The document discusses dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor for patients receiving coronary stents. It addresses three questions on optimal DAPT duration: 1) Is shorter DAPT (3-6 months) as effective as 12 months for newer-generation drug-eluting stents? 2) Does longer DAPT (>12 months) reduce ischemic events more than 12 months of DAPT? 3) Does continued DAPT past 12 months benefit stable post-MI patients more than aspirin alone? The document summarizes several studies investigating these questions and guidelines on DAPT duration and choice of P2Y12 inhibitor.

1. SOUMYA KANTI DUTTA
IPGMER ICVS
KOLKATA

2. The term and acronym’ DAPT’ has been used to specifically
refer to combination antiplatelet therapy with aspirin and a
P2Y12 receptor inhibitor (clopidogrel, prasugrel, or
ticagrelor).
Most contemporarystudies of DAPT have compared either
shorter (3 to 6 months) or longer (18 to 48 months)
duration of therapy with 12 months of DAPT, which is the
recommended or minimal duration of therapy for
most patients in ACC/AHA and European Society of
Cardiology guidelines published between 2011 and
2014.

3.  Three critical questions on DAPT are
 In patients treated with newer (non-first) generation DES
for (1) SIHD or (2) ACS, compared with 12 months of DAPT,
is 3–6 months of DAPT as effective in preventing stent
thrombosis, preventing MACE and/or reducing bleeding
complications?
 In patients treated with newer (non-first) generation DES,
compared with 12 months of DAPT, does >12 (18–48)
months of DAPT result in differences in mortality rate,
decreased MACE, decreased stent thrombosis, and/or
increased bleeding?
 In post-MI (NSTEMI or STEMI) patients who are clinically
stable and >12 months past their event, does continued
DAPT, compared with aspirin monotherapy, result in
differences in mortality rate, decreased nonfatal MI,
decreased MACE, and/or increased bleeding?

5. Antiplatelet Agents—Oral P2Y12 Inhibitors
++++++Bleeding Risk

8. 8
2011 ACC/AHA/SCAI Guideline for PCI
The duration of P2Y12 inhibitor therapy
should generally be as follows:
DURATION
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
a. In patients receiving a stent (BMS or DES)
during PCI for ACS, P2Y12 inhibitor therapy should
be given for at least 12 months. Options include
clopidogrel 75 mg daily,prasugrel 10 mg daily or
ticagrelor 90mg twice daily
b. In patients receiving DES for non-ACS indication,
clopidogrel should be given for at least 12 months if
patients are not at high risk for bleeding.
c. In patients receiving BMS for a non-ACS indication,
clopidogrel should be given for a minimum of 1 month
and ideally up to 12 months (unless patient is at
increased risk for bleeding;then it should be given for
a minimum of 2 weeks) Circulation 2011;124:e574-651
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

9. Duration
Trial Patients Test Randomizatio
n 1° EP
Prolonged DAPT Studies
REAL/ZEST Late 2701
DES 1 vs. 2 yrs A vs. A+C
Superiority
D/MI
2 yrs after
rand
DAPT
N=20,645
(15,245 DES)
(5,400 BMS)
1 vs. 2.5 yrs*
A+P vs. DAPT
(clop or pras)
NI and Sup
D/MI/CVA
ST, Bleeding
PRODIGY N=1,800
DES, BMS
6 mos vs. 2
yrs
A vs. A+C
Superiority D/MI/CVA
Abbreviated DAPT Studies
EXCELLENT N=1,443
SES and EES 6 vs. 12 mos A vs. A+C
Noninferiority D/MI/TVR
ISAR-SAFE** N=6,000
DES 6 vs. 12 mos* A+P vs. A+C
Noninferiority
D/MI/CVA/
ST/TIMI MB
ITALIC N=3,700
EES 6 vs. 12 mos A vs. A+C
Noninferiority
D/MI/CVA/
Urg
Revasc/MB
OPTIMIZE N=3,120
ZES 3 vs. 12 mos A vs. A+C
Noninferiority
D/MI/CVA/M
B
RESET‡ N=2,148
E-ZES vs RZES, SES, EES 3 vs. 12 mos A+C vs. A+C CVD/MI/ST/
ID-TVR, Bleed
*Plus a 3 month washout period‡Strategy not DAPT duration **2014-2015

10. The “Will this trial change my practice?” sessions
at PCR 2015
Will this trial change my practice?
The Dual Antiplatelet Therapy (DAPT) study – 12 or 30 months of
dual antiplatelet therapy after drug-eluting stents
Should the DAPT study shift the standard of care from 12
months to 30 months in patients who receive a DES?
 Does the increased risk of bleeding essentially offset the
benefits?
 To whom would you recommend continued DAPT?
 In whom would you avoid it?

11. 4.3
5.9
0
5
10
DAPT
 DES PCI: MACCE for DAPT vs. placebo: 4.3%
vs. 5.9%, p < 0.001; MI: 2.1% vs. 4.1%, p < 0.001;
stent thrombosis: 0.4% vs. 1.4%, p < 0.001; all-
cause mortality: 2.0% vs. 1.5%, p = 0.05;
GUSTO moderate/severe bleeding: 2.5% vs.
1.6%, p = 0.001
 BMS PCI: MACCE for DAPT vs. placebo: 4.0% vs.
4.7%, p = 0.72; MI: 2.7% vs. 3.1%, p = 0.74; stent
thrombosis: 0.5% vs. 1.1%, p = 0.24; all-cause
mortality: 1% vs. 1.2%, p = 0.83
Trial design: Patients undergoing DES/BMS PCI, no ischemic/bleeding complications, and
with documented compliance at 1 year, were randomized to receive another 18 months of dual
antiplatelet therapy (DAPT) or placebo. Patients were followed for 18 months.
Results
Conclusions
Mauri L, et al. N Engl J Med
2014;371:2155-66
DAPT DES
(n = 5,020)
MACCE
• Prolonged DAPT ~30 months following DES PCI
results in lower stent thrombosis/recurrent MIs
compared with 12-month DAPT, although
bleeding and all-cause mortality were higher;
BMS subset showed a less impressive treatment
effect
Placebo DES
(n = 4,941)
%
(p < 0.001)
4.0
4.7
0
5
10
%
(p = 0.72)
DAPT BMS
(n = 842)
Placebo
BMS PCI
(n = 845)

12.  Studies of Shorter-Duration DAPT:
 After Stent Implantation five RCTs of patients treated
with elective DES implantation have compared shorter-
duration (3 to 6 months) DAPT with 12 months of
DAPT.
 The trials primarily enrolled low-risk (non-ACS)
patients, with only a small proportion having had a
recent MI.
 The main endpoints of these noninferiority trials were
composite ischemic events and stent thrombosis.
 These studies, as well as several meta-analyses did
not find any increased risk of stent thrombosis
with shorter-duration DAPT in patients currently
being treated with “newergeneration”
(e.g., everolimus- or zotarolimus-eluting) DES.

13. Extended DAPT
 “prolonged” or “extended”
DAPT for an additional 18
to 36 months after DES
found an absolute decrease
in late stent thrombosis
and ischemic
complications of ≈1% to
2% and an absolute
increase in bleeding
complications of ≈1%
 . Extended DAPT resulted
in a 0.7% absolute
reduction in very late stent
thrombosis, a 2.0%
absolute reduction in MI, a
1.6% absolute reduction in
major adverse cardiac
events (MACE),
 a 0.9% absolute increase
in moderate or severe
bleeding.

14. Mortality in prolonged DAPT
 30 months of DAPT versus
12 months of DAPT in DES
treated patients, which was
due to significantly
increased deaths from
noncardiovascular causes
(most commonly cancer),
with no increase in
cardiovascular deaths, and
no significant increase in
fatal bleeding.
 OPTIDUAL (Optimal Dual
Antiplatelet Therapy) trial,
found numerically or
statistically significant
increased risk of all cause
(though not
cardiovascular) death
associated with prolonged
duration of DAPT

15. Increased Ischemic Risk/Risk of Stent Thrombosis
(may favor longer-duration DAPT)
 Increased ischemic risk
•Advanced age
• Multiple prior MIs
Extensive CAD • Diabetes
mellitus • CKD
 Increased risk of stent
thrombosis
Diabetes mellitus •
Left ventricular ejection
fraction <40%
First-generation drug-
eluting stent
• Stent undersizing , Stent
underdeployment • Small
stent diameter • Greater
stent length • Bifurcation
stents • In-stent restenosis

16. “DAPT Score” of ≥2 is associated with a favorable
benefit/risk ratio for prolonged DAPT
Age ≥75 y -2
Age 65 to <75 y -1
Age <65 y 0
Current cigarette smoker 1
Diabetes mellitus 1
MI at presentation 1
Prior PCI or prior MI 1
Stent diameter <3 mm 1
Paclitaxel-eluting stent 1
CHF or LVEF <30% 2
Saphenous vein graft PCI 2

17. Fallacy of DAPT
Not included :
 Hypertension , renal
insufficiency &
peripheral artery
disease – predict both
ischaemia & bleeding .
 although the study
included four different
metal-platform, durable
polymer, drug-eluting
stents and two platelet
P2Y12 inhibitors,
whether the treatment
benefits observed will
be generalizable to
other stent types30,31
or non-thienopyridine
P2Y12 inhibitors is
unknown

18. Aspirin Dosing in Patients Treated
With DAPT: Recommendation
 In patients treated with
DAPT, a daily aspirin dose of
81 mg (range, 75 mg to 100
mg) is recommended .
 Class I ,LOE B
 lower aspirin doses (≤100 mg
daily) are associated with less
major and total bleeding than
are higher doses, either when
used as monotherapy or
when combined with the
P2Y12 inhibitor clopidogrel .
 The efficacy of ticagrelor
seems to be decreased in
patients treated with higher
aspirin doses (≥300 mg daily)
versus lower aspirin doses
(≤100 mg daily)

19. Choice of DAPT
II A B
In patients with ACS (NSTE-ACS or STEMI) treated with
DAPT after coronary stent implantation and in patients
with NSTE-ACS treated with medical therapy alone
(without revascularization), it is reasonable to use
ticagrelor in preference to clopidogrel for maintenance
P2Y12 inhibitor therapy
IIA B
In patients with ACS (NSTE-ACS or STEMI) treated with
DAPT after coronary stent implantation who are not at high
risk for bleeding complications and who do not have a
history of stroke or TIA, it is reasonable to choose prasugrel
over clopidogrel for maintenance P2Y12 inhibitor therapy
III B
Prasugrel should not be administered to patients with a
prior history of stroke or TIA

20. Duration of DAPT in Patients With SIHD Treated With PCI:
I A
In patients with SIHD treated with DAPT after BMS implantation,
P2Y12 inhibitor therapy with clopidogrel should be given for a
minimum of 1 month
I B
In patients with SIHD treated with DAPT after DES implantation,
P2Y12 inhibitor therapy with clopidogrel should be given for at least 6
months
I B
In patients treated with DAPT, the recommended daily dose of aspirin
is 81 mg(75-100 mg)
IIB A
In patients with SIHD treated with DAPT after BMS or DES
implantation who have tolerated DAPT without a bleeding
complication and who are not at high bleeding risk continuation of
DAPT with clopidogrel for longer than 1 month in patients treated
with BMS or longer than 6 months in patients treated with DES may
be reasonable
IIB C
In patients with SIHD treated with DAPT after DES implantation who
develop a high risk of bleeding (e.g., major intracranial surgery), or
develop significant overt bleeding, discontinuation of P2Y12 inhibitor
therapy after 3 months may be reasonable.

21. Duration of DAPT in Patients With ACS Treated With PCI
I B
In patients with ACS (NSTE-ACS or STEMI) treated with DAPT
after BMS or DES implantation, P2Y12 inhibitor therapy
(clopidogrel, prasugrel, or ticagrelor) should be given for at least 12
months
I B In patients treated with DAPT, the recommended daily dose of
aspirin is 81 mg
IIA B
In patients with ACS (NSTE-ACS or STEMI) treated with DAPT
after coronary stent implantation, it is reasonable to use ticagrelor
in preference to clopidogrel for maintenance P2Y12 inhibitor
therapy
IIA B
In patients with ACS (NSTE-ACS or STEMI) treated with DAPT
after coronary stent implantation who are not at high risk for
bleeding complications and who do not have a history of stroke or
TIA, it is reasonable to choose prasugrel over clopidogrel for
maintenance P2Y12 inhibitor therapy
III B
Prasugrel should not be administered to patients with a prior
history of stroke or TIA

22. Duration of DAPT in Patients With ACS Treated With
PCI
IIB A
In patients with ACS (NSTE-ACS or STEMI) treated with
coronary stent implantation who have tolerated DAPT
without a bleeding complication and who are not at high
bleeding risk (e.g., prior bleeding on DAPT, coagulopathy,
oral anticoagulant use), continuation of DAPT (clopidogrel,
prasugrel, or ticagrelor) for longer than 12 months may be
reasonable
IIB C
In patients with ACS treated with DAPT after DES
implantation who develop a high risk of bleeding (e.g.,
treatment with oral anticoagulant therapy), are at high risk
of severe bleeding complication (e.g., major intracranial
surgery), or develop significant overt bleeding,
discontinuation of P2Y12 inhibitor therapy after 6 months
may be reasonable

23. TRITON-TIMI 38(Therapeutic Outcomes by
Optimizing Platelet Inhibition With Prasugrel–
Thrombolysis In Myocardial Infarction 38)
 Prasugrel treatment resulted in fewer ischemic
complications and stent thromboses but more
frequent bleeding, including life-threatening and fatal
bleeding. Because of increased rates of major bleeding
with prasugrel there was no net benefit of prasugrel
therapy in those ≥75 years of age and those <60 kg,
and there was net harm (including increased risk of
intracranial hemorrhage) in those with prior stroke or
transient ischemic attack (TIA).

24.  In the PLATO (Platelet Inhibition and Patient
Outcomes) trial , patients with ACS were treated with
either medical therapy alone or medical therapy plus
PCI. Treatment with ticagrelor 90 mg twice daily,
compared with clopidogrel 75 mg once daily, resulted
in fewer ischemic complications and stent thromboses
but more frequent non–CABG-related bleeding.

25.  Patients in the PEGASUS-TIMI 54 trial after a mean of
33 months of therapy, DAPT(Aspirin plus ticagrelor),
when compared with aspirin monotherapy, resulted in
a 1.2% to 1.3% absolute reduction in the primary
composite endpoint of cardiovascular death, MI, or
stroke and a 1.2% to 1.5% absolute increase in major
bleeding, with no excess in fatal bleeding or
intracranial hemorrhage in patients with prior MI.
 The two doses of ticagrelor had similar overall efficacy,
but bleeding and other side effects tended to be less
frequent with 60 mg bid dose.

26. In patients with CABG
 1. In patients treated with DAPT after coronary stent
implantation who subsequently undergo CABG, P2Y12
inhibitor therapy should be resumed postoperatively so
that DAPT continues until the recommended duration of
therapy is completed(I).
 2.In patients with ACS (NSTE-ACS or STEMI) being treated
with DAPT whundergo CABG, P2Y12 inhibitor therapy
should be resumed after CABG tocomplete 12 months of
DAPT therapy after ACS(I).
 3. In patients with SIHD, DAPT (with clopidogrel initiated
early postoperatively) for 12 months after CABG may be
reasonable to improve vein graft patency(IIb).

27. Duration of DAPT in Patients With ACS Treated With Medical
Therapy Alone (Without Revascularization or Fibrinolytic Therapy):
Recommendations
I B
In patients with ACS who are managed with medical therapy
alone (without revascularization or fibrinolytic therapy) and
treated with DAPT, P2Y12 inhibitor therapy (either clopidogrel or
ticagrelor) should be continued for at least 12 months
IIA B
In patients with NSTE–ACS who are managed with medical
therapy alone (without revascularization or fibrinolytic therapy)
treated with DAPT, it is reasonable to use ticagrelor in
preference to clopidogrel for maintenance P2Y12 inhibitor
therapy
IIB A
In patients with ACS treated with medical therapy alone (without
revascularization or fibrinolytic therapy) who have tolerated
DAPT without bleeding complication and who are not at high
bleeding risk (e.g., prior bleeding on DAPT, coagulopathy, oral
anticoagulant use), continuation of DAPT for longer than 12
months may be reasonable.

28. Duration of DAPT in Patients With STEMI Treated With
Fibrinolytic Therapy:
I A
In patients with STEMI treated with DAPT in conjunction with
fibrinolytic therapy, P2Y12 inhibitor therapy (clopidogrel)
should be continued for a minimum of 14 days (Level of
Evidence: A) and ideally at least 12 months
I B
In patients treated with DAPT, a daily aspirin dose of 81 mg
(range, 75 mg to 100 mg) is recommended
IIB A
In patients with STEMI treated with fibrinolytic therapy who
have tolerated DAPT without bleeding complication and who
are not at high bleeding risk (e.g., prior bleeding on DAPT,
coagulopathy, oral anticoagulant use), continuation of DAPT
for longer than 12 months may be reasonable

29. Perioperative Management–Timing of Elective Noncardiac Surgery
in Patients Treated With PCI and DAPT: Recommendations
I B
Elective noncardiac surgery should be delayed 30 days after BMS
implantation and optimally 6 months after DES implantation
I C
In patients treated with DAPT after coronary stent implantation who
must undergo surgical procedures that mandate the discontinuation of
P2Y12 inhibitor therapy, it is recommended that aspirin be continued if
possible and the P2Y12 platelet receptor inhibitor be restarted as soon as
possible after surgery
IIA C
When noncardiac surgery is required in patients currently taking a P2Y12
inhibitor, a consensus decision among treating clinicians as to the
relative risks of surgery and discontinuation or continuation of
antiplatelet therapy can be useful.
IIB C
Elective noncardiac surgery after DES implantation in patients for whom
P2Y12 inhibitor therapy will need to be discontinued may be considered
after 3 months if the risk of further delay of surgery is greater than the
expected risks of stent thrombosis.
III B
Elective noncardiac surgery should not be performed within 30 days after
BMS implantation or within 3 months after DES implantation in patients
in whom DAPT will need to be discontinued perioperatively

30. Shifting between two anti P2Y12 inhibitors
 TRANSLATE ACS study:inhospital ADP receptor
inhibitor swiching occurs 1 in 10 patients.
 Switching to prasugrel or ticagrelor was not associated
with increased bleeding compared to clopidogrel.
 Switching from prasugrel or ticagrelor to clopidogrel
was not associated with increased MACE.
 Patients receiving maintenance clopidogrel therapy
after an ACS event ,switching from clopidogrel to
prasugrel is associated with further reduction in
platelet function by 1 week or within 2 hrs of loading .

32. 'Triple Therapy' Raises Bleed Risk vs
Dual Antiplatelets After PCI for MI
 Combining an oral anticoagulant with dual-agent
antiplatelet therapy (DAPT) after PCI performed for
acute MI increases the risk of bleeding complications
compared to DAPT alone, regardless of which
P2Y12 receptor inhibitor—clopidogrel or prasugrel .
 Among patients receiving triple therapy, prasugrel was
associated with a significantly higher bleeding risk at
39% compared with clopidogrel at 24.4% (P=0.003).

33. DAPT in patients with NOAC
 Patients taking NOACs presenting with STEMI should
receive a loading dose of aspirin (325 mg) and a P2Y12
inhibitor.
 In the randomized trials establishing the efficacy of
ticagrelor or prasugrel over clopidogrel, patients on NOACs
were not included.
 The rate of major bleeding was significantly higher with
ticagrelor and prasugrel compared to clopidogrel.
 comparison of dual antithrombotic therapy(DAT) vs
tripple therapy are being compared in PIONEER AF
PCI(RIVAROXABAN) and REDUAL PCI(DABIGATRAN) in
Patients With AF That Undergo a PCI With Stenting .
.

34. Any Nonadherance(ANA) to P2Y12 inhibitors
 Missing more than 1 day of DAPT.
 9.6% in one study after DES implantation is reported.
 EDUCATE trial:endeavor DES
ANA within 6 months of DES is associated with
increased all cause ,cardiovascular mortality,and
outcome.