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

2. Disclosures
Consultant, Honoraria
Terumo Medical
Speaker:
Pfizer

3. 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

4. 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?

5. 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 % 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

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
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

7. 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
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

8. 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

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

10. 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%

11. Hazard Ratios for Bleeding
The Lancet. 2009;374(9706):

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

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

14. Why not ASA + Warfarin?
AHJ 2007

15. 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 %
Drug Eluting Stent %
Fears of bleeding with triple therapy appear to drive therapeutic decisions in the cath lab

16. 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 |

17. 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= %CI[ ] |

18. 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= %CI[ ]

19. All-Cause Mortality WOEST Triple therapy group Double therapy group
7.5 %
Triple therapy group
Double therapy group
6.4%
HR= %CI[ ]
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

20. 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

21. ESC Recommendations in Patients with AF at Moderate to High Stroke Risk in Whom OAC is Required
Low bleeding risk
VKA (INR )
Elective BMS*
Elective DES (-olimus)
VKA (INR ) +
Clopidogrel (or ASA)
Elective DES (paclitaxel)
ACS + BMS/DES
1 mo
6 mo
12 mo
High bleeding risk**
VKA (INR ) +
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: ), warfarin alone (INR ) 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:

22. Moser M. Eur Heart J , 216–223

23. 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

24. Thank you