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Monotherapy to Prevent DES
Thrombosis: The Future of DAPT
Patrick W. Serruys MD PhD
Imperial College London, United Kingdom
Professor of
Cardiology of
Imperial College
Monday, February 20, 2017
10:12 AM – 10:20 AM
Room: Empire Ballroom
Emeritus Professor
of Cardiology
Dr. Honoris Causa in
Biomedical Engineering
Patrick W. Serruys, MD, PhD
Affiliation/Financial Relationship
• Grant/Research Support
• Consulting Fees/Honoraria
Company
• Abbott
• AstraZeneca
• Biotronik
• Boston scientific
• Cardialysis
• GLG Research
• Medtronic
• Sinomedical Sciences Technology
• Société Europa Digital Publishing,
• Stentys France
• Svelte Medical Systems
• Volcano
• Qualimed
• St. Jude Medical
• Xeltis
Background
1. Atherosclerosis, and its attendant complication of thrombosis
(atherothrombosis), is the leading cause of cardiovascular mortality
and morbidity
2. Antiplatelet therapy post percutaneous coronary intervention (PCI) is
a must
3. Aspirin is imperfect, relatively weak (COX-1 inhibitor), and associated
with gastrointestinal bleeding complications
4. For >10 years, the mainstay of antiplatelet therapy post PCI has been
the combination of COX-1 inhibitor aspirin, and ADP-receptor
antagonist clopidogrel
5. The 1 year duration of dual antiplatelet therapy (DAPT) post-PCI with
drug eluting stents is based on “anecdotal historical data”
Miyazaki Y, Serruys PW et al. Nat Rev Cardiol. 2017 Feb 9.
Timeline of antiplatelet therapy after PCI
•
•
Andreas Grüntzig performs first successful
coronary angioplasty.
Aspirin was used preprocedure followed by an
anticoagulant.
•
•
In FIM Cypher, aspirin and
clopidogrel was continued
for 60 days
J. Eduardo Sousa, Circulation. 2001
SIRIUS trial
Aspirin + clopidogrel
3 months, at 9 months
SES ST 0.4% vs. BMS
0.8%
Aspirin and dipyridamole were specifically tested as anti
restenosis drug
Schwartz, L. et al. The New England journal of medicine (1988).
•
Colombo et al. reported that aspirin plus
ticlopidine after optimal stent expansion was
safe, and anticoagulant can be safely omitted.
Moses, J. W. et al. The New England
journal of medicine (2003).
Colombo, A. et al. Circulation (1995)
1977
1984
1988
1991
1995
1998
Serruys et al. reported that 24% of
patients had complete occlusion after
stent implantation; at that time,
subcutaneous heparin, aspirin plus
dipyridamole, and anticoagulant were
used in trial for 6 month.
Serruys, P. W. et al. The New England journal of medicine
(1991).
•
Aspirin was shown to be a superior
antithrombotic drug compared with
warfarin after PCI.
Thornton, M. A. Circulation (1984).
•
2001
2002
2003
Antiplatelet therapy was tested to decrease
adverse cardiac events
Antiplatelet therapy was tested for
antirestenosis
•
2000
•
Clopidogrel and
aspirin showed
superior of safety
and tolerability to
ticlopidine
Bertrand, M. E. Circulation
102, 624-629 (2000).
RAVEL trial;
Aspirin +clopidogrel
2 months, no ST at
6 months
Morice, M. C. et al. The
New England journal of
medicine (2002).
Aspirin and ticlopidine were tested for superiority to reduce rate
of ST at 1 month compared with anticoagulant or aspirin alone.
Bertrand, M. E. et al. Circulation (1998).Leon, M. B. et al. The New England journal of medicine
(1998).
Timeline of antiplatelet therapy after PCI
SEPTEMBER
“ESC firestorm”
•
Cook, S. & Windecker, Circulation (2009).
DECEMBER
US FDA supported empiric
treatment of 12 months DAPT
based on consensus opinion
•
First report of RCT trial in
prolonged DAPT
Park, S. J. et al. The New England journal of
medicine (2010).
•
Ticagrelor and Prasugrel
were included in ESC
guideline
PLATO was announced and
showed its superiority of
clopidogrel
GLOBAL LEADERS
start enrollment
Wallentin, L. et al. The New England journal of
medicine (2009).
2006
2007
2008
2009
2010
Antiplatelet therapy was tested to decrease
adverse cardiac events
•
•
ARC definition
TRITON-TIMI 38
was announced.
Wiviott, S. D. et al. The New
England journal of medicine (2007).
•
Aspirin +clopidogrel
were included in
ACC/AHA guideline
PEGASUS TIMI-54 was
announced
TWILIGHT
start enrollment
2012
2013
2015
Duration of DAPT was tested
SAPT being tested
First report of RCT trial in abbreviated
DAPT vs. prolonged DAPT
DAPT start
enrollment
•
Mauri, L. et al. The New
England journal of
medicine (2014).
Valgimigli, M. et al. Circulation (2012).
•
First meta-analysis of DAPT duration
Cassese, S. et al. European heart journal (2012).
•
Abbott claimed 3 months DAPT is safe
for XIENCE
Miyazaki Y, Serruys PW et al. Nat Rev Cardiol. 2017 Feb 9.
Heterogeneity of Primary Endpoints and Bleeding
in RCT Trials
Bleeding (%)
Primary endpoints (%)
Miyazaki Y, Serruys PW et al. Nat Rev Cardiol. 2017 Feb 9.
How to generate further needed evidence?
• Should we try to eliminate the
confounding issues related to the dual
antiplatelet therapy by testing mono
therapy?
• By testing single specific and potent
antiplatelet therapy and getting rid of an
old and unspecific antiplatelet drug called
acetylsalicylic acid, are we going to
simplify this field of investigation?
Ticagrelor benefits in PLATO
potential influence of increasing doses of aspirin
?
Source: www.fda.gov/downloads
Global Leaders Vision
1. Avoid the higher risk of bleeding potentially
associated with adding ASA (even low dose) to
Ticagrelor
2. Maintain the clinical benefits of potent platelet
inhibition after PCI, beyond the initial period of high
stent thrombosis risk (30 days)
3. More potent, more consistent antiplatelet inhibition
with Ticagrelor, may be a better foundation for long
term antiplatelet therapy compared to ASA in at-risk
patients
4. The trial may pave the way for future studies of
Ticagrelor as a single foundation therapy
GLOBAL LEADERS: Trial Schema
Global PI: Patrick.W.Serruys
All-Comers PCI Population
ACS and Elective/Stable patients
(n=16,000)
Biolimus-eluting stent (BES)
BioMatrix Flex™
Recruitment
completed: November
2015
Trial (2 year follow
up) completed
1:1 Randomisation, Open-Label Design
ASA
Ticagrelor
ASA
Study Treatment Strategy
Reference Treatment Strategy
1-month
ASA + Ticagrelor
12-months DAPT
ACS pts (ASA+Ticagrelor)
Elective pts (ASA+ Clopidogrel)
23-months
Monotherapy Ticagrelor
12-months
Monotherapy ASA
Primary Endpoint
Study treatment strategy superior to
reference treatment strategy on cumulative 2 year
composite of all cause mortality and new Q-wave MI
TicagrelorClopidogrel
[Not allowed [Only in
in elective pts]elective
pts]
SMART-CHOICE: Trial Schema
Multicenter, prospective, open label
PI: Hyeon-Cheol Gwon MD, PhD
Patients who received PCI
(n=5,100)
Inclusion Criteria
• Patients undergoing successful PCI
12 months DAPT group
3 month DAPT group
Exclusion Criteria
P2Y12i instability
+
P2Y12i
+
• Hemodynamic
or
cardiogenic
shock
• BifurcationASA
lesions requiring ASA
side branch
stenting
3 month
• Lesion treated with 3 or more overlapped
stents
P2Y12i +
P2Y12i
ASA
12 months
Primary endpoints: A composite of death, myocardial infarction, cerebrovascular events, or BARC
bleeding (grade II or higher) over 3 to 12 months after the index procedure
STOPDAPT-2: Trial Schema
Multicenter, prospective, randomized, open label
PI: Takeshi Kimura MD, PhD
Patients received PCI with cobalt-chromium everolimus–eluting stent (Xience)
(n=3,000)
Randomized
after
successful
P2Y12i +
P2Y12i +
ASA
ASA
PCI without
complications
1 month
(MI, stroke, bleeding)
during
Clopidogrel
Clopidogrel
+ ASA
hospital
stay
12 months
1 month DAPT group
Clopidogrel
12 months DAPT group
ASA
5 years
Primary endpoints: Composite event of cardiovascular death/myocardial infarction/definite stent
thrombosis/stroke/bleeding (TIMI major or minor)
Twilight: Inclusion criteria
High-risk patients who have undergone successful elective or urgent PCI with at least
one locally approved drug eluting stent discharged on DAPT with aspirin and
ticagrelor
Enrollment into the study will require meeting at least one clinical inclusion, one
angiographic inclusion
Clinical Inclusion Criteria:
• Adult patients ≥ 65 years of age
• Recent (≥3 days) presentation with
ACS with clinical stabilization and
decreasing cardiac enzymes
• Previous MI, documented PAD or
CAD/PAD revascularization
• DM treated with oral Rx /insulin)
• CKD [eGFR < 60 ml/min/1.73m2 or
creatinine clearance (CrCl) < 60
ml/min]
Angiographic Inclusion Criteria:
• MVD
• total stent length >30 mm
• SYNTAX score ≥23
• Bifurcation lesions requiring at least
2 stents
• Left main (≥50%) or proximal LAD
(≥70%) lesion
• Calcified target lesion requiring
atherectomy
TWILIGHT: Trial Schema
Multicenter, prospective, blinded dual-arm study
Global PI: Roxana Mehran
Primary endpoints: Bleeding episode at 12 months defined as BARC Types 2, 3 or 5 bleeding.
Short course DAPT to minimize stentrelated thrombotic events
Monotherapy with potent platelet
inhibitor provides ischemic protection
while reducing ASA related bleeding
Observation
period starts
Randomization
period ends
N=8200
Randomize
HIGH RISK PCI PATIENTS,
N = 9000
Secondary endpoints: Ischemic episode at 12 months -- time to cardiovascular death, nonfatal MI, ischemic stroke or ischemia-driven revascularization
Observational period
ASET (Acetylsalicylic acid eliminate trial): Trial Schema
Chairman: Patrick W. Serruys, PI: Pedro Lemos
Patients with chronic stable angina or stabilized ACS (normal
biomarkers) and SYNTAX score <23
Loading with DAPT standard of care (if not on long-term therapy) at
least 2 hours prior to catheterization or PCI
Optimal result with PCI with SYNERGYTM stents
(Based on clinical, angiographic and/or intracoronary imaging findings)
Yes
Loading 180 mg ticagrelor during/post PCI
ASA discontinued on the day after PCI, Ticagrelor monotherapy
for 3 months, ASA monotherapy thereafter
3 months reporting of the Primary Endpoint
Additional 1 month observational period (4 months follow-up)
after discontinuation of the drug
No
Conventional DAPT according to
institutional protocol
Conclusion
• By testing single specific and potent
antiplatelet therapy and getting rid of an
old and unspecific antiplatelet drug called
acetylsalicylic acid, are we going to simplify
this field of investigation?
History of DAPT used after PCI
1977
Andreas Grüntzig treated his patients with aspirin post-angioplasty.
At that time aspirin was stopped after the critical period for
restenosis (6 months).
1984
Aspirin was shown to be a superior anti-thrombotic drug compared
to warfarin post PCI.
MARGARET A. THORNTON. Circulation 1984, 69: 721-727
1991
The single daily administration of at least 80 mg aspirin for life
conferred a mortality benefit in females with atherosclerotic disease
(87 678 women followed up for 6 years).
Manson JE for the Nurses Health Study Investigators. JAMA 1991; 266: 521-27
1998
Ticlopidine became the indispensable second anti-platelet
medication (DAPT) for 1 month duration after BMS implantation
Leon MB, NEJM. 1998 Dec 3;339(23): 1665-71
Dual therapy with ticlopidine and aspirin after coronary stenting
significantly reduced rates of bleeding and subacute stent occlusion
compared with conventional anticoagulation.
Bertrand ME for FANTASTIC Investigators. Circulation. 1998; 98: 1597-603
History of DAPT used after PCI
2000
Ticlopidine duration of 1 month was replaced by clopidogrel due to
an improved safety profile (e.g. leucopenia). The 300-mg loading
dose of clopidogrel was well tolerated, notably with no increased
risk of bleeding.
Bertrand ME for CLASSICS Investigators. Circulation. 2000; 102: 624-9
2000-2003
In the FIM Cypher, duration of DAPT was arbitrarily given for 2
months
RAVEL: 2 months; SIRIUS: 3 months; TAXUS: 6 months.
Current guidelines: 12 months DAPT (derived primarily from clinical
experience… and the use of stent in ACS)
2003
The P2Y12 polymorphism was discovered with clopidogrel
There was a need to overcome the inter-individual variability
associated with clopidogrel therapy
Fontana P et al. Circulation 2003; 108: 989-95
Schömig A. N Engl J Med. 2009; 361: 1108-11
History of DAPT used after PCI
2006
Sep
Mediatic medical coup at European Society of Cardiology
(“the ESC storm”)
Dec
The U.S. Food and Drug Administration advisory panel supported
this empiric recommendation of 12 months DAPT after DES
placement and determined that these guidelines be incorporated
into DES product labeling. This recommendation was not based on
any prospective randomized trial evidence associating extendedduration DAPT with a reduction in late ST; rather, the
recommendation was based on consensus opinion.
“there needs to be larger and longer studies that would
specifically look for the risk of stent thrombosis. Studies on the
direction of dual antiplatelet therapy are also urgently needed”
2007
The ARC definition for stent thrombosis are published in Circulation.
Planning is made for the DAPT study.
or
the “hunting
season”
meta-analysis
Available
evidence
onfor
DAPT
duration
Trial
Meta-analysis/Pooled Analysis
REAL-LATE
ZEST-LATE[2011]
12 Vs. 33 Months
Cassese et al
Meta-analysis
PRODIGY[2012]
6 Vs. 24 Months
Palmerini et al
Pooled analysis
EXCELLENT [2012]
6 Vs. 12 Months
Stefanini et al
Meta-analysis
RESET [2013]
3 Vs. 12 Months
Pandit et al
Meta-analysis
OPTIMIZE [2014]
3 Vs. 12 Months
El-Hayek et al
Meta-analysis
ARCTIC-Interruption
[2014]
12 Vs. 18-30 Months
SECURITY [2014]
6 Vs. 12 Months
Evidence
• No differences in MACE between shorter
(median 6.2 months) and longer (median
16.8 months) DAPT
• Shorter DAPT associated with less bleeding
• No differences in MACE between shorter
• (3 or 6 months) and longer ( ≥ 12 months)
DAPT.
• Shorter DAPT associated with less bleeding
• No differences in MACE and bleeding
between 3 or 6 months DAPT
Bulluck et al
Network
Meta-analysis
ITALIC [2014]
6 Vs. 12 Months
ISAR-SAFE [2014]
6 Vs. 12 Months
DAPT [2014]
12 vs. 30 months
Mehran R, et al. J Am Coll Cardiol 2015 Mar 24;65(11):1103-6.
• No differences in MACE and major bleeding
between 6 and 12 months of DAPT
• Lower rates of MACE, ST and MI with
longer DAPT
• Lower rates of major bleeding with
shorter DAPT
• Higher all-cause mortality with longer
DAPT
Caution in interpreting trial evaluation
abbreviated DAPT regimens
• Underpowered to detect differences in hard
endpoints
•
•
•
•
•
•
study design, slow enrollment, premature
interruption, low expected event rates,
under-reporting
Treatment cross-over, regression to the mean
Short follow-up (1 Year FU) – insufficient to
evaluate late outcomes
Under-reported lost to follow-up
Non-inferiority design with wide inferiority margin
Lack of generalizability (except PRODIGY)
Heterogeneous primary endpoint
Miyazaki Y, Serruys PW et al. Nat Rev Cardiol. 2017 Feb 9.