1. Poly Pharmacy Anticoagulation: OAC + DAPT
Roxana Mehran MD, FACC, FSCAI, FAHA, FESC
Professor of Medicine (Cardiology), and
Population Health Science and Policy
The Icahn School of Medicine at Mount Sinai
CRT 2017
20th Anniversary
Washington, DC

2. Disclosure Statement of Financial Interest
Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship
Company
The Medicines Co., BMS, Astra Zeneca, Lilly/Daiichi Sankyo
Abbott Vascular, Boston Scientific, CSL Behring, Janssen (J+J), Claret
Advisory board for Janssen (J+J), Medscape, Osprey
Grant/Research Support
Consulting Fees/Honoraria

3. The clinical challenge in patients with atrial fibrillation undergoing PCI
5-10% of patients undergoing PCI have atrial fibrillation
STENT THROMBOSIS
STROKE
OAC > DAPT
for Stroke prevention
DAPT > OAC
for Stent Thrombosis prevention
TRIPLE THERAPY
Connolly et al. Lancet. 2006; 367:
BLEEDING

4. Goals for patients under chronic OAC and need for antiplatelet therapy
Prevention of ischemic events (e.g. MI, ST, TLR, death)
DAPT
Prevention of ischemic events (e.g. stroke and death)
OAC
Avoid an increase in bleeding risk

5. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with AFib
Hansen M. Arch Intern Med. 2010;170(16):1433.

6. clinicaltrials.gov (NCT00769938)
Dual therapy (clopidogrel +OAC) v.s. Triple therapy (clopidogrel +ASA +OAC)
clinicaltrials.gov (NCT )
Dewilde W. Lancet 2013; 381:1107

7. WOEST Study Primary Endpoint Incidence of TIMI Bleeding Events
Treatment duration (days)
Cumulative Incidence of Bleeding (%) 30 60 90
120
180
270
365 10 20 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%
HR= % CI
p<0.001
19.5%
Dewilde W. Lancet 2013; 381:1107

8. WOEST Study Secondary Endpoint Incidence of Death, MI, Stroke, Stent Thrombosis & Target Vessel Revascularization 30 60 90
120
180
270
365 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%
HR= % CI
p=0.025
11.3%
Cumulative Incidence of Events (%)
Treatment duration (days)
Dewilde W. Lancet 2013; 381:1107

9. End of treatment at 12 months
XARELTO® (rivaroxaban) Use in Patients With AF Undergoing PCI: PIONEER AF-PCI
End of treatment at 12 months
XARELTO® 15 mg qd* Clopidogrel 75 mg qd† R A N D O M I Z E
2100 patients with NVAF
No prior stroke/TIA
PCI with stent placement
1,6, or 12 months
≤72 hours
After
Sheath
removal
XARELTO® 2.5 mg bid Clopidogrel 75 mg qd†
Aspirin mg qd‡
XARELTO® 15mg QD
Aspirin mg qd
1,6, or 12 months
VKA (target INR ) Aspirin mg qd
VKA (target INR ) Clopidogrel 75 mg qd†
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.
Gibson et al., N Engl J Med Dec 22;375(25):

10. XARELTO® 15 mg qd* Clopi 95%, Ticag 4%, Prasugrel 1%
Pre-Randomization Choice of Thienopyridine & Duration of DAPT: PIONEER AF-PCI
XARELTO® 15 mg qd* Clopi 95%, Ticag 4%, Prasugrel 1%
WOEST Like R A N D O M I Z E
2100 patients with NVAF
Coronary stenting
No prior stroke/TIA, GI bleeding, Hb<10, CrCl<30
1 mo: 16%
6 mos: 35%
12 mos: 49%
≤ 72 hours
After
Sheath
removal
XARELTO® 2.5 mg bid Clopi 95%, Ticag 4%, Prasugrel 1%
Aspirin mg qd‡
XARELTO® 15mg QD
Aspirin mg qd
ATLAS Like
1 mo: 16%
6 mos: 35%
12 mos: 49%
VKA (target INR ) Aspirin mg qd
TTR 65%
VKA (target INR ) Clopi 95%, Ticag 4%, Prasugrel 1%
Aspirin mg qd
Triple
Therapy
Gibson et al., N Engl J Med Dec 22;375(25):

11. Baseline Characteristics
Riva + P2Y12
(N=709)
Riva + DAPT
VKA + DAPT
(N=706)
Age, mean ± SD
70.4 ± 9.1
70.0 ± 9.1
69.9 ± 8.7
Sex, female, n (%)
181 (25.5%)
174 (24.5%)
188 (26.6%)
Diabetes Mellitus, n (%)
204 (28.8%)
199 (28.1%)
221 (31.1%)
Type of Index Event, n (%)
NSTEMI
130 (18.5%)
129 (18.4%)
123 (17.8%)
STEMI
86 (12.3%)
97 (13.8%)
74 (10.7%)
Unstable Angina
145 (20.7%)
148 (21.1%)
164 (23.7%)
Stable Angina
340 (48.5%)
329 (46.8%)
330 (47.8%)
Drug-eluting stent, n (%)
464 (65.4%)
471 (66.8%)
468 (66.5%)
Type of Atrial Fibrillation, n (%)
Persistent
146 (20.6%)
149 (21.1%)
Permanent
262 (37.0%)
238 (33.6%)
243 (34.5%)
Paroxysmal
300 (42.4%)
325 (45.8%)
313 (44.4%)
* p < 0.05
Gibson et al., N Engl J Med Dec 22;375(25):

12. Overall TTR for INR of 2.0 to 3.0: 65.0%
Proportion of Time in Therapeutic Range (TTR) by Region for the VKA Subjects
Overall TTR for INR of 2.0 to 3.0: 65.0%
8.9
10.0
7.0
10.3
7.9
8.2
3.7
3.3
3.9
4.5
4.1
4.4
TTR
65.0
60.7
64.4
64.4
66.6
63.6
9.0
8.1
9.9
9.6
10.4
9.2
15.9
16.9
12.7
10.5
13.1
14.2
N=651
N=60
N=43
N=237
N=276
N=35
Gibson et al., N Engl J Med Dec 22;375(25):
Excluding the First 14 days of Exposure.
Proportion calculated within each subject firstly and then average across subjects within each region.

13. Kaplan-Meier Estimates of First Occurrence
of Clinically Significant Bleeding Events
TIMI Major, TIMI Minor, or Bleeding Requiring Medical Attention (%)
26.7%
p<
p<
18.0%
VKA + DAPT
16.8%
VKA + DAPT
VKA + DAPT
VKA + DAPT
Riva + DAPT
Riva + DAPT
Riva + P2Y12
Riva + P2Y12
HR = 0.63 (95% CI )
ARR = 8.7
NNT = 12
HR = 0.59 (95% CI )
ARR = 9.9
NNT = 11
Riva + P2Y12 v. VKA + DAPT
HR=0.59 (95% CI: )
p <
ARR=9.9
NNT=11
Riva + DAPT v. VKA + DAPT
HR=0.63 (95% CI: )
p <
ARR=8.7
NNT=12
Days
No. at risk
VKA + DAPT
Riva + P2Y12
Riva + DAPT
VKA + DAPT
Riva + DAPT
VKA + DAPT
Riva + P2Y12
VKA + DAPT
696
697
697
706
697
696
706
697
628
593
593
628
636
593
636
593
606
555
555
606
600
555
600
555
579
521
585
579
521
521
585
521
461
543
461
543
461
543
461
426
509
426
510
509
426
510
426
383
409
329
409
329
329
383
329
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA. Hazard ratios as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test.
Gibson et al. AHA 2016

14. Bleeding Endpoints Using TIMI Criteria (Primary Analysis)
Kaplan-Meier Estimates
Hazard Ratio (95% CI)
Overall
Riva + P2Y12 (N=696)
Riva + DAPT (N=706)
Comb. Riva (N=1402)
VKA + DAPT (N=697)
Riva + P2Y12
vs. VKA + DAPT
Riva + DAPT vs. VKA + DAPT
Combined vs. VKA + DAPT
Clinically significant bleeding
109 (16.8%)
117 (18.0%)
226 (17.4%)
167 (26.7%)
0.59 ( ) p<0.001
0.63 ( ) p<0.001
0.61 ( ) p<0.001
TIMI Major
14 (2.1%)
12 (1.9%)
26 (2.0%)
20 (3.3%)
0.66 ( ) p=0.234
0.57 ( ) p=0.114
0.61 ( ) p=0.093
TIMI minor
7 (1.1%)
14 (1.1%)
13 (2.2%)
0.51 ( ) p=0.144
0.50 ( ) p=0.134
0.51 ( ) p=0.071
BRMA
93 (14.6%)
102 (15.8%)
195 (15.2%)
139 (22.6%)
0.61 ( ) p<0.001
0.67 ( ) p=0.002
0.64 ( ) p<0.001
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Clinically significant bleeding is the composite of TIMI major, TIMI minor, and BRMA events. A subject could have more than component event. n = number of subjects with events, N = number of subjects at risk, % = KM estimate at the end of study. Hazard ratios as compared to VKA group are based on the (stratified, only for Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank p-values as compared to VKA group are based on the (stratified, only for Overall 2.5 mg BID/15 mg QD comparing VKA) two-sided log rank test. BRMA = Bleeding requiring medical attention, TIMI = Thrombolysis in myocardial infarction, CI = confidence interval, DAPT = dual antiplatelet therapy, HR = hazard ratio, VKA = vitamin K antagonist
Gibson et al. AHA 2016

15. Bleeding Events Using ISTH Scales (Pre-Specified Secondary Analysis)
Riva + P2Y12
(N = 696)
Riva + DAPT
(N = 706)
Combined Riva
(N = 1402)
VKA + DAPT
(N = 697)
Group 1
vs Group 3
p-value
Group 2
Combined
ISTH classification
Major bleeding
27 (3.9%)
25 (3.5%)
52 (3.7%)
48 (6.9%)
0.013
0.005
0.001
Hemoglobin drop*
21 (3.0%)
19 (2.7%)
40 (2.9%)
34 (4.9%)
0.075
0.032
0.018
Transfusion†
15 (2.2%)
13 (1.8%)
28 (2.0%)
0.997
0.677
0.813
Critical organ bleeding‡
6 (0.9%)
5 (0.7%)
11 (0.8%)
11 (1.6%)
0.224
0.125
0.093
Fatal
2 (0.3%)
4 (0.3%)
0.452
0.285
0.167
CRNM bleeding
90 (12.9%)
97 (13.7%)
187 (13.3%)
130 (18.7%)
0.003
Minimal bleeding
123 (17.7%)
151 (21.4%)
274 (19.5%)
163 (23.4%)
0.008
0.369
0.041
Gibson et al., N Engl J Med Dec 22;375(25):
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. ISTH denotes International Society on Thrombosis and Haemostasis,
*Hemoglobin drop = a fall in hemoglobin of 2 g/dL or more.
† Transfusion = a transfusion of 2 or more units of packed red blood cells or whole blood.
‡ Critical organ bleeding are cases where investigator-reported bleeding site is either intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome or retroperitoneal

16. Bleeding Events Using GUSTO & BARC Scales (Pre-Specified Secondary Analyses)
Riva + P2Y12
(N = 696)
Riva + DAPT
(N = 706)
Combined Riva
(N = 1402)
VKA + DAPT
(N = 697)
Group 1
vs Group 3
p-value
Group 2
Combined
GUSTO classification
Severe
7 (1.0%)
10 (1.4%)
17 (1.2%)
20 (2.9%)
0.012
0.060
0.007
Moderate
13 (1.9%)
23 (1.6%)
9 (1.3%)
0.388
0.839
0.539
Mild
193 (27.7%)
214 (30.3%)
407 (29.0%)
255 (36.6%)
<0.001
0.013
BARC classification
Type 0
14 (2.0%)
0.820
0.428
0.721
Type 1 (minimal)
125 (18.0%)
153 (21.7%)
278 (19.8%)
167 (24.0%)
0.006
0.307
0.029
Type 2 (actionable)
92 (13.2%)
91 (12.9%)
183 (13.1%)
126 (18.1%)
0.002
Type 3a
8 (1.2%)
15 (1.1%)
12 (1.7%)
0.369
0.237
0.212
Type 3b (>5g, pressors)
16 (2.3%)
29 (2.1%)
26 (3.7%)
0.035
0.108
0.025
Type 3c
2 (0.3%)
5 (0.7%)
7 (0.5%)
4 (0.6%)
0.687
>0.999
0.760
Type 4
0 (0.0%) -
Type 5a
1 (0.1%)
0.497
.554
Type 5b (Definite Fatal)
3 (0.2%)
0.070
0.106
0.019
Gibson et al., N Engl J Med Dec 22;375(25):
BARC denotes Bleeding Academic Research Consortium, GUSTO Global Utilization Of Streptokinase and Tpa For Occluded Arteries Probable fatal bleeding (type 5a) is bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed and there is no autopsy or confirmatory imaging. Definite fatal bleeding (type 5b) is bleeding that is directly observed (by either clinical specimen [blood, emesis, stool, etc] or imaging) or confirmed on autopsy. Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug.

17. Kaplan-Meier Estimates of First Occurrence of CV Death, MI or Stroke
Cardiovascular Death, Myocardial Infarction, or Stroke (%)
6.5%
Riva + P2Y12
6.0%
5.6%
Riva + DAPT
VKA + DAPT
Riva + P2Y12 v. VKA + DAPT
HR=1.08 (95% CI: )
p=0.750
Riva + DAPT v. VKA + DAPT
HR=0.93 (95% CI: )
p=0.765
No. at risk
Days
Riva + P2Y12
Riva + DAPT
VKA + DAPT
694
704
695
648
662
635
633
640
607
621
628
579
590
596
543
562
570
514
430
457
408
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug.
Composite of adverse CV events is composite of CV death, MI, and stroke. Hazard ratios as compared to VKA group are based on the (stratified, only for the Overall, 2.5 mg BID/15 mg QD comparing VKA) Cox proportional hazards model. Log-Rank P-values as compared to the VKA group are based on the (stratified, only for Overall, 2.5 mg BID/115 mg QD comparing VKA) two-sided log rank test.
Gibson et al. AHA 2016

18. All Cause Death or All Cause Hospitalization for an Adverse Event
Gibson et al. AHA 2016

19. All Cause Death or All Cause Hospitalization for an Adverse Event
All Cause Death or All Cause Rehospitalization (%)
41.9%
34.9%
VKA + DAPT
Riva + P2Y12
31.9%
Riva + DAPT
Riva + P2Y12 v. VKA + DAPT
HR=0.79 (95% CI: )
p=0.008
ARR=7.0
NNT=15
Riva + DAPT v. VKA + DAPT
HR=0.75 (95% CI: )
p=0.002
ARR=10.0
NNT=10
No. at risk
Days
Riva + P2Y12
Riva + DAPT
VKA + DAPT
696
706
697
609
607
592
582
570
540
559
548
490
496
493
422
437
454
369
322
367
272
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Rehospitalizations do not include the index event and include the first rehospitalization after the index event. Hazard ratios as compared to the VKA group are based on the Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the two-sided log rank test.
Gibson et al. AHA 2016

20. All Cause Hospitalization for an Adverse Event
All Cause Rehospitalization (%)
41.5%
34.1%
VKA + DAPT
Riva + P2Y12
31.2%
Riva + DAPT
Riva + P2Y12 v. VKA + DAPT
HR=0.77 (95% CI: )
p=0.005
ARR=7.4
NNT=14
Riva + DAPT v. VKA + DAPT
HR=0.74 (95% CI: )
p=0.001
ARR=10.3
NNT=10
No. at risk
Days
Riva + P2Y12
Riva + DAPT
VKA + DAPT
696
706
697
609
607
592
582
570
540
559
548
490
496
493
422
437
454
369
322
367
272
Treatment-emergent period: period starting after the first study drug administration following randomization and ending 2 days after stop of study drug. Rehospitalizations do not include the index event and include the first rehospitalization after the index event. Hazard ratios as compared to the VKA group are based on the Cox proportional hazards model. Log-Rank P-values as compared to VKA group are based on the two-sided log rank test.
Gibson et al. AHA 2016

21. Summary
A strategy of either rivaroxaban 15 mg daily plus a P2Y12 or rivaroxaban 2.5 mg BID + DAPT was associated with a reduction in clinically significant bleeding compared with conventional triple therapy of VKA + DAPT (HR = 0.59 ( ), p < 0.001, NNT 11, and HR = 0.63 ( ), p <0.001, NNT 12 respectively ).
CV death / MI / stroke were comparable among the groups (Riva 15 mg+ P2Y12 = 6.5%, Riva 2.5 mg+ DAPT = 5.6%, VKA + DAPT = 6.0%) with broad confidence intervals
Rates of all cause death or hospitalization were reduced in the Rivaroxaban arms (Riva 15 mg + P2Y12 = NNT 15, Riva DAPT, NNT =10)
Gibson et al., N Engl J Med Dec 22;375(25):

22. The Pioneer-AF-PCI trial

23. Gibson et al. AHA 2016

24. STUDY TITLE STUDY HYPOTHESES Worldwide Event Driven Trial R
A prospective Randomised, open label, blinded endpoint (PROBE) study to Evaluate DUAL antithrombotic therapy with dabigatran etexilate (110mg b.i.d. and 150mg b.i.d.) plus clopidogrel or ticagrelor vs. triple therapy strategy with warfarin (INR 2.0 – 3.0) plus clopidogrel or ticagrelor with aspirin in patients with non valvular atrial fibrillation (NVAF) that have undergone a percutaneous coronary intervention (PCI) with stenting. (RE-DUAL PCI)
D110 plus a P2Y12 inhibitor is:
Non-inferior with respect to the combined thrombotic event rate (TE: death + MI + stroke/SE)
AND
Non-inferior* with respect to clinically relevant bleeding relative to a triple combination of warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) plus ASA
STUDY
HYPOTHESES
D150 plus a P2Y12 inhibitor is:
Non-inferior with respect to the combined thrombotic event rate (TE: death + MI + stroke/SE)
AND
Non-inferior* with respect to clinically relevant bleeding relative to a triple combination of warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) plus ASA
Worldwide Event Driven Trial
Paroxysmal, persistent or permanent AF
(PCI with stenting [BMS or DES] elective or ACS)
Dabigatran 150mg BID + P2Y12 inhibitor¥**
1° End Point
Time to first combined thrombotic
event or death
(all death, MI, Stroke/SE)
Plus
Time to first clinically relevant bleeding rate
(ISTH Major)
Dabigatran 110mg BID + P2Y12 inhibitor¥** R
Screening
0-72 hours
post-PCI
Warfarin (INR ) + P2Y12 inhibitor¥ + ASA** 3M 6M 9M
12M
15M
18/24/30M
or EOT
n = 2840 patients per arm
(Total = 8520 patients)
After establishing non-inferiority of the D110 and D150 DAT regimens, testing for superiority will be conducted
ASA is discontinued immediately after a successful procedure in patients randomized to receive dabigatran
ASA will be discontinued in the warfarin arm. BMS: Discontinuation of ASA at month 1 ; DES: discontinuation of ASA at month 3
P2Y12 inhibitor (either Clopidogrel or Ticagrelor). The P2Y12 inhibitor can be discontinued after month 12 of follow up at the discretion of the physician * **
AFIB608904PROF

25. 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 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

26. Antithrombotic treatment in patients undergoing PCI who require oral anticoagulation