc.22572; 2. ClinicalTrials.gov Identifier: NCT ; 3. ClinicalTrials.gov Identifier: NCT ;
4. ClinicalTrials.gov Identifier: NCT

39. 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 /clc.22572

40. 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 mg qd‡
≤72 hours
XARELTO® 15mg QD
Aspirin mg qd
1,6, or 12 months
VKA (target INR )
Clopidogrel 75 mg qd† Aspirin mg qd
VKA (target INR )
Aspirin 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 ( mg/d). Data on File. Janssen Pharmaceuticals, Inc.

48. 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

49. 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: /europace/euv309

50. 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
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)

51. 경청해 주셔서 감사합니다 !