- The PIONEER AF-PCI trial found that rivaroxaban plus a P2Y12 inhibitor was non-inferior to VKA plus dual antiplatelet therapy (DAPT) for preventing cardiovascular events in patients with atrial fibrillation undergoing percutaneous coronary intervention. However, the trial did not use approved doses of rivaroxaban for stroke prevention. - The RE-DUAL PCI trial showed that dual antiplatelet therapy (DAT) with dabigatran was non-inferior to triple antiplatelet therapy (TAT) with warfarin for preventing thrombotic events. DAT significantly reduced bleeding risks compared to TAT. - The AUGUST

1. ANTI THROMBOTIC IN PATIENTS WITH AF
UNDERGOING PCI
AJAY PRATAP SINGH
DEPARTMENT OF CARDIOLOGY
DR. RAM MANOHAR LOHIA HOSPITAL, NEW DELHI.

2. EPIDEMIOLOGY OF ATRIAL FIBRILLATION
TOTAL POPULATION OF
INDIA 1.35 BILLION
INCIDENCE OF AF IN
INDIA 0.1% [1] =13.5
CRORES
INCIDENCE OF CAD IN AF
RANGES FROM 16.2-34.5%
Approx. 3.375 Cr. [2][3]
1.Kapoor A. "Epidemiology Of Atrial Fibrillation - An Indian Perspective". Japi.Org, 2020, https://www.japi.org/u2c474c4/epidemiology-of-
atrial-fibrillation-an-indian-perspective.
2.Vora A, Kapoor A, Nair M, et al. Clinical presentation, management, and outcomes in the Indian Heart Rhythm Society-Atrial Fibrillation
(IHRS-AF) registry. Indian Heart J. 2017;69(1):43-47. doi:10.1016/j.ihj.2016.06.006
3.Charantharayil Gopalan B, Namboodiri N, Abdullakutty J, et al. Kerala Atrial Fibrillation Registry: a prospective observational study on
clinical characteristics, treatment pattern and outcome of atrial fibrillation in Kerala, India, cohort profile. BMJ Open. 2019;9(7):e025901.
Published 2019 Jul 27. doi:10.1136/bmjopen-2018-025901

3. WHY THIS SUBGROUP IS TRICKY?
AF is associated with stroke
5-fold increase risk in non valvular AF
17-fold in valvular AF
Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical
perspective. Lancet. 2014;383(9921):999-1008. doi:10.1016/S0140-6736(13)61752-3

4. CONFUSION REGARDING THE TREATMENT
What regimen must be used?
• Dual anti-thrombotic
• Triple anti-thrombotic
What drug must be given?
• Aspirin
• Warfarin
• NOAC
• P2Y12 inhibitor (clopidogrel vs ticagrelor vs prasugel)
For what duration?
• 1/3/6/12 month for each drug.

5. Considering the available options
Gibson CM. J Am Coll Cardiol 2017;69:172–5

6. Timeline of trials helping us to decide the appropiate treatment
WOEST TRIAL (2008)
TAT VS DAT
ISAR – TRIPLE TRIAL
(2008) TAT
DURATION WITH
RESPECT TO
ASPIRIN 6 WKS VS 6
MONTHS
PINIEER AF PCI
TRIAL (2016)
RIVOROXABAN
REGIMEN VS TAT
RE-DUAL PCI TRIAL
(2019) DABIGATRAN
VS TAT
AUGUSTUS TRIAL
(2019) APIXABAN VS
TAT
ENTRUST AF PCI
TRIAL (2020)
ENDOXABAN VS TAT
ONGOING TRIALS
APPROACH ACS AF
TRIAL
APIXABAN VS
PnenpRocon
DAT VS TAT
COACH AF PCI
TRIAL DAT WITH
WARFARIN VS DAT
WITH DABOGATRAN

7. What is the Optimal antiplatElet and anticoagulant
therapy in patients with oral anticoagulation and coronary
StenTing - WOEST
The goal of the trial was to evaluate treatment with clopidogrel alone compared with
aspirin and clopidogrel among patients on oral anticoagulation therapy undergoing
percutaneous coronary intervention (PCI).
Hypothesis:
Clopidogrel alone would be superior at reducing the incidence of bleeding without
increasing thrombotic events
Dewilde, Willem JM et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant
therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled
trial. The Lancet, Volume 381, Issue 9872, 1107 - 1115

10. • WOEST trial, despite the small sample size and open label design, provided some
randomized evidence that the early discontinuation of aspirin reduces bleeding in
comparison to TAT, without any apparent increase in ischemic events.
• But the question of HOW LONG DAPT ? Was not answered by the WOEST trial.

11. • The trial sought to compare a 6-week versus a 6-month duration of triple therapy
in patients undergoing drug-eluting stent (DES) implantation.
Fiedler KA, Maeng M, Mehilli J, et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After
Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015;65(16):1619-1629.
doi:10.1016/j.jacc.2015.02.050

14. • This trial really tested two strategies:
1) is a shorter duration of triple therapy safer, and
2) is aspirin + OAC better than aspirin + clopidogrel + OAC.
• The WOEST trial found that clopidogrel + OAC was in fact superior to aspirin +
clopidogrel + OAC in reducing bleeding outcomes.
Trial didn’t answer the effect of abbreviation of Aspirin (previously proposed by
WOEST trial) as clopidogrel was used in short term therapy.

15. • Following these two trials there was introduction of NOAC’s for Stroke
prevention in patients with non valvular AF. Leading to development of trials
evaluating their utility in AF PCI group of patients.
RE-LY TRIAL – Dabigatran
ROCKET AF TRIAL – Rivaroxaban
ARISTOTLE TRIAL – Apixaban
ENGAGE-TIMI 48 TRIAL – Endoxaban
Miller CS, Grandi SM, Shimony A, et al.. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran,
rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110:453–460.

16. ARE NOAC’S USEFUL IN PATIENTS WITH AF and
undergoing PCI

17. RECENT TRIALS AND GUIDELINES FOR TREATMENT
OF AF WITH PCI

18. published on November 14, 2016, at NEJM.org.
PIONEER AF-PCI

19. PIONEERAF-PCI TRIAL
Key Inclusion and Exclusion Criteria
Key
inclusion
criteria
Key
exclusion
criteria
 Medical history of paroxysmal, persistent or
permanent NVAF.
placement for primary Undergone PCI with stent
atherosclerotic disease.
 INR ≤2.5 at randomization.
*Including, but not limited to, platelet count <90,000/µl at screening, history of ICH, 12-month history of clinically
significant GI bleeding, non-VKA-induced elevated PT at screening, anaemia of unknown cause with a
haemoglobin level <10 g/dl (<6.21 mmol/l) or significant liver disease or liver function test abnormalities
Janssen Scientific Affairs, LLC. 2016. https://clinicaltrials.gov/ct2/show/NCT01830543 [accessed 14 Oct 2016]
 Contraindication for anticoagulant or antiplatelet therapy or
unacceptable risk of bleeding*.
 History of stroke or TIA.
 CrCl <30 ml/min at screening.

20. PIONEERAF-PCI TRIAL
*CrCl 30–49 ml/min: 10 mg OD; #first dose 72–96 hours after sheath removal; ‡clopidogrel (75 mgdaily)
(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); §ASA (75–100 mg daily) plus clopidogrel (75 mg daily)
(alternative use of prasugrel or ticagrelor allowed, but capped at 15%); ¶first dose 12–72 hours after sheath removal
1.Janssen Scientific Affairs, LLC. 2016. https://clinicaltrials.gov/ct2/show/NCT01830543 [accessed 10 Oct 2016];
2.Gibson CM et al, Am Heart J 2015;169:472–478e5; 3. Gibson CM et al, New Engl J Med 2016; doi:10.1056/NEJMoa1611594
Design: An open-label, randomized, controlled phase IIIb safety study
Rivaroxaban 15 mg OD*# plus singleantiplatelet‡
End oftreatment
(12 months)
Rivaroxaban 2.5 mgBID¶
plus DAPT§
VKA (INR2.0–3.0)¶
plus DAPT§
Rivaroxaban 15 mgOD*
plus low-doseASA
VKAplus low-doseASA
N=2,124
1:1:1
Population:
patients with
paroxysmal,
persistentor
permanent
NVAF
undergoing
PCI (withstent
placement)
R
DAPT
1 m:15%
6 m:35%
12 m:50%
DAPT
1 m:16%
6 m:35%
12 m: 49%
Decision
for DAPT
duration:
1, 6 or12
months
DAPT duration
(1, 6 or 12months)

21. Efficacy was Comparable Between All Three Treatment Strategies
Trial not powered to definitively demonstrate either superiority or non-inferiority for efficacy
endpoints Gibson CM et al, New Engl J Med 2016; doi:10.1056/NEJMoa1611594
CVdeath,MIorstroke(%)
6
4
2
0
0 30 60 90 180
Time(days)
270 360
Group 2(Rivaroxaban
2.5 mg BID plusDAPT)
Group 1 (Rivaroxaban
15 mg OD plus single
antiplatelet)
Group 3 (VKA plusDAPT)
6.5%
6.0%
5.6%
Rivaroxaban15 mg OD plus singleantiplateletvs VKAplus DAPT: HR=1.08; (95% CI 0.69–1.68);p=0.75
Rivaroxaban2.5 mg BID plus DAPT vs VKAplus DAPT: HR=0.93 (95% CI 0.59–1.48);p=0.76
8

23. • It is important to note that the dosing regimens of rivaroxaban used in the trial do
not represent the approved doses for stroke prevention in AF.
• Question not answered
• Choice of P2Y12 inhibitor (93% pt. were on clopidogrel)
• Clopidogrel was used in abbreviated regimen unlike WOEST Trial where
evidence of benefit was with Aspirin.
• Duration for TAT was not defined 1 or 6 months?

25. Warfarin
Study Design: Multicenter, randomized,
open-label trial following a PROBEdesign
R
Randomization
≤120hours
post-PCI* 6-month minimum treatment duration with visits every 3 months for the first year, then
visits and telephone contact alternating every 3 months and a 1-monthpost-treatment
visit
Dabigatran (110 or 150mg)
Dabigatran 110 mg BID + P2Y12inhibitor
Warfarin (INR 2.0–3.0) + P2Y12 inhibitor +ASA
Dabigatran 150 mg BID + P2Y12inhibitor
Mean durationof
follow-up:
~14 months
1 month of ASA (BMS)
3 months of ASA(DES)
*Study drug should be administered 6 hours after sheath removal and no later than ≤120 hrs post-PCI (≤72 hrs is preferable). PROBE, prospective, randomized, open, blinded end-point;
R, randomization; BMS, bare metalstent; DES, drug-elutingstent. ClinicalTrials.gov:NCT02164864;Cannonet al. Clin Cardiol 2016
Patients
with AF
undergoin
g PCI with
stenting
N=2725

26. Patients were randomized based on agegroup
and location
Patients aged <80years
worldwide (<70 years in
Japan), and patients
aged ≥80 years in theUSA
Patients aged ≥80years
outside the USA
(≥70 years in Japan)
Dabigatran 150 mg dualtherapy
n=763
Dabigatran 110 mg dualtherapy
n=769
Warfarin tripletherapy
n=766
Warfarin tripletherapy
n=212
n=215
Dabigatran 110 mg dualtherapy

28. • The risk of thromboembolic events was noninferior in the 2 DAT groups
combined as compared with the TAT group, although a numerical (nonsignificant)
absolute risk increase was noted with the lower 110-mg dabigatran dose (11%) ad
compared with the higher 150-mg dabigatran dose (7.9%)
• And 110-mg dabigatran dose is not approved for stroke prevention.
• In this trial a subgroup analysis was done in patient with AF with ACS (52%)
where they compared its efficacy with TAT and compared the P2Y12 inhibitor
used ( Tica vs Clopi ) to conclude that DAT with both doses of dabigatran was no
inferior to TAT.

30. PIONEER-AF PCI and RE-DUAL PCI, they could not distinguish whether the
reduction in bleeding was attributed to the use of a DOAC versus VKA, to the
avoidance of aspirin, or both.

32. • The goal of the trial was to evaluate the role of dual therapy compared with triple
therapy among patients with atrial fibrillation undergoing coronary
revascularization.
• Hypothesis : DAT is better than TAT and aspirin is associated with increased
bleeding when added to any of the therapy

33. VITAMIN K
ANTAGONIST
+
ASPRIN
(1123)
APIXABAN
+
ASPRIN
(1145)
VITAMIN K
ANTAGONIST
+
PLACEBO
(1126)
APIXABAN
+
PLACEBO
(1143)
2 X 2 FACTORIAL DESIGN
ASPRIN
PLACEBO
VITAMIN K
ANTAGONIST
APIXABAN
All patients received P2Y12 inhibitor

34. VKA
(INR 2–3)
Apixaban 5 mg BID
Apixaban 2.5 mg BID in selected patients
Randomize
n=4614
patients
INCLUSION
• >18 years;
• AF (prior, persistent, permanent or
paroxysmal):
– Physician decision for OAC ; &
• ACS or PCI
– Planned P2Y12 inhibitor for ≥6months
EXCLUSION
• Contraindication to DAPT
• Other reason for VKA
(prosthetic valve, moderate / severe
mitral stenosis)
• Renal insufficinecy, bleeding.
Aspirin for all on the day of ACS or PCI
Aspirin versus placebo after randomization
Open
Label
Aspirin Placebo
Double
Blind Aspirin Placebo
Double
Blind
Lopes RD, et al. Am Heart J. 2018;200:17-23.

35. VKA: 14.7%
Apixaban: 10.5%
Major / CRNM Bleeding
Apixaban vs. VKA
HR 0.69, 95% CI 0.58–0.81
P<0.001 for non-inferiority
P<0.001 for superiority
ARR=4.2%
NNT=24
ARR:
NNT:
absolute risk reduction
number needed totreat

36. Placebo: 9.0%
Aspirin: 16.1%
Major / CRNM Bleeding
Aspirin vs. Placebo
HR 1.89, 95% CI 1.59–2.24
P<0.001
ARI=7.1%
NNH=14
ARI:
NNH:
absolute risk increase
number needed toharm

37. VKA + Aspirin (18.7%)
Apixaban + Aspirin (13.8%)
VKA + Placebo (10.9%)
Apixaban + Placebo (7.3%)
Major / CRNM Bleeding

38. Apixaban: 23.5%
VKA: 27.4%
Death / Hospitalization
Apixaban vs. VKA
HR 0.83, 95% CI 0.74–0.93
P=0.002
ARR=3.9%
NNT=26
ARR:
NNT:
absolute risk reduction
number needed totreat

40. Conclusion
• By means of its factorial design and at variance with PIONEER-AF PCI and RE-
DUAL PCI, AUGUSTUS helps to disentangle the individual contribution of
DOACs and aspirin withdrawal on the risk of bleeding, demonstrating that both
aspects are beneficial.
• AUGUSTUS also included medically managed ACS patients who did not receive
stents, who are known to be at high ischemic risk.

41. Vranckx P, Lewalter T, Valgimigli M, et al. Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients
with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the
ENTRUST-AF PCI trial. Am Heart J. 2018;196:105-112. doi:10.1016/j.ahj.2017.10.009

43. Discussion
• The ENTRUST-AF PCI trial showed that, among patients with AF who had successful
PCI, a full-dose anticoagulation therapy with edoxaban 60 mg once daily plus a P2Y12
inhibitor is non- inferior to a triple therapy with VKA (aspirin given for 1–12 months)
regarding the risks of major or CRNM bleeding events at 12 months.
• The edoxaban dual therapy regimen and the triple VKA regimen showed similar rates for
the main efficacy outcome, a composite of death from cardiovascular causes, stroke,
SEE, myocardial infarction, or definite stent thrombosis.

44. • The aim of this analysis is to assess the tradeoff of risk (bleeding) and benefit (ischemic events)
over time with apixaban versus VKA and aspirin versus placebo.
• In a post hoc analysis, we compared the risk of 3 composite bleeding outcomes and 3 composite
ischemic outcomes from randomization through 30 days and from 30 days to 6 months with
apixaban and VKA and with aspirin and placebo.
ASPRIN vs PLACEBO RANDOMIZATION TO 30 DAYS 30 DAYS TO 6 MONTHS
BLEEDING aspirin caused more severe
bleeding (absolute risk
difference, 0.97% [95% CI,
0.23–1.70])
risk of severe bleeding was
higher with aspirin than
placebo (absolute risk
difference, 1.25% [95% CI,
0.23–2.27]),
ISCHEMIA Aspirin caused fewer severe
ischemic events (absolute risk
difference, −0.91% [95% CI,
−1.74 to −0.08]) than
placebo.
risk of severe ischemic events
was similar (absolute risk
difference, −0.17% [95% CI,
−1.33 to 0.98]).

45. Lopes RD, Hong H, Harskamp RE, et al. Safety and Efficacy of Antithrombotic Strategies in Patients With Atrial Fibrillation Undergoing
Percutaneous Coronary Intervention: A Network Meta-analysis of Randomized Controlled Trials. JAMA Cardiol. 2019;4(8):747–755.

48. • In patients with AF undergoing PCI, a regimen of NOAC plus P2Y12 inhibitor
was associated with fewer bleeding complications, including intracranial bleeding
, without a significant difference in ischemic events compared with VKA plus
DAPT.
• This metanalysis support the use of an NOAC and P2Y12 inhibitor as the
preferred treatment option for this high-risk patient population.
• In the absence of future trials showing incremental efficacy with acceptable
bleeding resulting in a favorable net clinical benefit of triple therapy, regimens
that include a VKA plus a P2Y12 inhibitor plus aspirin should generally be
avoided.
Lopes RD, Hong H, Harskamp RE, et al. Safety and Efficacy of Antithrombotic Strategies in Patients With Atrial Fibrillation
Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis of Randomized Controlled Trials. JAMA
Cardiol. 2019;4(8):747–755. doi:10.1001/jamacardio.2019.1880

49. WHAT GUIDELINES SUGGEST ?
Saito Y, Kobayashi Y. Triple therapy: A review of antithrombotic treatment for patients with atrial fibrillation
undergoing percutaneous coronary intervention. J Cardiol. 2019;73(1):1-6. doi:10.1016/j.jjcc.2018.09.001

50. Capodanno D, Huber K, Mehran R, et al. Management of Antithrombotic Therapy in Atrial Fibrillation Patients
Undergoing PCI: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;74(1):83-99. doi:10.1016/j.jacc.2019.05.016

52. Capodanno D, Huber K, Mehran R, et al. Management of Antithrombotic Therapy in Atrial Fibrillation Patients
Undergoing PCI: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;74(1):83-99.
doi:10.1016/j.jacc.2019.05.016

53. Capodanno D, Huber K, Mehran R, et al. Management of Antithrombotic Therapy in Atrial Fibrillation Patients
Undergoing PCI: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;74(1):83-99. doi:10.1016/j.jacc.2019.05.016

54. Step 1 : evaluation of STROKE risk using CHA2DS2-VASc score
Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and
thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial
fibrillation. Chest. 2010:137;263-272.

55. Step 2 : evaluation of BLEEDING risk using HASBLED score
Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess one-year risk of
major bleeding in atrial fibrillation patients: The Euro Heart Survey. Chest. 2010 Mar 18.
score of ≥3 indicates "high risk"

56. Step 3 : consider the THROMBOTIC risks ?
Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in
collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology
(ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213-260.
doi:10.1093/eurheartj/ehx419

57. THANK YOU

58. What practical decision should be taken in patient with AF
undergoing PCI
• Step 1 : evaluation of STROKE risk using CHA2DS2-VASc score
• Step 2 : evaluation of BLEEDING risk using HASBLED score
• Step 3 : consider the THROMBOTIC risks ?
Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy
in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213-260.