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European Journal of Internal Medicine xxx (xxxx) xxx
Please cite this article as: Pierre Sabouret, European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2022.12.008
0953-6205/© 2022 The Authors. Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Review Article
De-escalation of antiplatelet therapy in patients with coronary artery
disease: Time to change our strategy?
Pierre Sabouret
a
,
b
,
1
,
*
, Luigi Spadafora
c
,
1
, David Fischman
d
, Waqas Ullah
d
, Michel Zeitouni
a
,
Martha Gulati
e
, Salvatore De Rosa
f
, Michael P. Savage
d
, Juan Pablo Costabel
g
, Maciej Banach
h
,
Giuseppe Biondi-Zoccai
i
,
j
, Mattia Galli
k
,
l
a
Heart Institute, ACTION Study Group-CHU Piti´
e-Salp´
etri`
ere, 47-83 Boulevard de l’Hˆ
opital, Paris, France
b
Coll`
ege National des Cardiologues Français (CNCF), Paris, France
c
Department of Clinical, Internal Medicine, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Italy
d
Thomas Jefferson University Hospitals, Philadelphia, PA, USA
e
Barbra Streisand Women’s Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, USA
f
Magna Graecia University of Catanzaro, Catanzaro, Italy
g
Division of Cardiology, Instituto Cardiovascular de Buenos Aires (ICBA), Buenos Aires, Argentina
h
Department of Preventive Cardiology and Lipidology, Medical University of Lodz and Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
i
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
j
Mediterranea Cardiocentro, Napoli, Italy
k
Catholic University of the Sacred Heart, Rome, Italy
l
Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy
ARTICLE INFO
Keywords:
De-escalation
Antiplatelet therapy
Acute coronary syndrome
Chronic coronary syndrome
Percutaneous coronary intervention
ABSTRACT
Dual antiplatelet therapy (DAPT) is the gold standard after acute coronary syndromes (ACS) or chronic coronary
syndromes (CCS) undergoing percutaneous coronary intervention (PCI).
Because local and systemic ischemic complications can occur particularly in the early phase (i.e. 1–3 months)
after ACS or PCI, the synergistic platelet inhibition of aspirin and a P2Y
12
inhibitor is of the utmost importance in
this early phase. Moreover, the use of the more potent P2Y
12
inhibitors prasugrel and ticagrelor have shown to
further reduce the incidence of ischemic events compared to clopidogrel after an ACS. On the other hand,
prolonged and potent antiplatelet therapy are inevitably associated with increased bleeding, which unlike
thrombotic risk, tends to be stable over time and may outweigh the benet of reducing ischemic events in these
patients.
The duration and composition of antiplatelet therapy remains a topic of debate in cardiology due to competing
ischemic and bleeding risks, with guidelines and recommendations considerably evolving in the past years. An
emerging strategy, called “de-escalation”, consisting in the administration of a less intense antithrombotic
therapy after a short course of standard DAPT, has shown to reduce bleeding without any trade-off in ischemic
events. De-escalation may be achieved with different antithrombotic strategies and can be either unguided or
guided by platelet function or genetic testing. The aim of this review is to summarize the evidence and provide
practical recommendations on the use of different de-escalation strategies in patients with ACS and CCS.
1. Introduction
Since more than two decades, dual antiplatelet therapy (DAPT) with
aspirin and a P2Y
12
receptor inhibitor is considered the gold standard for
patients with acute coronary syndrome (ACS) as well as for those with
chronic coronary syndrome (CCS) undergoing percutaneous coronary
Abbreviations: DAPT, Dual Anti-Platelet Therapy^; ACS, Acute Coronary Syndromes; CCS, Chronic Coronary Syndromes; RCTs, Randomized Clinical Trials; PCI,
Percutaneous Coronary Intervention; ST, Stent Thrombosis; MI, Myocardial Infarction; DES, Drug Eluting Stents; PFT, Platelet Function Tests; HPR, High Platelet
Reactivity; LPR, Low Platelet Reactivity; BARC, Bleeding Academy Research Consortium.
* Corresponding author at: Cardiology Department, Heart Institute, Sorbonne University, 47-83 Bld de l’hˆ
opital, Piti´
e-Salp´
etri`
ere Hospital, Paris F-75013, France.
E-mail address: cardiology.sabouret@gmail.com (P. Sabouret).
1
These authors contributed equally to the work.
Contents lists available at ScienceDirect
European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
https://doi.org/10.1016/j.ejim.2022.12.008
Received 5 November 2022; Received in revised form 14 December 2022; Accepted 16 December 2022
European Journal of Internal Medicine xxx (xxxx) xxx
2
intervention (PCI) [1]. The more potent P2Y
12
inhibitors prasugrel and
ticagrelor have shown to reduce ischemic events at the cost of increased
bleeding compared with clopidogrel [2,3]. Therefore, a 12-month DAPT
with potent P2Y
12
inhibitors represents the standard-of-care after ACS
and may be considered after PCI in CCS patients in specic high
ischemic risk situations [4–6]. However, the efcacy and safety of a
12-month DAPT duration have been established in randomized
controlled trials (RCTs) presenting several differences compared with
the modern clinical setting, such as the low use of concomitant optimal
medical therapy (i.e. statins) and the use of PCI without stenting or with
old generation stent platforms, occurring late after the diagnosis of ACS
and often performed by operators with little experience [7]. Moreover,
fragile and high bleeding risk patients were typically excluded from an
invasive strategy in early RCTs, while PCI is now currently extended to
patients previously considered at prohibitive risk.
The increasing understating that bleeding events carry important
clinical implications and that the response to antiplatelet agents vary
widely according to the ischemic and bleeding risks as well as to the
individual pharmacodynamic response to antiplatelets, suggests that a
one-size-ts-all approach may represent a suboptimal approach in
several subgroup of patients [8]. Recent guidelines have proposed a
personalization of therapy according to patient’s bleeding and ischemic
risks, with dedicated scores designed to predict such risks [4–6].
Nevertheless, in the real world setting, a prolonged and intense anti-
platelet therapy is often difcult to maintain due to the patient’s clinical
characteristics and comorbidities, and the use of scores is limited by a
several challenges such as the large overlap between factors associated
with increased ischemic and bleeding events. Therefore, a number of
antithrombotic strategies have been tested in the last years with the aim
of optimizing the balance between bleeding and ischemic risks [1].
Because the ischemic risk is highest in the early phase after ACS/PCI
while bleeding risk remains relatively stable over time, there has been a
great interest towards the use of a more intense antithrombotic regimen
early after ACS or PCI, followed by a less intense regimen thereafter, in
the attempt to reduce bleeding without any trade-off in ischemic events
(the so called “de-escalation” strategy). In this review we discuss the
rationale and provide an appraisal of the evidence in support of such a
strategy.
2. Rationale for a de-escalation of antiplatelet therapy
Early after the introduction of PCI, the main focus of antithrombotic
therapy was not only the reduction of ischemic recurrences, such as
spontaneous myocardial infarction (MI), but also the prevention of local
ischemic events such as stent thrombosis (ST) [9]. Later, with the
introduction of rst generation drug eluting stents (DES) which were
burdened by an increased risk of ST, including those occurring late after
PCI, a more prolonged and intense antithrombotic therapy has been
implemented in the attempt of preventing ST [10]. Such intensied
antithrombotic regimens led to an increased risk of bleeding, which
have been recently recognized to have important clinical implications,
leading to increased mortality through direct and indirect mechanisms
[11,12]. Indeed, bleeding can cause direct damages such as haemor-
rhagic stroke but can also lead to many indirect consequences associated
with poor outcomes [13]. For example, a bleeding event results in the
interruption of antiplatelet therapy which leads to a higher risk of
thrombotic complications. Furthermore, anemia results in decreased
oxygen supply and increased oxygen consumption due to neuroendo-
crine activation and requires blood transfusions which lead to depletion
of 2,3-diphosphoglyceric acid and nitric oxide, resulting in low tissue
oxygen and vasoconstriction which enhance platelets aggregation [12].
Compelling evidence supports the fact that, in both ACS or CCS patients
undergoing PCI, the very early period after ACS or PCI is characterized
by the greatest ischemic risk [1]. Indeed, MI and ST tend to be more
common in the rst 1–3 month following ACS or PCI, while the risk of
bleeding represents a major threat continuously over time (Fig. 1) [1].
This is particularly evident among ACS patients in which the rst
months are characterized by enhanced inammatory markers and
thrombophilic status [1,14]. Based on the observation that ischemic risk
tends to decrease while bleeding risk remains stable over time, there has
been increasing interest in the developed of a strategy called “de-es-
calation”, aimed at using an intense antiplatelet therapy early after ACS
or PCI, in order to reduce ischemic complications, followed by a less
intense antiplatelet therapy thereafter, aimed at reducing bleeding
events [15]. Another important issue to be considered when using an-
tiplatelet therapy after PCI is that the superior clinical efcacy at the cost
of increased bleeding of the potent P2Y
12
inhibitors prasugrel and
ticagrelor, as opposed to clopidogrel, is mainly related to the fact
Fig. 1. Rationale for de-escalation strategy. In the early phase after ACS or PCI, the risk of thrombotic events is highest and an aggressive antiplatelet therapy is
needed to reduce ischemic events. After 3 months since ACS or PCI, the risk of thrombotic events decreases signicantly and other risk factors are responsible for the
risk of ischemic events. The bleeding risk remains stable over time, resulting in a benet/risk ratio in favor of an aggressive antiplatelet therapy only in the early (1–3
months) phase after ACS or PCI. Abbreviations: acute coronary syndrome (ACS); chronic coronary syndrome (CCS); percutaneous coronary intervention (PCI).
P. Sabouret et al.
European Journal of Internal Medicine xxx (xxxx) xxx
3
20–40% of patients treated with clopidogrel are non-responders, while
this rate is trivial in patients treated with prasugrel or ticagrelor [16,17].
Indeed, the wide interindividual variability in the gene responsible for
the transcription of the hepatic cytochrome P450 (CYP) 2C19 system,
which is responsible for the activation of clopidogrel, is associated with
diminished levels of clopidogrel active metabolite [18]. Patients treated
with clopidogrel, but not those treated with prasugrel or ticagrelor, who
are carriers of one (intermediate metabolizer) or two (poor metabolizer)
loss-of-function (LoF) alleles (CYP2C19×2 and CYP2C19×3) are asso-
ciated with diminished CYP2C19 enzyme activity and diminished levels
of clopidogrel active metabolite, leading to high platelet reactivity
(HPR) and increased thrombotic risk [19,20]. Moreover, the potent
P2Y
12
inhibition provided by prasugrel and ticagrelor has been associ-
ated with low platelet reactivity (LPR) and increased rates of bleeding
without any benet in ischemic events compared with patients
responding to clopidogrel [21]. Patients not responding to clopidogrel
may be identied by specic tools: platelet function tests (PFT), aiming
at identifying the level of platelet inhibition, and genetic tests, aiming at
identifying patients carriers of LoF allels of the CYP2C19 gene [22]. The
implementation of these tools aims to perform a guided selection of
P2Y
12
inhibiting therapy, selectively administering clopidogrel to pa-
tients responding to this drug and prasugrel or ticagrelor to patients
non-responding to clopidogrel, with the goal of decreasing bleeding
without any trade-off in ischemic events.
3. De-escalation among ACS patients undergoing PCI
De-escalation strategies among patients with ACS consist in the
shortening of DAPT duration and in the use of reduced dose or reduced
potency of P2Y
12
inhibitors, which can be either guided by platelet
function or genetic testing or unguided (Fig. 2) (Table 1).
3.1. Current recommendations from international guidelines
The de-escalation strategies recommended by the European Society
of Cardiology (ESC) guidelines consist in the shortening of DAPT fol-
lowed by aspirin or by a P2Y12 inhibitor monotherapy, depending on
the balance between the ischemic and bleeding risk [1,4–6]. In partic-
ular, the use of ticagrelor monotherapy after 3 months of standard DAPT
is recommended in non-ST-elevation acute coronary syndromes
(NSTE-ACS) with low bleeding risk, with class IIa, level of evidence
(LoE) A. Among patients at HBR, current ESC guidelines recommend the
use of clopidogrel as the P2Y12 inhibitor of choice and DAPT duration
can be shortened to 6 months in ST-elevation acute coronary syndromes
(STE-ACS) patients followed by aspirin alone, 1 month in NSTE-ACS
patients followed by clopidogrel monotherapy or 3 months when
DAPT discontinuation is followed by aspirin alone [4–6]. Moreover, in
NSTE-ACS patients, ESC guidelines recommend a guided de-escalation
by platelet function test or genetic testing or unguided de-escalation
from potent P2Y
12
inhibitors to clopidogrel with a class IIb, level of
evidence B [4].
3.2. Short DAPT followed by aspirin monotherapy
With regards to DAPT shortening with P2Y
12
discontinuation in ACS,
several trials have been carried out, comparing 6 versus 12-month DAPT
and 3 versus 12-month DAPT durations [1,36] (Table 1). The
DAPT-STEMI was a non-inferiority trial conducted in 2018, enrolling
1100 patients and comparing 6 versus 12 months DAPT in ACS patients.
The primary endpoint was all-deaths, revascularization, stroke and
major bleedings at 18 months [23]. In this study, six months DAPT was
not inferior to standard 12-month DAPT [23].
The SMART-DATE trial was a non-inferiority trial comparing 6
versus 12 months DAPT in 2712 East Asian patients with ACS. The
primary endpoint was the composite of all-cause death, MI or stroke
[24]. Despite the primary endpoint of non-inferiority consisting in
Fig. 2. De-escalation of antiplatelet therapy among ACS patients. De-escalation strategies among patients with ACS include: (1) shortening DAPT followed by aspirin,
clopidogrel or ticagrelor monotherapy; (2) guided de-escalation; and (3) unguided de-escalation. Abbreviations: acute coronary syndrome (ACS); percutaneous
coronary intervention (PCI); dual antiplatelet therapy (DAPT).
P. Sabouret et al.
European Journal of Internal Medicine xxx (xxxx) xxx
4
all-deaths, MI, or stroke was met, short DAPT was associated with a
doubled risk of MI and with a 50% increased risk of ST, compared to
standard DAPT [24]. The REDUCE trial compared 3 versus 12-month
DAPT in 1496 patients. The primary endpoints were all-cause death,
MI, ST, stroke, target vessel revascularization and Bleeding Academic
Research Consortium (BARC) 2–5 bleedings at 12 months [25]. Short
DAPT was associated with a doubled risk of ST and a 62% increased risk
of CV death compared to standard DAPT [25]. Red ags, raising some
concern about the use of aspirin monotherapy after a short course of
DAPT were the non-inferiority design of these three trials and, in the
DAPT-STEMI and the REDUCE, the inclusion of both ischemic and
bleeding outcomes as primary endpoint. Of note, an individual patient
data meta-analysis has shown a higher rate of MI or ST with reduced
DAPT duration followed by aspirin alone in ACS [37].
3.3. Short DAPT followed by clopidogrel monotherapy
Another possible strategy for shortening DAPT is the discontinuation
of aspirin after a short course of DAPT maintaining clopidogrel mono-
therapy [1]. RCTs in this setting have tested a strategy of aspirin
discontinuation 1 or 3 months after ACS versus standard 12-month
DAPT (Table 1). Despite RCTs including both ACS and CCS patients
showed encouraging results with this strategy, the recent STOPDAPT-2
ACS non-inferiority trial including 4169 East Asian patients with ACS
showed clopidogrel monotherapy after a 1 or 2-months DAPT not to be
non-inferior to standard DAPT for the primary endpoint of CV death, MI,
any stroke, denite ST or bleeding. Moreover, despite short DAPT fol-
lowed by clopidogrel reduced by 54% the incidence of bleeding, it was
associated with a 50% increase in the composite CV death MI, ST and
stroke and a nearly doubled risk of MI, compared with standard DAPT
[26]. Importantly, it must be highlighted that the evidence of clopi-
dogrel monotherapy after a short course of DAPT comes from RCTs
including only East-Asians, which are a population typically exposed to
greater bleeding and lower ischemic risks compared to other ethnicities
[36]. Furthermore, the non-inferiority design of STOPDAPT-2 ACS and
the inclusion of both ischemic and bleeding outcomes as primary
endpoint limit the statistical power with respect of ischemic outcomes,
which requires further studies to be addressed [26].
3.4. Short DAPT followed by ticagrelor monotherapy
If some concerns exists for a shortening of DAPT followed by clopi-
dogrel monotherapy, a strategy of ticagrelor monotherapy after 1–3
month of DAPT has shown to reduce bleeding events without any trade-
off in ischemic risk among ACS patients, in RCTs including both Eastern
and Western countries [1,36,27,38]. Specically, TICO randomized
3056 South Korean ACS patients to either 3-month DAPT followed by
ticagrelor monotherapy compared with standard 12-month DAPT with
ticagrelor, showing a reduction of bleeding with no trade-off in ischemic
events [27]. Indeed, the primary composite endpoint of net adverse
clinical event, dened as a composite of major bleeding, all-deaths, MI,
ST, stroke, or target-vessel revascularization, was reduced by 44% in the
de-escalation versus standard DAPT group. Further evidence on the
safety and efcacy of this strategy - mainly including patients from
Western Countries - were provided by the sub-analysis of GLOBAL
LEADERS and TWILIGHT trials, showing a greater reduction of bleeding
with a de-escalation strategy in the subgroup of ACS as compared with
CCS [29,28]. It should be acknowledged that these two subgroup anal-
ysis should only be considered hypothesis generating, also in light of the
fact the GLOBAL LEADERS trial did not meet its primary endpoint and
that the rate of ischemic events was lower than expected in high-risk PCI
patients in the TWILIGHT trial [39,40]. Although these studies are un-
derpowered to assess ischemic outcomes, a study-level meta-analysis
has suggested ticagrelor monotherapy after a short court of DAPT may
represent a safe and effective strategy [38]. Finally, possible practical
concerns surrounding the use of ticagrelor monotherapy stems from the
fact ticagrelor is associated with higher rates (20–25%) of discontinua-
tion by the patients due to the incidence of side effects (i.e. dyspnea)
when compared with other antiplatelet drugs and to the fact its action is
reversible and short, potentially leading to a prompt increase in platelet
reactivity in case of voluntary or involuntary discontinuation of the drug
by the patient [41].
3.5. Guided de-escalation
Among patients with ACS, a guided selection of P2Y
12
inhibitors
allows for a selective administration of clopidogrel to clopidogrel re-
sponders, limiting the use of prasugrel and ticagrelor to clopidogrel non-
responders, with aim of reducing bleeding without any trade-off in
ischemic events [15]. This strategy, resulting in a guided de-escalation
of antiplatelet therapy early (<7 days) after ACS or PCI, may be ach-
ieved by the use of PFT or genetic testing (Table 1).
The rst study comparing a PFT-guided de-escalation with standard
therapy in elderly patients with ACS undergoing PCI was ANTARCTIC
(n =877). This study failed to show any difference in the primary
endpoint of CV death, MI, stroke, ST, urgent revascularization, and
BARC 2–5 bleeding with a guided de-escalation versus standard therapy
[30]. Nevertheless, low dose of prasugrel rather than clopidogrel was
used in this study both in the guided and standard groups, potentially
blunting the superior safety of a de-escalation strategy [30].
TROPICAL-ACS is the largest RCT comparing a PFT-guided de-escalation
with standard therapy among ACS patients (n =2610). A guided
Table 1
RCTs exploring de-escalation in acute coronary syndromes.
STUDY TIMING OF DE-
ESCALATION
STRATEGY OF DE-
ESCALATION
NUMBER OF
PATIENTS
ACS
DAPT STEMI
[23]
6 MONTHS ASPIRIN ALONE 1100
(STEMI
100%)
SMART DATE
[24]
6 MONTHS ASPIRIN ALONE 2712
(STEMI
38%)
REDUCE [25] 3 MONTHS ASPIRIN ALONE 1496
(STEMI
46%)
STOPDAPT-2-
ACS [26]
1–2 MONTH CLOPIDOGREL
ALONE
3045
(STEMI
57%)
TICO [27] 3 MONTHS TICAGRELOR ALONE 3056
(STEMI
36%)
GLOBAL
LEADERS
Substudy [28]
1 MONTH TICAGRELOR ALONE 3737
(STEMI
46%)
TWILIGHT ACS
[29]
3 MONTHS TICAGRELOR ALONE 4614
(STEMI 0%)
ANTARCTIC [30] EARLY AFTER PCI PFT GUIDED DE-
ESCALATION
877 (STEMI
34%)
TROPICAL-ACS
[31]
EARLY AFTER PCI PFT GUIDED DE-
ESCALATION
2610
(STEMI
55%)
POPular
GENETICS
[32]
EARLY AFTER PCI GENOTYPE GUIDED
DE-ESCALATION
2488
(STEMI
19%)
TOPIC [33] 1 MONTH UNGUIDED DE-
ESCALATION TO
CLOPIDOGREL
646 (STEMI
40%)
TALOS MI [34] 1 MONTH UNGUIDED DE-
ESCALATION TO
CLOPIDOGREL
2697
(STEMI
54%)
HOST-REDUCE-
POLYTECH-
ACS [35]
PRASUGREL 5 MG
DAPT VS
PRASUGREL 10 MG
DAPT
UNGUIDED DE-
ESCALATION
3429
(STEMI
14%)
Abbreviations: acute coronary syndrome (ACS), platelet function test (PFT),
ST-elevation myocardial infarction (STEMI).
P. Sabouret et al.
European Journal of Internal Medicine xxx (xxxx) xxx
5
de-escalation was non-inferior in the primary composite endpoint of CV
death, MI, stroke or BARC bleeding 2–5 as compared to standard DAPT,
with a trend towards reduced bleeding at 12 months compared to the
standard group [31]. Furthermore, POPular genetics showed both the
non-inferiority of the primary endpoint of all-deaths, MI, denite ST,
stroke, or major bleeding and a signicant 22% reduction of the
co-primary endpoint of major and minor bleeding at 12 months, in 2488
STE-ACS patients randomized to either genotype-guided de-escalation
or standard therapy (mainly ticagrelor) within 48 h after PCI [32].
Limitations of RCTs testing a guided de-escalation in ACS patients
are the use of a primary composite endpoint including both ischemic and
bleeding outcomes and the non-inferiority design, both leading to a
relatively low statistical power with respect to hard ischemic events.
Nevertheless, a recent comprehensive meta-analysis at least partially
overcoming this limitation, showed that a strategy of guided de-
escalation is associated with a 19% reduction of bleeding without any
trade-off in ischemic events [42]. Furthermore, a network meta-analysis
focusing on ACS has shown a guided selection of P2Y
12
inhibitors is
associated with the most favorable safety and efcacy prole compared
to standard treatment with prasugrel or ticagrelor [43].
3.6. Unguided de-escalation
Unguided de-escalation of P2Y
12
inhibiting therapy may be imple-
mented at least 1 month after ACS or PCI, when the risk of local ischemic
events has declined signicantly, and consists in the use of clopidogrel
or reduced dose of prasugrel or ticagrelor after a short course (>1
month) of DAPT with full dose prasugrel or ticagrelor. TOPIC was a
single center trial enrolling 646 ACS patients that compared an un-
guided de-escalation from potent P2Y12 inhibitor to clopidogrel after
one month of DAPT versus 12-month standard DAPT [33]. There was a
52% reduction of the primary endpoint of CV death, urgent revascu-
larization, stroke and BARC 2–5 bleeding in the de-escalation compared
to standard group, driven by a reduction of BARC 2–5 bleeding. Of note,
this was a relatively small trial mainly including patients not undergoing
complex-PCI [33].
TALOS-MI trial was the largest RCT (n =2697) comparing an un-
guided de-escalation from ticagrelor to clopidogrel 1 month after ACS
versus standard 12-month DAPT with ticagrelor. There was a 45%
reduction of the primary endpoint of CV death, MI, stroke and BARC 2–5
bleeding with a de-escalation as compared to standard therapy driven by
a reduction of BARC 2–5 bleeding [34].
Finally, HOST-REDUCE-POLYTHEC-ACS was the rst trial to
compare a de-escalation strategy by reducing prasugrel from 10 to 5 mg
1 month after ACS versus standard 12-month DAPT with prasugrel in
3429 East Asian patients. The primary endpoint of all-cause death, MI,
ST, repeat revascularization, stroke, and BARC bleeding 2–5 was
reduced by 30% in the de-escalation versus standard group [35].
Collectively, limitations of an unguided de-escalation of antiplatelet
therapy are the fact they were underpowered to assess ischemic out-
comes, the fact the vast majority of patients enrolled were East Asians
undergoing non-complex PCI, and the fact that this strategy may not
sufciently consider the individual increased ischemic risk of patients
not responding to clopidogrel.
4. De-escalation among CCS patients undergoing PCI
De-escalation strategies among patients with CCS consist in the
shortening of DAPT duration followed by either aspirin or P2Y
12
in-
hibitors monotherapy (Fig. 3) (Table 2).
4.1. Current recommendations from international guidelines
In the clinical setting of CCS, according to current ESC guidelines,
DAPT should be administered for six months, regardless of the stent used
during PCI [5]. Aspirin remains the cornerstone of DAPT, while the
P2Y
12
inhibitor of choice is clopidogrel [5]. The only de-escalation
strategy allowed by current recommendations consists in DAPT short-
ening, ranging from 3 months in patients at high bleeding risk, to 1
month in patients at extremely high bleeding risk [5].
4.2. Short DAPT followed by aspirin monotherapy
A total of 10 RCTs including both ACS and CCS patients have
compared a strategy of DAPT shortening to 1, 3 or 6 months versus a
standard DAPT duration (Table 2) [1,44–53]. These studies have
generally provided reassuring results on the efcacy and showed a
consistent reduction of bleeding in favor of a short or very short DAPT as
opposed to a standard DAPT duration [57]. However, none of these trials
have focused only on CCS patients. It could be speculated that because
ACS patients are at increased ischemic risk compared to CCS patients,
the fact that the majority of RCTs on the topic included a variable per-
centage of ACS patients should provide a further reassurance on the
efcacy and safety of a shortening of DAPT duration in these patients,
despite the level of evidence remaining limited, especially for high
ischemic risk patients.
4.3. Short DAPT followed by clopidogrel monotherapy
The STOPDAPT-2 and the SMART-CHOICE trials reported promising
results on the possible discontinuation of aspirin 1–3 months after ACS
or PCI followed by clopidogrel monotherapy in a mixed population of
Fig. 3. De-escalation of antiplatelet therapy among CCS patients undergoing PCI with or without concomitant AF. De-escalation strategies among patients with CCS
with or without concomitant AF include shortening DAPT followed by aspirin or clopidogrel monotherapy. Abbreviations: dual antiplatelet therapy (DAPT); oral
anticoagulant (OAC); chronic coronary syndrome (CCS); atrial brillation (AF).
P. Sabouret et al.
European Journal of Internal Medicine xxx (xxxx) xxx
6
ACS and CCS [55,54]. A sub-study of the STOPDAPT-2 trial suggested
clopidogrel monotherapy after 1-month of DAPT was superior in major
bleeding and non-inferior in the primary endpoint of CV death, MI,
denite ST, any stroke or bleeding compared to 12 months DAPT,
regardless ACS or CCS presentation [58]. Moreover, while 1-month
DAPT was associated with a numerical increase in CV events in ACS
patients, there was no increase in CCS patients [58].
Limitations of this strategy are represented by the fact these studies
were underpowered for ischemic outcomes, the fact the populations
from these two trials were from East-Asia and the fact that the use of
unguided clopidogrel monotherapy does not take into account of the
interindividual response to this antiplatelet agent.
4.4. Short DAPT followed by prasugrel monotherapy
Prasugrel monotherapy after a short course of DAPT has not been
adequately tested in RCTs, and its use is limited to a pilot study enrolling
201 patients [56]. In this study, selected low-risk CCS patients treated
with third-generation DES underwent aspirin discontinuation on the day
of the index procedure and prasugrel monotherapy represented the only
antiplatelet agent used. At 3 months, the rate of ischemic and bleeding
events was extremely low in both treatment arms [56].
4.5. Short DAPT followed by ticagrelor monotherapy
No RCTs using ticagrelor monotherapy after a short course of DAPT
have focus on CCS patients (Table 1). Evidence in this setting comes
from a pre-specied sub-analysis of the GLOBAL LEADERS trial ac-
cording to clinical presentation (ACS versus CCS)[58]. In this study,
while there was no difference in efcacy, dened as all-deaths and MI,
between treatment strategies by subgroup, a strategy of ticagrelor
monotherapy after 1 month of DAPT appeared to reduce bleeding risk in
patients with ACS but not in patients with CCS, compared to standard
DAPT with ticagrelor [40].
5. Special clinical settings
5.1. Patients with concomitant atrial brillation
Atrial brillation (AF) is as frequent as 10% in patients with ACS or
undergoing PCI [1]. The need for the concomitant use of oral antico-
agulants (OAC) and DAPT in these patients is associated with a pro-
hibitive bleeding risk [59]. This setting was the rst in which a very
early de-escalation strategy, consisting in clopidogrel monotherapy after
a very short course of DAPT (about one week) on the background of OAC
was adopted [60]. Guidelines suggest as gold standard in this setting a
triple therapy (aspirin plus clopidogrel plus an oral anticoagulant) for 1
week after PCI, followed by aspirin discontinuation for 6 months in CCS
and 12 months in ACS [4–6]. Among high ischemic risk patients,
duration of triple therapy could be prolonged up to 1 month [4]. Finally,
ticagrelor or prasugrel may be considered in association with a NOAC
with a class IIa, LOE B [4]. This recommendation stems from the results
of 4 recent RCTs, each using a different novel OAC (NOAC, dabigatran,
rivaroxaban, apixaban, or edoxaban) in combination with a P2Y12 in-
hibitor (mainly clopidogrel) versus a prolonged triple therapy [59,61].
However, because of several limitations of these studies and the fact they
were not statistically powered to rule out any increase in ischemic events
with a de-escalation strategy, whether the optimal duration of triple
therapy for the majority of patients should be 1 week or 1 month re-
mains debated [60]. Meta-analysis have played an important role in
increasing statistical power for ischemic endpoints, but found incon-
sistent results with a possible increase of ST with the de-escalation
strategy in the overall population and of MI in the ACS subgroup
[62–64]. Moreover, the use of ticagrelor was low (<10%) and that of
prasugrel very low (<3%) in this trials, limiting the evidence in support
of the use of P2Y
12
inhibitors different from clopidogrel in this setting.
Finally, the use of unguided clopidogrel monotherapy very early after
ACS or PCI, which is the period considered at highest ischemic risk, may
represent a source of concern especially in ACS and high ischemic risk
patients, as it does not take into account of the interindividual response
to this antiplatelet agent (Fig. 3).
6. Conclusions and future perspectives
Current evidence support a larger use of de-escalation strategies of
antiplatelet therapy in clinical practice. An individualized approach
remains more than ever mandatory to determine the best antithrombotic
strategy, providing an optimal balance between bleeding and ischemic
risks at the individual patient level. Because the primary scope of de-
Table 2
RCTs exploring de-escalation in acute coronary syndrome and chronic coronary
syndrome settings.
STUDY TIMING OF DE-
ESCALATION
STRATEGY OF
DE-ESCALATION
NUMBER
OF
PATIENTS
ACS/CCS
EXCELLENT
[44]
6 MONTHS ASPIRIN ALONE 1443 (ACS
51%, CCS
49%)
RESET [45] 3 MONTHS ASPIRIN ALONE 2148 (ACS
54%, CCS
46%)
OPTIMIZE [46] 3 MONTHS ASPIRIN ALONE 3211 (ACS
32%, CCS
68%)
SECURITY [47] 6 MONTHS ASPIRIN ALONE 1404 (ACS
39%, CCS
61%)
ISAR-SAFE [48] 6 MONTHS ASPIRIN ALONE 4005 (ACS
39%, CCS
61%)
I-LOVE-IT [49] 3 MONTHS ASPIRIN ALONE 1829 (ACS
85%, CCS
15%)
NIPPON [50] 6 MONTHS ASPIRIN ALONE 3773 (ACS
32%, CCS
68%)
OPTIMA-C [51] 6 MONTHS ASPIRIN ALONE 1368 (ACS
51%, CCS
49%)
One-Month
DAPT [52]
1 MONTH ASPIRIN ALONE 3020 (ACS
39%, CCS
61%)
MASTER DAPT
[53]
1 MONTH ASPIRIN ALONE 4434 (ACS
49%, CCS
51%)
SMART-
CHOICE [54]
3 MONTHS CLOPIDOGREL
ALONE
2993 (ACS
58%, CCS
42%)
GLOBAL
LEADERS
[40]
TICAGRELOR
MONOTHERAPY FOR 23
MONTHS VS STANDARD
DAPT
TICAGRELOR
ALONE
2712 (ACS
38%, CCS
62%)
TWILIGHT [39] 1 MONTH TICAGRELOR
ALONE
7119 (ACS
64%, CCS
3%)
STOPDAPT-2
[55]
1 MONTH CLOPIDOGREL
ALONE
3045 (ACS
38%, CCS
62%)
CCS
GLOBAL
LEADERS
Substudy
[28]
1 MONTH TICAGRELOR
ALONE
3750
ASET [56] ON THE DAY OF THE
INDEX PROCEDURE
PRASUGREL
ALONE
201
Abbreviations: acute coronary syndrome (ACS), chronic coronary syndrome
(CCS).
P. Sabouret et al.
European Journal of Internal Medicine xxx (xxxx) xxx
7
escalation strategies is to reduce bleeding, the benet of this strategy is
greater among patients at high bleeding risk. Thus, the identication of
this cohort of patients is of the utmost importance in clinical practice
and should be routinely performed. Furthermore, the increasing evi-
dence supporting the clinical impact of the interindividual variability in
response to clopidogrel support the implementation of tools aiming a
guiding the use of P2Y
12
inhibitor after ACS or PCI.
Since a number of de-escalation strategies have been proposed, a
careful appraisal of the available evidence is key for the adoption of
these strategies in clinical practice. Unfortunately, no comparison be-
tween different de-escalation strategies is currently available, as the
only evidence in this regards is represented by a network meta-analysis
in which effect estimates are mainly based on indirect comparisons and
its results should be interpreted with caution [65]. Among ACS, a guided
selection of antiplatelet therapy is of particular interest, allowing for a
guided de-escalation from the potent P2Y
12
inhibitor (prasugrel and
ticagrelor) to clopidogrel selectively among patients responding to clo-
pidogrel, reducing bleeding without any trade-off in ischemic events. To
this extent, the availability of bedside point-of-care, rapid, relatively
cheap and easy to use genetic testing may facilitate the adoption of this
strategy in the future. Another very promising strategy in ACS is rep-
resented by the use of a potent P2Y
12
inhibitor or of guided clopidogrel
after 1 to 3 months of standard DAPT. Nevertheless, current evidence are
only available on the use of ticagrelor monotherapy after 3 months of
standard DAPT, a strategy already recommended by guidelines. In the
light of the available evidence, a 12-month DAPT duration with potent
P2Y
12
inhibitors should only be applied to selected patients with
high-ischemic risk and low bleeding risk.
On the other hand, among CCS with or without concomitant AF, the
evidence in support of a de-escalation strategy is weaker and basically
consists in the shortening of DAPT duration followed by aspirin in pa-
tients with sinus rhythm or clopidogrel in patients with concomitant AF.
A de-escalation strategy in these patients is likely to be advantageous in
high bleeding risk patients, but whether it should represent the standard
of care remains uncertain. Moreover, whether the use of clopidogrel
(either unguided or guided) may be advantageous as compared to
aspirin after DAPT discontinuation requires further investigations.
Furthermore, because prasugrel and ticagrelor are associated with
increased bleeding risk compared to clopidogrel, whether the use of
prasugrel or ticagrelor monotherapy could represent a valuable option
for CCS patients is unlikely.
Finally, other fundamental issues to be considered when adopting
de-escalation strategies are the control of risk factors and patient’s
compliance with guideline recommended treatments. Patients with
intensive control of all cardiovascular risk factors, with a good compli-
ance to therapy and receiving the best possible cardiovascular therapy
(statins, ezetimibe +/- proprotein convertase subtilisin/kexin type 9
inhibitors, glucagon-like peptide 1-receptor agonists, sodium-glucose
cotransporter-2 inhibitors, beta-blockers) are the best candidates to
receive a de-escalated antiplatelet therapy.
Disclosures
P.S. reports consulting fees by Astra Zeneca, Amgen, BI, BMS, Lilly,
Novartis, Sano, Servier, Vifor, outside the submitted work. M.B.:
speakers bureau: Amgen, KRKA, Polpharma, Novartis, Sano-Aventis,
Teva, and Zentiva; consultant to Amgen, Daiichi Sankyo, Esperion,
Novartis, and Sano-Aventis; grants from Amgen, Sano, and Valeant,
outside the submitted work. M.G. reports consulting fees by Terumo,
outside the submitted work. L.S., D.F., W.U., M.G., J.P.C., S.D.R., M.S.,
report no disclosures. GBZ has consulted for Balmed, Cardionovum,
Crannmedical, Eukon, Innovheart, Guidotti, Meditrial, Microport,
Opsens Medical, Replycare, Teleex, and Terumo outside the submitted
work. No funding for this article.
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