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Luis A Guzman, MD, FACC, FSCAI
Associate Professor of Medicine
Director, Cardiac and Vascular Cath Lab
University of Florida College of Medicine - Jacksonville
Optimal Duration of Dual Antiplatelet
Therapy
Current Controversies on DAPT in PCI
• Which drug?
• When to start?
• Which dose?
• How long?
Is shorter DAPT better?
• Less bleeding
• Less cost
• Current DES are safer than I
generation DES
• Many patients do fine with short DAPT
duration
After PCI, aspirin should be continued indefinitely.
The duration of P2Y12 inhibitor therapy after stent implantation
should generally be as follows:
a) In patients receiving a stent (BMS or DES) during PCI for ACS,
P2Y12 inhibitor therapy should be given for at least 12 months
(clopidogrel 75 mg daily); prasugrel 10 mg daily; and ticagrelor
90 mg twice daily.
b) In patients receiving a DES for a non–ACS indication,
clopidogrel 75 mg daily should be given for at least 12 months
if patients are not at high risk of bleeding.
c) In patients receiving a BMS for a non-ACS indication,
clopidogrel should be given for a minimum of 1 month and
ideally up to 12 months (unless the patient is at increased risk
of bleeding; then it should be given for a minimum of 2 weeks).
Postprocedural Antiplatelet Therapy
I IIa IIb III
I IIa IIb III
2011 ACCF/AHA/SCAI Guideline for PCI
DES and Prolonged DAPT
What are we treating?
The patient or the stent?
NSTE-ACS: Evidence for Clopidogrel Use
0
2
4
6
8
10
12
14
Death
, M
I, o
r S
tro
ke (
%)
Clopidogrel
+ ASA
3 6 9
Placebo
+ ASA
Months of Follow Up
11.4%
9.3%
20% RRR
P<0.001
0 12
CURE Primary Results (N=12,562)
NSTE-ACS = non-ST segment elevation-acute coronary syndrome. RRR = relative risk ratio.
Yusuf S, et al. N Engl J Med. 2001;345:494-502.
TRITON TIMI 38 (prasugrel vs clopidogrel)
PLATO
(ticagrelor vs clopidogrel)
TRITON TIMI 38 (prasugrel vs clopidogrel)
PLATO
(ticagrelor vs clopidogrel)
DES and Prolonged DAPT
In the setting of ACS (across the spectrum: UA, NSTEMI, STEMI) dual antiplatelet
therapy with aspirin and a P2Y12 receptor inhibitor is the standard of care irrespective
of management (medical therapy, percutaneous revascularization with
POBA/BMS/DES, surgical revascularization)
Guideline recommendations since 2002 based on
robust large scale clinical trial data.
Little room to debate shorter duration of DAPT in DES
treated patients with ACS.
DES and Prolonged DAPT
What are we treating?
The patient or the stent?
Incidence, Predictors, and Outcome of Thrombosis
After Successful Implantation of Drug-Eluding Stents
Univariate Predictors of Cumulative Stent Thrombosis
Iakovou, I, et al. JAMA. 2005;293:2126-30.
0 10 20 30 40
Incidence of Stent Thrombosis
Premature Antiplatelet Therapy Discontinuation
Prior Brachytherapy
Renal Failure
Bifurcation with 2 Stents
Bifurcation Lesion
Unprotected Left Main Artery
Diabetes
Hazard Ratio for ATP Discontinuation = 89
Basket Late
Pfisterer et al. JACC 2006
Duke registry
Eisenstein et al. JAMA 2007
Challenging the guidelines
Duration of dual antiplatelet therapy is:
Too long!
Not long enough!
DES and Prolonged DAPT
Are we overreacting to ST data from first generation DES?
Does DES type make a difference on duration on DAPT?
1st vs 2nd
DES
Thin strut BMS, thick BMS, and drug-eluting stent (XIENCE V)
Kolandaivelu K et al. Circulation 2011;123:1400-1409
Relative ex vivo Thrombogenicity between
Different Stent Designs
Single Stent Overlapping Stent
Palmerini et al. Lancet 2012;379:1393-402
Stent Thrombosis Network Meta-
analysis
Palmerini et al. Lancet 2012;379:1393-402
Stent Thrombosis Network Meta-
analysis
Palmerini et al. Lancet 2012;379:1393-402
Stent Thrombosis Network Meta-
analysis
PRODIGY Study Design
Valgimigli M et al, Circulation. 2012;125:2015-26
1,970 patients with BMS, ZES,
PES, EES (1:1:1:1)
Short-term of DAPT
6 months*
Long-term of DAPT
24 months
24 months of follow up after randomization
Primary Endpoint: Composite of death, myocardial infarction,
cerebrovascular accidents
R
30 days of DAPT
6 months vs 24 months
*<6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI
OPTIMIZE Study Design
Feres F et al, JAMA. 2013;
3.119 patients with, ZES
Short-term of DAPT
3 months*
Long-term of DAPT
12 months
12 months of follow up after randomization
Primary Endpoint: Composite of death, myocardial infarction,
cerebrovascular accidents
R
3 months vs 12 months
*<6 months clopidogrel was allowed in BMS pts with stable CAD at the time of PCI
SECURITY Study Design
Colombo A et al, TCT 2014
1,399 patients
with 2 nd generation DES
Short-term of DAPT
6 months
Long-term of DAPT
12 months
24 months of follow up after randomization
Primary Endpoint: Composite of death, myocardial infarction,
cerebrovascular accidents
R
6 months vs 12 months
Courtesy Dr Tullio Palmereni
Can we consider these data
conclusive? Open label trials
Underpowered for ischemic events
Randomization performed at the time of PCI and not at the time of platelet discontinuation
Inclusion of discordant endpoint in the PE
May apply to low risk patients
Different DES included
…but they point all to the
same direction!
With Second Generation DES
3-6 months appears to be sufficient
Challenging the guidelines
Duration of dual antiplatelet therapy is:
Too long!
Not long enough!
Stone et al. N Engl J Med. 2011;364:226-35
Arguments for DAPT prolongation:
Benefits of prolonging DAPT could be other than stent related
MA
CE
(%
)
Time in Years 0 1 2 3
All
Culprit lesion (CL) related
Non culprit lesion (NCL) related
Indeterminate
0
5
10
15
20
25
12.9%
20.4%
11.6%
2.7%
18 mo 12 mo
Dual Antiplatelet Therapy (DAPT) Study
50% of patients continue on
dual antiplatelet therapy
(clopidogrel or prasugrel)
50% of patients receive
aspirin + placebo
Total 33-month patient evaluation including additional 3-month follow-up
All patients on
aspirin + open-label
thienopyridine
therapy for
12 months
DES
n=15,245
BMS
n=5400 1:1 Randomization
at month 12
PCI and the Need for oral Anticoagulation
The Triple Therapy Dilemma
The US perspective
Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534
Low ST
and
Bleeding
Risk
High ST
and low
Bleeding
Risk
Any ST and
High
Bleeding
Risk
BMS –Triple Tx
for 1 months
OAC + 1 AP for
12 months
DES –Triple Tx
for 6 months
OAC + 1 AP
for 12 months
BMS –Triple
Tx for 6
months
OAC + 1 AP
for 12 months
DES –Triple
Tx for 12
months
BMS –Triple
Tx for 1
months
OAC + 1 AP
for 12 months
NO
DES
After 12 months. Single OAC
The US perspective
Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534
Low ST
and
Bleeding
Risk
High ST
and low
Bleeding
Risk
Any ST and
High
Bleeding
Risk
DES –Triple Tx
for 6 months
OAC + 1 AP
for 12 months
DES –Triple
Tx for 12
months NO DES
After 12 months. Single OAC
North American Consensus Statement Regarding Antithrombotic Therapy in AF
Requiring Stent (2011)
• Aspirin in a dose < 100 mg daily
• Clopidogrel is preferred in combination with
aspirin and warfarin
• Prasugrel or Ticagrelor are not recommended
• Warfarin adjusted to 2.0-2.5 INR
• Not unreasonable to use Dabigatran in place of
warfarin based on PETRO trial
Faxon D, et al. Circ Cardiovasc Interv. 2011;4:522-534
100
90
80
70
60
50
0 200 300 450 600
%
Dual therapy
Triple therapy (INR: 2.0-2.5)
95.1 %
95.1 %
Days
Ble
ed
ing e
ve
nt fr
ee
su
rviv
al
Triple therapy (INR > 2.5)
66.7 %
†
‡
† Log Rank, p<0.0001 vs dual therapy
‡ Log Rank, p<0.0001 vs triple therapy (INR: 2.0-2.5)
Rossini & Angiolillo, Am J Cardiol. 2008;102:1618-23
Bleeding risk in PCI patients on dual antiplatelet
therapy requiring oral anticoagulation
Risk of Bleeding with Single, Dual, or Triple
Therapy With Warfarin, Aspirin, and Clopidogrel in
Patients With Atrial Fibrillation: Risk of nonfatal (n = 12 191) and fatal (n = 1381) bleeding
Hansen et al. Arch Intern Med. 2010;170(16):1433-1441.
Risk of Stroke with Single, Dual, or Triple Therapy
With Warfarin, Aspirin, and Clopidogrel in Patients
With Atrial Fibrillation: Risk of nonfatal (n = 9785) and fatal (n = 3537) ischemic stroke
Hansen et al. Arch Intern Med. 2010;170(16):1433-1441.
Warfarin
Dabigatran
150 mg
Dabigatran
110 mg
No APT
SAPT
DAPT No APT
SAPT
DAPT
No APT
SAPT
DAPT
Major Bleeding in Patient with Oral Anticoagulation and Dual, Single or no
Antiplatelet Treatment in RE-LY
Dans A, et al. Circulation 2013;127:634-40
Similar trends were found for minor bleeding and no intracranial
bleeding. No increase risk of intracranial bleeding was noted.
Oral Anticoagulation and Antiplatelets in Atrial
Fibrillation Patients After MI and PCI
Denmark National Registry: 12,965 pts
Lambert M, et al JACC, Volume 62, Issue 11, 2013, 981 - 989
Triple therapy is used as
reference (hazard ratio =1.00).
Triple Therapy With Aspirin, Prasugrel, and VKA’s
Sarafoff N et al. J Am Coll Cardiol. 2013;61:2060-2066.
Kaplan-Meier analysis for the primary endpoint
(TIMI major and minor bleeding) at 6 months.
6 [28.6%) vs. 24 [6.7%];
unadjusted HR: 4.6, CI: 1.9-11.4,
p 0.001;
adjusted HR: 3.2, CI: 1.1 to 9.1, p
0.03
377 DES treated pts
of whom 21
switched to
prasugrel because
of HPR
Bleeding Risk
Atherothrombotic Events
ST and Stroke
PCI and the Need for oral Anticoagulation
The Triple Therapy Dilemma
Bleeding Risk
Atherothrombotic Events
ST and Stroke
Oral Anticoagulants
Triple Therapy
PCI and the Need for oral Anticoagulation
The Triple Therapy Dilemma
How long Triple? (0 or 1 month)
Double Therapy
• No Aspirin?
• No Clopidogrel?
• Either one?
• How long? (3, 6, 12 months)
Role of New anticoagulants
PCI and the Need for oral Anticoagulation
The Triple Therapy Dilemma
The WOEST Trial: Randomised trial with or without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting
Dewilde WJ et al. Lancet. 2013;381(9872):1107-15
ISAR-TRIPLE Study Randomized 600 patients
Fiedler KA, et al. Presented at TCT September 2014.
XARELTO® (rivaroxaban) Use in Patients With AF Undergoing PCI: PIONEER AF-PCI
• 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 (75-100 mg/d).
Data on File. Janssen Pharmaceuticals, Inc.
2100 patients
with NVAF
No prior
stroke/TIA
PCI with stent
placement
R
A
N
D
O
M
I
Z
E
1,6, or 12 months
XARELTO® 15 mg qd*
Clopidogrel 75 mg qd†
XARELTO® 15mg QD
Aspirin 75-100 mg qd
XARELTO® 2.5 mg bid
Clopidogrel 75 mg qd†
Aspirin 75-100 mg qd‡
VKA (target INR 2.0-3.0)
Aspirin 75-100 mg qd
VKA (target INR 2.0-3.0)
Clopidogrel 75 mg qd†
Aspirin 75-100 mg qd
≤72
hours
After
Sheath
removal
1,6, or 12 months
End of treatment at 12 months
PCI and the Need for oral Anticoagulation
ESC 2014 Guidelines
1) Which stent?
- Define if PCI/stenting is “appropriate”
- 2nd generation DES is the prefer stent (no BMS)
- Preferential use of radial approach during PCI
2) Which antiplatelet agent?
- Clopidogrel (± low dose aspirin)
- Avoid prasugrel/ticagrelor; avoind/limit NSAIDs
- Add PPI (preferably non CYP2C19 interfering)
3) Always OAC. Which OAC?
- I prefer VKA (more data; antidote), targeting an INR 2.0-2.5
- If already on NOAC, continue with same NOAC
- Limited data on NOACs (no antidote; negative press; patients concerned)
4) For how long?
- Triple Rx for 1 Month. May consider longer (6 months) if low bleeding risk
- After: Dual Rx with OAC + clopidogrel (stop aspirin) up to 12 month
- >1 year: Dual Rx with OAC ± aspirin (depending on patient risk)
What do I do in my practice?
MUCHAS GRACIAS
Lip G, et al. Eur Heart J 2010; 31, 1311–1318 / ESC Guidelines for AF 2010
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
Elective 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
≤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
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 BMS 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)
Lifelong: VKA (INR 2.0–3.0) alone
Lip G, et al. Eur Heart J 2010; 31, 1311–1318 / ESC Guidelines for AF 2010