European Heart Journal (2023) 44, 3059–3072 STATE OF THE ART REVIEW

https://doi.org/10.1093/eurheartj/ehad362 Thrombosis and antithrombotic treatment

Personalised antiplatelet therapies for

coronary artery disease: what the future holds
1 2
Davide Capodanno and Dominick J. Angiolillo *
1
Division of Cardiology, Azienda Ospedaliero-Universitaria ‘G. Rodolico – San Marco’, University of Catania, Via Santa Sofia, 78 - 95123 Catania, Italy; and 2Division of Cardiology, University

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of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA

Received 5 March 2023; revised 7 May 2023; accepted 22 May 2023; online publish-ahead-of-print 22 June 2023

Graphical Abstract

Personalized approach to antiplatelet therapy in coronary artery disease

High ischaemic risk High ischaemic risk

Low bleeding risk High bleeding risk

Addition of a P2Y12 Discontinuation of

inhibitor aspirin
Switch to a more potent Selection of the P2Y12
P2Y12 inhibitor inhibitor based on PFT
or genotype

Ischaemic risk
Low ischaemic risk Low ischaemic risk

Low bleeding risk High bleeding risk

Standard Switch to a less potent

antiplatelet therapy P2Y12 inhibitor

Discontinuation of the
P2Y12 inhibitor
or aspirin

Bleeding risk

Proposed strategies for tailoring antithrombotic therapy according to individual ischaemic and bleeding risk. Patients at high
risk of ischemic events and low risk of bleeding may benefit from an intensified antiplatelet therapy regimen (e.g., escalation), while those at high risk
of bleeding and low risk of ischemic events require a less intensive and more cautious approach (e.g, de-escalation). In patients at low risk of ischemic
events and low risk of bleeding the benefits of antiplatelet therapy may not outweigh the risks, while patients who have high risks of both ischemic
and bleeding events require a delicate balance, as the approach to managing their conditions must weigh the potential benefits against the potential
risks. Abbreviations: PFT, platelet function testing. Adapted from Cao et al.1

* Corresponding author. Tel: +1 904 244 3933, Fax: +1 904 244 3102, Email: dominick.angiolillo@jax.ufl.edu
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
3060 D. Capodanno and D. J. Angiolillo

Abstract

Coronary artery disease (CAD) is one of the leading causes of death globally, and antiplatelet therapy is crucial for both its prevention and treatment.
Antiplatelet drugs such as aspirin and P2Y12 inhibitors are commonly used to reduce the risk of thrombotic events, including myocardial infarction,
stroke, and stent thrombosis. However, the benefits associated with the use of antiplatelet drugs also come with a risk of bleeding complications. The
ever-growing understanding of the poor prognostic implications associated with bleeding has set the foundations for defining strategies that can
mitigate such safety concern without any trade-off in antithrombotic protection. To this extent, personalised antiplatelet therapy has emerged
as a paradigm that optimizes the balance between safety and efficacy by customizing treatment to the individual patient’s needs and risk profile.
Accurate risk stratification for both bleeding and thrombosis can aid in selecting the optimal antiplatelet therapy and prevent serious and life-threa­
tening outcomes. Risk stratification has traditionally included clinical and demographic characteristics and has expanded to incorporate angiographic
features and laboratory findings. The availability of bedside platelet function testing as well as rapid genotyping assays has also allowed for a more

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individualized selection of antiplatelet therapy. This review provides a comprehensive overview of the current state of the art and future trends in
personalised antiplatelet therapy for patients with CAD, with emphasis on those presenting with an acute coronary syndrome and undergoing per­
cutaneous coronary revascularization. The aim is to provide clinicians with a comprehensive understanding of personalised antiplatelet therapy and
facilitate informed clinical decision-making.
.............................................................................................................................................................................................
Keywords Antiplatelet therapy • Coronary artery disease • Risk assessment • Personalised antiplatelet therapy • Platelet function
testing • Genotyping

Introduction Antiplatelet therapies in

Coronary artery disease (CAD) is a leading global cause of death and
antiplatelet therapy plays a critical role in its prevention and treatment.2
Aspirin and P2Y12 receptor inhibitors are commonly used antiplatelet
drugs that lower the risk of thrombotic events across the spectrum
of CAD manifestations.3,4 However, the benefits associated with the
use of antiplatelet drugs also come with a risk of bleeding complica­
tions.5 The ever-growing understanding of the poor prognostic implica­
tions associated with bleeding, including increased mortality, has set the
foundations for defining strategies that can mitigate such safety concern
without any trade-off in antithrombotic protection.6,7 To this extent,
personalised antiplatelet treatment regimens represent a developing
concept that seeks to achieve a net benefit between safety and efficacy
by tailoring treatment to each patient’s unique needs and risk profile.8,9
The identification of patients’ risk for both bleeding and thrombosis can
aid in the selection of the optimal antiplatelet therapy and reduce the
incidence of serious adverse events.
Multiple clinical, demographic, angiographic, and laboratory factors
have been identified as predictors of bleeding and thrombosis.10–15
By considering these factors, clinicians are better equipped to risk strat­
ify patients and in turn select the antiplatelet treatment regimen with
the best risk-benefit profile for a given individual. Platelet function test­
ing (PFT) and rapid genotyping are emerging as advancements that en­
able the assessment of a patient’s individual response to antiplatelet
therapy, allowing for an even more individualized selection of antiplate­
let therapy.16 This review provides an overview of current state of the
art and future trends in the role of risk assessment and personalised ap­
proach in antiplatelet therapies for patients with CAD, with emphasis
on those presenting with an acute coronary syndrome (ACS) and
undergoing percutaneous coronary revascularization. The review also
highlights the growing field of personalised antiplatelet therapy, includ­
ing PFT and genotyping, and discusses their future directions and poten­
tial implications.
cardiovascular disease
Mechanisms of action of oral and intravenous antiplatelet drugs cur­
rently approved for clinical use are visualized in Figure 1.17
In accordance with type I classes of recommendations from practice
guidelines,3,4 aspirin is generally indicated for the secondary prevention
of CAD, including patients with previous myocardial infarction (MI) or
revascularization, and the P2Y12 inhibitor clopidogrel is an alternative to
aspirin for patients with allergy or intolerance. Additionally, clopidogrel
is prescribed after percutaneous coronary intervention (PCI) in pa­
tients who present with a chronic coronary syndrome (CCS).
Prasugrel is recommended in patients with an ACS undergoing PCI
and ticagrelor in patients with ACS with or without revascularization.
A description on the use of oral anticoagulants in patients with CAD
and antiplatelet therapy in patients on oral anticoagulants goes beyond
the scope of this manuscript and is described elsewhere.18–20
Risk assessment
The 2021 guidelines from the European Society of Cardiology (ESC) for
cardiovascular disease prevention in clinical practice emphasize the im­
portance of timely recognition of risk factors, predictors, and modifiers
that impact the likelihood of CAD complications.3 This paradigm can be
easily extended to the risks confronted by patients on antiplatelet ther­
apy. In fact, the key to thrombosis and bleeding prevention is to identify
those patients who will receive the greatest benefit from antiplatelet
drugs at the least possible safety price.
In general, the higher the absolute risk of CAD, the higher the ex­
pected absolute benefit of antiplatelet therapy in reducing thrombotic
complications (e.g. MI, stroke, stent thrombosis). However, antiplatelet
therapy carries an unavoidable risk of bleeding, which can be mitigated
by weighing the benefits and risks for the individual patient and adjusting
Personalised antiplatelet therapies for CAD 3061

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Figure 1 Platelet activation mechanisms. Platelet activation is initiated by soluble agonists, such as thrombin, thromboxane A2 (TXA2), 5-hydroxy­
tryptamine (5-HT) and ADP (via the P2Y1 receptor), and by adhesive ligands, such as collagen and von Willebrand factor (vWF). Consequently, dense
granule secretion of platelet agonists and secretion of TXA2, as a result of phospholipase A2 activation, lead to the amplification of platelet activation and
the associated responses. The P2Y12 receptor has a major role in the amplification of platelet activation, which is also supported by outside–in signalling
via integrin αIIbβ3 (the glycoprotein IIb/IIIa receptor). Aspirin inhibits platelet function by acetylation of the platelet cyclooxygenase, which prevents the
access of arachidonic acid to the catalytic site of the enzyme and results in irreversible inhibition of platelet dependent TXA2 formation. Therefore, the
combined use of aspirin and a P2Y12 receptor inhibitor (such as clopidogrel, prasugrel, or ticagrelor) has additive effects on the inhibition of platelet
activation and the associated platelet responses. Conversely, discontinuation of aspirin results in some degree of increased platelet reactivity driven by
pathways mediated by arachidonic acid and collagen, whereas other pathways remain inhibited by P2Y12 inhibitor monotherapy. 5-HT2A, 5-hydroxy­
tryptamine receptor 2A; GPVI, platelet glycoprotein VI; NO, nitric oxide; PAR, proteinase-activated receptor; PGI2, prostaglandin I2; TPα, thromb­
oxane A2 receptor isoform α. Reproduced with permission from Capodanno et al.17

the treatment plan accordingly. Therefore, determining the fine balance
between thrombotic and bleeding risks is crucial for the effective man­
agement of antiplatelet therapy.
Predictors of thrombotic and bleeding
events
Risk stratification tools for the prediction of ischemia, bleeding, or their
trade-off in CAD patients on dual antiplatelet therapy (DAPT, i.e. the
combination of aspirin and a P2Y12 inhibitor) are summarized in
Table 1. 10–15 These models were generally derived from large cohorts
of patients undergoing PCI and therefore their generalizability to other
DAPT settings (i.e. CAD without PCI) is uncertain.
The PARIS risk score encompasses six clinical variables for the pre­
diction of thrombosis and six variables for the prediction of bleeding.10
Other scores for bleeding include PRECISE-DAPT,11 which uses five
clinical predictors, and BleeMACS, which uses seven clinical predic­
tors.12 While these models follow a quantitative approach, a semiquan­
titative approach from the Academic Research Consortium for High
Bleeding Risk (ARC-HBR) has recently been introduced,13 with patients
at high bleeding risk defined as those fulfilling one major criterion or
two minor criteria from a set of variables defined by expert consensus.
Two models (DAPT score and ARC-HBR trade-off model) are also
available that integrate ischemic and bleeding risk factors to provide a
prediction rule for outcomes of ‘net benefit’.14,15
Overall, the discriminatory performance of the available risk models
for ischemia and/or bleeding is in the range of c-statistics between 0.65
and 0.75 in validation studies10–15,21, indicating their suboptimal cap­
acity to distinguish the patients who will experience an event from
and those who will not. Importantly, high bleeding risk patients have of­
ten been excluded from study populations used to derive bleeding risk
scores, and these scores have been evaluated in the context of standard
DAPT, which makes their generalisability uncertain when other scen­
arios are considered (e.g. de-escalation). Notably, the ESC guidelines as­
sign a low class of recommendation to the use of risk scores to guide
antiplatelet therapy (e.g. class IIb in the European guidelines for
ACS).22 Therefore, clinical considerations and sound clinical judgment
are crucial on top of utilizing these predictive models in guiding patient
management and treatment decisions.21 Yet, identifying patients who
are most likely to benefit from antiplatelet therapy (e.g. those at very
high risk of CAD events) and have a low risk of bleeding is challenging,
3062 D. Capodanno and D. J. Angiolillo

Table 1 Risk stratification tools for ischemia, bleeding, or their trade-off in patients on dual antiplatelet therapy

Score/Model No of Development cohort Setting Predicted outcome Validation

variables (patients, design) cohort(s) (patients,
c-index)
......................................................................................................................................................................................
Ischemia
PARIS Six clinical 4190 patients, multicentre registry PCI patients on DAPT Ischemia at 24 months 8665 patients, 0.65
thrombosis10 after PCI
Bleeding
PARIS bleeding10 Six clinical 4190 patients, multicentre registry PCI patients on DAPT Bleeding at 24 months 8665 patients, 0.64
after PCI

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PRECISE-DAPT11 Five clinical 14 963 patients, pooled analysis of PCI patients on DAPT Bleeding at 12 months 8595 patients, 0.70;
randomised clinical trials after PCI 6172 patients, 0.66
BleeMACS12 Seven clinical 15 401 patients, multicentre PCI patients on DAPT Bleeding at 12 months 96 239 patients, 0.65
registry after PCI
ARC-HBR13 Thirteen clinical - PCI patients on DAPT Bleeding at 12 months -
after PCI
Trade-off
DAPT score14 Five clinical, 11 648 patients, multicentre PCI patients on DAPT Ischemia and bleeding 8136 patients, 0.64 for
three randomised clinical trial who were event-free between 12 and 30 both ischaemia and
procedural for 12 months months after PCI bleeding
ARC-HBR Ten clinical, 6641 patients, pooled analysis of PCI patients on DAPT Ischemia and bleeding at 1458 patients, 0.74 for
trade-off15 two procedural randomised clinical trials and a 12 months after PCI both ischaemia and
multicentre registry bleeding

ARC-HBR, Academic Research Consortium for High Bleeding Risk; BleeMACS, Bleeding Complications in a Multicenter Registry of Patients Discharged With Diagnosis of Acute
Coronary Syndrome; DAPT, Dual Antiplatelet Therapy Trial; PARIS, patterns of non-adherence to anti-platelet regimens in stented patients; PCI, percutaneous coronary
intervention; PRECISE-DAPT, Predicting Bleeding Complications In Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy.

especially because patients at increased ischemic and bleeding risks typ­
ically share common CAD risk factors.15,23
Additionally, patients with established atherosclerotic cardiovascular
disease are generally considered at very high risk of events by current
ESC guidelines for secondary prevention.3 This broad group include
those with documented CAD, including previous MI, ACS, and coronary
revascularization. Patients with unequivocally documented cardiovascular
disease on imaging are also considered at very high risk, including those
with atherosclerotic plaques on coronary angiography or computed tom­
ography angiography.
A scrutiny of most common predictors derived by the available risk
stratification tools (Table 2) allows to isolate some crucial risk determi­
nants of ischemic complications in spite of antiplatelet therapy (e.g. dia­
betes mellitus, ACS or MI at presentation, prior PCI, MI or
cerebrovascular accident, smoking, renal insufficiency, peripheral artery
disease) and a number of key predictors of bleeding (e.g. age, renal in­
sufficiency, cirrhosis, anaemia or low haemoglobin levels, oral anticoa­
gulation, prior bleeding and/or transfusion, cancer) that are visually
schematized in Figure 2.
Personalised approach
Tailoring the right antiplatelet therapy to individual ischemic and bleed­
ing characteristics is crucial in optimizing the benefits and minimizing the
risks of treatment for patients with CAD (Graphical abstract).1 Patients
at high risk of ischemic events and low risk of bleeding may benefit from
a more intensive antiplatelet therapy regimen, while those at high risk of
bleeding and low risk of ischemic events require a less intensive and
more cautious approach. In patients at low risk of ischemic events
and low risk of bleeding, the benefits of antiplatelet therapy may not
outweigh the risks, while patients who have high risks of both ischemic
and bleeding events require a delicate balance, as the approach to man­
aging their conditions must weigh the potential benefits against the po­
tential risks.
There are two potential strategies to personalising the antiplatelet
treatment regimen based on the individual risk of ischemic and bleeding
complications.8 The first strategy is an approach based on clinical judg­
ment, where the practitioner uses commonly available parameters, in­
cluding clinical, demographic, laboratory, and procedural, along with
their experience to make decisions. The second strategy is an approach
based on guidance from assays that may inform on how a patient is re­
sponding (i.e. PFT) or may respond (i.e. genetic testing) to an antiplate­
let agent. This may include results from PFT that measure the
individual’s response to an antiplatelet drug which correlates with an
adverse outcome (e.g. hyper- and hypo-responders with bleeding and
thrombotic events, respectively). Alternatively, genetic testing provides
information about how an individual may respond to a given antiplatelet
agent (e.g. genetic polymorphisms coding for an enzyme involved in
drug metabolism may lead to different degrees of enzyme activity).
Both strategies aim to optimize the benefits of antiplatelet therapy in
reducing the risk of ischemic complications and mitigate the risk of
bleeding complications.
Personalised antiplatelet therapies for CAD 3063

Table 2 Predictors of ischemia and/or bleeding in patients on dual antiplatelet therapy

PARIS10 PRECISE BleeMACS12 ARC-HBR13 DAPT ARC-HBR

DAPT11 score14 Trade-off15
......................................................................................................................................................................................
Predictors of ischemia
Diabetes ◉ NA NA NA ◉ ◉
Smoking ◉ NA NA NA ◉ ◉
ACS or MI at presentation ◉ NA NA NA ◉ ◉
Prior PCI or MI ◉ NA NA NA ◉ ◉
Renal insufficiency ◉ NA NA NA ◉ ◉

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Prior CABG ◉ NA NA NA – –
Small stents – NA NA NA ◉ –
CHF or low LVEF – NA NA NA ◉ –
Paclitaxel-eluting stent – NA NA NA ◉ –
Vein graft stent – NA NA NA ◉ –
Vascular disease – NA NA NA ◉ –
Hypertension – NA NA NA ◉ –
Anaemia or haemoglobin – NA NA NA – ◉
Complex PCI – NA NA NA – ◉
Bare metal stent – NA NA NA – ◉
Predictors of bleeding
Age ◉ ◉ ◉ ◉ ◉ ◉
Renal insufficiency ◉ ◉ ◉ ◉ ◉ ◉
Anaemia or low haemoglobin ◉ ◉ ◉ ◉ – ◉
Oral anticoagulation ◉ – – ◉ – ◉
Prior bleeding and/or transfusion – ◉ ◉ ◉ – –
Cancer – – ◉ ◉ – ◉
Smoking ◉ – – – – ◉
Liver cirrhosis – – – ◉ – ◉
Planned major noncardiac surgery – – – ◉ – ◉
Hypertension – – ◉ – ◉ –
Vascular disease – – ◉ – ◉ –
Low or high body mass index ◉ – – – – –
Leucocytosis – ◉ – – – –
Thrombocytopenia – – – ◉ – –
Chronic bleeding diathesis – – – ◉ – –
Long-term use of NSAIDs or steroids – – – ◉ – –
Previous ischemic stroke or ICH – – – ◉ – –
Recent major surgery or trauma – – – ◉ – –
COPD – – – – – ◉
Complex PCI – – – – – ◉

Abbreviations: ACS, acute coronary syndromes; CABG, coronary artery bypass surgery; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; ICH, intracranial
haemorrhage; LVEF, low ventricular ejection fraction, MI, myocardial infarction; NA, not applicable; NSAIDs, nonsteroidal anti-inflammatory drugs; PCI, percutaneous coronary
intervention. Other abbreviations as in Table 1.
3064
Diabetes Smoking ACS/MI
CKD
Predictors
of ischaemia
PAD
Prior MI Prior PCI Prior CVA
Figure 2 Determinants of ischaemic and bleeding risk in patients on dual antiplatelet therapy. Abbreviations: ACS, acute coronary syndrome; CKD,
chronic kidney disease; CVA, cerebrovascular accidents; MI, myocardial infarction; OAC, oral anticoagulation; PAD, peripheral artery disease; PCI, per­
cutaneous coronary intervention.
Clinically guided approach
The standard approach to antiplatelet therapy in patients with CAD is to
prescribe 6 months of DAPT after PCI for CCS and 12 months after an
ACS with or without PCI.22,24–27 In particular, in addition to aspirin, clo­
pidogrel is the P2Y12 inhibitor of choice in patients with CCS, while pra­
sugrel (in patients undergoing PCI) and ticagrelor (regardless of
revascularization) are preferred over clopidogrel in patients with ACS,
with ESC guidelines recommending prasugrel over ticagrelor in patients
undergoing PCI.22,28 Indeed, the duration of DAPT can be prolonged or
shortened according the ischemic and bleeding risk profile of the patient.
In patients who are at increased risk for both ischemic and bleeding com­
plications, bleeding, more than ischemic risk or PCI complexity, should
inform decision-making on the duration of DAPT.29 After completion of
DAPT, patients should resume single antiplatelet therapy (SAPT).
Aspirin has been the standard of care for SAPT in most patients with
CAD. However, there is emerging evidence in the post-PCI setting sup­
porting the use of a P2Y12 inhibitor as chronic monotherapy instead.30,31
In addition to variations in the duration of DAPT, the availability of
different oral antiplatelet agents as well as a better understanding of
the timing at which patients may be at an enhanced risk of thrombotic
or bleeding complications has led strategies of modulation of the inten­
sity of antiplatelet therapy as an approach to optimize the safety–
efficacy balance in an individual patient. In particular, modulation of
the antiplatelet treatment regimen may occur in two ways: by reducing
(i.e. de-escalation) or increasing (i.e. escalation) the intensity of platelet
inhibition (Figure 3).32,33 Table 3 summarizes the results of contempor­
ary randomized clinical trials of antiplatelet therapy modulation. The re­
sults of these studies can guide a patient-centric approach where
physicians use their clinical judgment and expertise to determine which
candidates are best suited for a specific investigational treatment plan.
D. Capodanno and D. J. Angiolillo
Age CKD Cirrhosis
Cancer
Predictors
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of bleeding
Anemia
OAC Transfusion Prior bleed
De-escalation—By reducing the intensity of platelet inhibition,
de-escalation is an approach aimed at decreasing the risk of bleeding
complications when they are deemed to be greater than the risk of
thrombotic complications. This can be achieved by adjusting the type,
dose, or number of antiplatelet drugs used. Several trials have investi­
gated these approaches in contemporary populations mostly including
patients undergoing PCI. Importantly, some of these trials only rando­
mized patients who did not experience a thrombotic or bleeding during
the initial period of DAPT.35,42,47 This may have resulted in some de­
gree of patient selection and therefore less generalizability compared
with trials that randomized at the time of PCI. On the other hand,
this design avoided the potential confounding arising from events oc­
curring at that time when the two arms were on the same regimen.
A first common form of de-escalation is switching (i.e. adjusting drug
type approach), where a clinician changes from an agent associated with
more potent to less potent P2Y12 inhibition.52 This is often performed
in patients who have been initially treated for an ACS with a guideline
recommended DAPT regimen including prasugrel or ticagrelor, as
these drugs are associated with an increased risk of major spontaneous
bleeding compared to clopidogrel.53,54 Two trials in ACS, named
TOPIC and TALOS-AMI, have demonstrated the net benefit of an un­
guided switching to clopidogrel at 1 month post-ACS.34,35 Both trials
reported a reduction in bleeding as the driving factor behind the im­
proved outcomes.
Another approach to de-escalating antiplatelet therapy is reducing the
dose (i.e. adjusting drug dose approach) of the P2Y12 inhibitor character­
ized by enhanced platelet inhibitory effects (i.e. prasugrel or ticagrelor)
used in DAPT combinations. This strategy may be desirable when there
are concerns about excessive drug exposure, particularly in ethnicities
such as East Asian patients. One trial, the HOST-REDUCE, found that
reducing the maintenance dose of prasugrel from 10 to 5 mg once daily
Personalised antiplatelet therapies for CAD
Increase in
intensity of platelet
inhibition
Switching
Dose increase
Add-on
Escalation
Figure 3 Strategies of antiplatelet therapy modulation. Antiplatelet therapy can be modulated in two ways: by reducing (i.e. de-escalation) or increas­
ing (i.e. escalation) the intensity of platelet inhibition.
at 1 month reduced the risk of net adverse cardiac events (NACE) at 1
year in patients with ACS undergoing PCI.36 Also, the recommended
maintenance dose of ticagrelor is 90 mg twice daily for the first year after
an ACS but de-escalation to a dosing regimen of 60 mg twice daily can be
used after 1 year based on the results of the PEGASUS-TIMI 54 trial,
where the 60 mg dosing regimen was found to have similar efficacy to
the 90 mg dosing regimen but had a more favorable safety profile in
terms of bleeding and non-bleeding side effects.50
A third viable de-escalation approach is the discontinuation of DAPT
(i.e. adjusting drug number approach), which means stopping of one of
the DAPT antiplatelet agents and transitioning to SAPT with aspirin or a
P2Y12 inhibitor. The timing of discontinuation has progressively been
moved earlier after PCI with the current generation of coronary stents.
Several single-arm studies using historical controls or objective per­
formance goals support the concept that 1 to 3 months of DAPT
may be enough in patients at high risk of bleeding.47,55–57 Regardless
of bleeding risk, studies such as the ONE-MONTH DAPT trial37,58 in
patients with CCS or ACS, and the SMART-DATE trial,38
REDUCE-ACS,39 and DAPT-STEMI40 trials in patients with ACS have
shown that early discontinuation of the P2Y12 inhibitor with transition
from DAPT to aspirin monotherapy (i.e. at 1 to 6 months) is noninfer­
ior to discontinuation at 6 to 12 months in terms of 1-year NACE.
These trials used wide noninferiority margins, which raises a note of
caution over generalizing their results. Additionally, there were signals
of an increase in thrombotic complications with shorter DAPT espe­
cially in ACS.38,39,58
Several studies compared strategies of aspirin discontinuation and
P2Y12 inhibitor monotherapy after a short (e.g. 1–3 months) period
of DAPT in patients undergoing PCI, including GLOBAL LEADERS41
and TWILIGHT42 (testing SAPT with ticagrelor), and
STOPDAPT-243 and SMART-CHOICE44 (testing SAPT with clopido­
grel). With the exception of the GLOBAL LEADERS that did not
meet its primary objective, these studies have shown a reduction in
bleeding without any trade-off in ischemic events with P2Y12 inhibitor
monotherapy compared with standard DAPT. Two more trials, named
3065
De-escalation
Switching
Dose reduction
Discontinuation
Decrease in
Dec
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intensity of platelet
inhibition
TICO45 and STOPDAPT-2 ACS,46 compared early aspirin discontinu­
ation and maintaining SAPT with a P2Y12 inhibitor vs. 12-month DAPT
on 1-year NACE specifically in ACS patients: TICO (testing SAPT with
ticagrelor) showed superiority, while STOPDAPT-2 ACS (testing SAPT
with clopidogrel) failed in showing noninferiority. Although PFT or gen­
etic testing were not performed in STOPDAPT-2 ACS, it may be ar­
gued that its findings could be in part attributed to impaired
response to clopidogrel which more commonly occurs in high-risk set­
tings. Indeed, this represents an opportunity for future studies of indi­
vidualized treatment options in which defining response to therapy
when relying on SAPT with P2Y12 inhibitor monotherapy should be
considered. Of note, ticagrelor monotherapy after a short period of
DAPT showed promising results also in ACS sub-analyses of the
GLOBAL LEADERS59 and TWILIGHT60 trials.
Finally, some trials compared standard DAPT with strategies of as­
pirin discontinuation or P2Y12 inhibitor monotherapy at the physician’s
discretion. The MASTER DAPT trial selectively randomized patients at
high bleeding risk and found that discontinuing the P2Y12 inhibitor or
aspirin at 1 month was noninferior to continuing for at least two add­
itional months with respect to 1-year NACE or major adverse cardiac
events (MACE), and was associated with reduced bleeding.61 In the
HOST-IDEA trial, the discontinuation of one of antiplatelet agent at
3–6 months was noninferior with respect to 1-year NACE in patients
with CCS or ACS undergoing PCI.48
Escalation—Antiplatelet therapy escalation is meant to decrease
thrombotic or ischemic complications by increasing the intensity of
platelet inhibition at a time when such risk is considered greater than
the risk of bleeding complications. Again, this can be achieved by adjust­
ing the type, dose, or number of antiplatelet drugs used.
Escalation by switching refers to the practice of changing from a
platelet P2Y12 receptor inhibitor with moderate platelet inhibitory ef­
fects, such as clopidogrel, to one with stronger platelet inhibitory ef­
fects, such as prasugrel or ticagrelor.52 This change is sometimes
considered for patients treated with a clopidogrel-based DAPT regi­
men who present with an acute cardiac event or patients with CCS
3066 D. Capodanno and D. J. Angiolillo

Table 3 Contemporary randomized controlled trials of unselective modulation of antiplatelet therapy

Trial Modulation Strategy n Population Follow-up Primary Findings

endpoint
......................................................................................................................................................................................
TOPIC34 De-escalation Switch from prasugrel or 646 ACS and PCI 12 months NACE HR, 0.48; 95% CI, 0.34–0.68;
ticagrelor to clopidogrel P < 0.01
TALOS-AMI35 De-escalation Switch from ticagrelor to 2697 Prior ACS 11 months NACE HR, 0.55; 95% CI, 0.40–0.76;
clopidogrel and PCI P = 0.0001
HOST-REDUCE36 De-escalation Dose reduction from prasugrel 10 2338 ACS and PCI 12 months NACE HR, 0.70; 95% CI, 0.52–0.92;
to 5 mg once daily P = 0.012
ONE-MONTH De-escalation Discontinuation of the P2Y12 3020 CCS and PCI 12 months NACE ARD, -0.7%; upper limit of

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DAPT37 inhibitor (1 vs. 6–12 months of 1-sided 97.5% CI, 1.33%; P <
DAPT) 0.001 for noninferiority
SMART-DATE38 De-escalation Discontinuation of the P2Y12 2712 ACS and PCI 18 months MACE ARD, 0.5%; upper limit of
inhibitor (6 vs. 12 months of 1-sided 95% CI, 1.8%; P = 0.03
DAPT) for noninferiority
REDUCE ACS39 De-escalation Discontinuation of the P2Y12 1496 ACS and PCI 12 months NACE ARD, -0.0022%; upper limit of
inhibitor (3 vs. 12 months of 1-sided 95% CI, 0.027%; P <
DAPT) 0.001 for noninferiority
DAPT STEMI40 De-escalation Discontinuation of the P2Y12 1100 Prior ACS 18 months NACE HR, 0.73; 95% CI 0.41–1.27;
inhibitor (6 vs. 12 months of and PCI P = 0.004 for noninferiority
DAPT)
GLOBAL De-escalation Discontinuation of aspirin (1 vs. 12 15 968 PCI 24 months MACE Rate ratio, 0.87; 95% CI, 0.75–
LEADERS41 months of DAPT) 1.01; P = 0.073)
TWILIGHT42 De-escalation Discontinuation of aspirin (3 vs. 12 7119 PCI 12 months Bleeding HR, 0.56; 95% CI, 0.45–0.68;
months of DAPT) P < 0.001
STOPDAPT-243 De-escalation Discontinuation of aspirin (1 vs. 12 3045 PCI 12 months NACE HR, 0.64; 95% CI, 0.42–0.98;
months of DAPT) P = 0.04
SMART-CHOICE44 De-escalation Discontinuation of aspirin (3 vs. 12 2993 PCI 12 months MACE ARD, 0.4%, upper limit of
months of DAPT) 1-sided 95% CI, 1.3%; P =
0.007 for noninferiority
TICO45 De-escalation Discontinuation of aspirin (3 vs. 12 3056 ACS 12 months NACE HR, 0.66; 95% CI, 0.48–0.92;
months of DAPT) P = 0.01
STOPDAPT-2 De-escalation Discontinuation of aspirin (1–2 vs. 4169 ACS 12 months NACE HR, 1.14; 95% CI, 0.80–1.62;
ACS46 12 months of DAPT) P = 0.06 for noninferiority
MASTER DAPT47 De-escalation Discontinuation of aspirin or the 4434 PCI 11 months NACE ARD, -0.23%, upper limit of
P2Y12 inhibitor (1 vs. ≥3 months 95% CI, 1.33%; P < 0.001 for
of DAPT) noninferiority
HOST-IDEA48 De-escalation Discontinuation or the P2Y12 2013 PCI 12 months NACE ARD, -0.4%, upper limit of
inhibitor (3–6 vs. 12 months of 1-sided 95%, 1.1%; P < 0.001
DAPT) for noninferiority
DAPT49 Escalation Add-on P2Y12 inhibitor (30 vs. 9961 Prior PCI 18 months MACE HR, 0.71; 95% CI, 0.59–0.85;
12gr months of DAPT) P < 0.001
PEGASUS-TIMI Escalation Add-on ticagrelor (long-term 21 162 Prior MI ∼33 MACE HR (ticagrelor 90 mg), 0.85;
5450 DAPT vs. aspirin) months 95% CI, 0.75–0.96; P = 0.008;
HR (ticagrelor 60 mg), 0.84;
95% CI, 0.74–0.95; P = 0.004
THEMIS51 Escalation Add-on ticagrelor (long-term 19 220 CCS and ∼40 MACE HR, 0.90; 95% CI, 0.81–0.99;
DAPT vs. aspirin) diabetes months P = 0.04

Treatment effects are reported for the investigational strategy vs. standard dual antiplatelet therapy. In MASTER DAPT, NACE is reported as the first ranked primary outcome. P-values
are for superiority unless otherwise specified. Abbreviations: ACS, acute coronary syndrome; ARD, absolute risk difference; CCS, chronic coronary syndrome; CI, confidence interval;
DAPT, dual antiplatelet therapy; HR, hazard ratio; MACE, major adverse cardiac events; MI, myocardial infarction; NACE, net adverse cardiac events; PCI, percutaneous coronary
intervention.
Personalised antiplatelet therapies for CAD 3067

Table 4 Clopidogrel therapy based on CYP2C19 phenotype for ACS/PCI patients initiating antiplatelet therapy

Phenotype (genotype) Implications for clopidogrel Therapeutic recommendations

......................................................................................................................................................................................
UM (*1/*17, *17/*17) and Normal (EM) or increased (UM) platelet inhibition; normal (EM) or decreased Clopidogrel label-recommended dosage
EM (*1/*1) (UM) residual platelet aggregation and administration
Intermediate metabolizers Reduced platelet inhibition; increased residual platelet aggregation; increased Prasugrel or ticagrelor (if no
(*1/*2) risk for adverse cardiovascular events contraindications)
PM (*2/*2) Significantly reduced platelet inhibition; increased residual platelet aggregation; Prasugrel or ticagrelor (if no
increased risk for adverse cardiovascular events contraindications)

Adapted from Scott et al.72 Abbreviations: EM, extensive metabolizers; PM, poor metabolizers; UM, ultrarapid metabolizers.

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undergoing high-risk PCI. However, there are currently no data to sup­
port that prasugrel or ticagrelor are more effective than clopidogrel
among patients undergoing elective PCI.62,63
Escalation by dose increase refers to the practice of increasing the
dose of an antiplatelet drug with the goal of intensifying the platelet in­
hibitory effect. This approach has been tested in a clinical trial of
doubled clopidogrel or aspirin dose for patients undergoing PCI64
and a trial of doubled aspirin dose for patients with cardiovascular dis­
ease,65 but in both cases, the results have been neutral.
‘Add-on’ escalation refers to the practice of adding a second antipla­
telet drug to a patient who is already receiving SAPT, most commonly
aspirin. This strategy results in DAPT, and has been shown to be super­
ior to SAPT in reducing ischemic events in various patient populations,
including those with a history of prior PCI from the DAPT trial,49 those
with prior MI from the PEGASUS-TIMI 54 trial,50 and those with CAD
but without a prior acute cardiovascular event and with diabetes melli­
tus from the THEMIS trial.51 The benefit of DAPT in THEMIS was more
pronounced in patients with prior PCI.66
Platelet function and genotype-guided
approaches
Despite compliance to antiplatelet treatment, some patients may still
experience ischemic events, a phenomenon known as ‘therapeutic fail­
ure’.67 A number of factors contribute to therapeutic failure, including
impaired response to an antiplatelet agent, commonly referred to as
‘drug resistance’. Such finding is supported by a number of observation­
al studies, mostly conducted in patients undergoing PCI and treated
with clopidogrel-based DAPT, in which the use of PFT has shown
that individuals who persist with high on-treatment platelet reactivity
(HPR) are at increased risk for thrombotic complications.68 Some stud­
ies have also shown that patients with low on-treatment platelet re­
activity are at increased risk of bleeding,68 although the overall
evidence seems more robust for the prediction of ischemic risk.
The efficacy of clopidogrel is dependent on a two-step activation
process by the hepatic cytochrome P450 (CYP) system, with the
CYP2C19 enzyme involved in both metabolic steps.9,69 Notably,
CYP2C19 is highly polymorphic, meaning that variants in the gene confer
wide variability in the enzyme’s metabolic activity across individuals.
Therefore, there is wide variability in the activation of clopidogrel and
in the resulting platelet inhibitory effects across individuals. Prasugrel
and ticagrelor, however, are not affected by such genetic polymorph­
isms resulting in more consistent and sustained platelet inhibitory ef­
fects.9 Carriers of CYP2C19 loss of function (LOF) alleles have
significantly reduced clopidogrel metabolism, resulting in lower levels
of active metabolite, reduced clopidogrel-induced platelet inhibition
and higher rates of thrombotic complications in patients undergoing
PCI.70,71 The most common LOF alleles include CYP2C19*2 and
CYP2C19*3; less common LOF alleles include CYP2C19 *4, *5, *6, *7,
and *8. On the contrary, CYP2C19*17 is considered a gain of function
allele and is associated with increased transcription and enzyme expres­
sion.9 Combinations of CYP2C19 alleles define the metabolizer status
and serve for the basis of therapeutic recommendations (Table 4). 72
Allele frequencies vary by ancestry, with the highest prevalences among
of East Asians.73
Several studies have tried to answer whether a strategy of tailoring
antiplatelet therapy with guidance from PFT or genotyping is associated
with clinical benefit (Table 5). A meta-analysis including 11 randomised
controlled trials and three observational studies of guided selection of
antiplatelet therapy (PFT and genetic testing) for patients undergoing
PCI (n = 20 743 patients) showed improvements in both composite
and individual efficacy outcomes.83 More specifically, outcomes varied
according to the strategy used, with an escalation approach associated
with a significant reduction in ischaemic events without any trade-off in
safety, and a de-escalation approach by switch or dose reduction asso­
ciated with a significant reduction in bleeding, without any trade-off in
efficacy. In a more recent network meta-analysis of 15 randomised con­
trolled trials in patients with an ACS (n = 61 898 patients), compared
with routine selection of potent P2Y12 inhibiting therapy (prasugrel
or ticagrelor), a guided selection of P2Y12 inhibiting therapy was found
to be associated with the most favourable balance between safety and
efficacy.84
PFT—The availability of user-friendly and bedside assays has enabled
the execution of multicentre randomized clinical trials in patients
undergoing PCI testing the impact on outcomes associated with the
use of PFT. Some of these trials where specifically conducted among pa­
tients with HPR (identified by PFT) and comparing different antiplatelet
treatments,85,86 while other trials compared PFT guidance used as a
strategy vs. standard care.74–77
The GRAVITAS trial included patients with HPR, who were ran­
domly assigned to high-dose clopidogrel or standard-dose clopido­
grel; the primary composite outcome showed no significant
difference between the groups at 6 months.86 The TRIGGER PCI trial,
also conducted selectively in patients with HPR, compared prasugrel
and clopidogrel, but was terminated prematurely due to a
lower-than-anticipated risk of events at 6 months.85 The ARCTIC
and ANTARCTIC studies, evaluating a bedside strategy for monitor­
ing and adjusting antiplatelet therapy (i.e. de-escalation or escalation
by switch or dose adjustment as appropriate), also failed to show sig­
nificant benefits.74,75
3068 D. Capodanno and D. J. Angiolillo

Table 5 Strategy trials of modulation of antiplatelet therapy guided by platelet function or genetic testing in patients
undergoing percutaneous coronary intervention

Trial Intervention n Population Follow-up Primary Findings

endpoint
......................................................................................................................................................................................
Trials of PFT guidance
ARCTIC74 PFT-guided escalation or de-escalation 2240 CCS or ACS 12 months MACE HR, 1.13; 95% CI, 0.98–1.29; P = 0.10
by switch or dose adjustment
ANTARCTIC75 PFT-guided escalation or de-escalation 877 ACS 12 months NACE HR, 1.00, 95% CI 0.78–1.29; P = 0.98
by switch or dose adjustment
TROPICAL ACS76 PFT-guided de-escalation by switch 2610 ACS 12 months NACE HR, 0.81; 95% CI, 0.62–1.06;

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P = 0.0004 for noninferiority
PATH-PCI77 PFT-guided escalation by switch 2237 CCS 6 months NACE HR, 0.68, 95% CI, 0.49–0.95; P = 0.023
Trials of genetic guidance
PHARMCLO78 Genotype-guided de-escalation by 888 ACS 12 months NACE HR, 0.58; 95% CI, 0.43–0.78; P < 0.001
switch
POPULAR Genotype-guided de-escalation by 2488 ACS 12 months NACE ARD, -0.7%; upper limit of the 95% CI,
GENETICS79 switch 0.7%; P < 0.001 for noninferiority
ADAPT-PCI80 Genotype-guided escalation by switch 509 CCS or ACS ∼16 Use of prasugrel OR, 1.60; 95% CI, 1.07–2.42; P = 0.03
months or ticagrelor
TAILOR-PCI81 Genotype-guided escalation by switch 1849 CCS or ACS 12 months MACE HR, 0.66; 95% CI, 0.43–1.02; P = 0.06
82
Al-Rubaish et al. Genotype-guided escalation by switch 755 ACS 12 months NACE OR, 0.34; 95% CI, 0.20–0.59; P = NA

Treatment effects are reported for the investigational strategy vs. standard dual antiplatelet therapy; P-values are for superiority unless otherwise specified. Abbreviations: ACS; acute
coronary syndrome; ARD, absolute risk difference; CI, confidence interval; HPR, high platelet reactivity; HR, hazard ratio; LOF, loss of function; MACE; major adverse cardiac events; NA,
not available; NACE, net adverse cardiac events; OR, odds ratio; PCI, percutaneous coronary intervention; PFT, platelet function testing.

The inability of these early trials to demonstrate any clinical benefit
with the use of PFT could be attributed to a number of factors, such
as inclusion of low-risk patients, limited use of novel generation
P2Y12 inhibitors, and inadequate cut-off values to define HPR. More re­
cent studies conducted in high-risk settings have shown more promis­
ing findings.76,77 TROPICAL-ACS trial enrolled patients with ACS
undergoing PCI, randomly assigned to either PFT guidance with de-
escalation by switch from prasugrel to clopidogrel if responders or
standard care.76 The trial, powered for noninferiority on NACE vs.
standard DAPT, met its primary objective. The PATH-PCI trial also
met its primary objective, showing superiority for the PFT-based
approach.77
Guidance by genetic testing—Rapid CYP2C19 genotyping as­
says, with results available within 60 min, are commercially available
making genetic testing feasible in real-world practice.87,88 Genetic
testing has been evaluated as a method of guiding antiplatelet therapy
in five studies of patients with PCI and/or ACS, with mixed results78–82
(Table 5).
In patients with ACS undergoing PCI, the PHARMCLO78 and
POPULAR GENETICS79 trials compared the genotype-based selection
of P2Y12 inhibitors (i.e. selective use of prasugrel or ticagrelor among
CYP2C19 LOF carriers and clopidogrel in noncarriers) to unguided
standard of care DAPT. Despite being terminated early and therefore
resulting in lower power than anticipated, PHARMCLO showed the
genotype-based approach to significantly reduce the risk of NACE.
Similarly, in POPULAR GENETICS, the genotype-based approach was
non-inferior to standard therapy in terms of NACE at 12 months, and
resulted in a significantly lower incidence of major or minor bleedings.
In the ADAPT-PCI trial,80 the genotype-guided prescription was
found to significantly increase the use of prasugrel or ticagrelor com­
pared to an unguided approach in patients with ACS or CCS undergo­
ing PCI. TAILOR-PCI81 was the largest trial of genotype-guided
selection of oral P2Y12 inhibitor in which patients with ACS or CCS
undergoing PCI were randomized to genotype-guidance or conven­
tional therapy. In the genotype-guide group, CYP2C19 LOF carriers
were prescribed ticagrelor and noncarriers clopidogrel. Patients rando­
mized to the conventional group were prescribed clopidogrel.
Although the genotype-guided approach showed a numerical reduction
in MACE, this did not reach statistical significance, possibly due to a lack
of power. However, a recent analysis from the TAILOR-PCI study did
show superiority of a genotype-guided approach when considering re­
current events.89 Conversely, a trial from Al-Rubaish et al.,82 who only
included patients with ACS, showed a significant benefit of the
genotype-guided strategy in reducing NACE.
PFT and genetic testing: advantages and
disadvantages
PFT has the advantage of being more closely related with the clinical
outcome (i.e. increased thrombotic and bleeding complications with
high and low platelet reactivity, respectively).16 Nevertheless, results
of PFTs are subject to variability, particularly with clopidogrel early after
treatment initiation, requiring patients to be on treatment for a certain
period of time (e.g. for at least 1–2 weeks) to adequately assess antipla­
telet drug response. Hence, the potential need for serial assessments as
well as switching between different oral P2Y12 inhibitors may be
Personalised antiplatelet therapies for CAD
challenging to implement in clinical practice.90 In contrast, results of
genetic testing remain unchanged and allow to determine, even prior
to therapy, the CYP2C19 phenotype associated with different degrees
of clopidogrel response (Table 4). Accordingly, CYP2C19 LOF carriers
can be treated with ticagrelor or prasugrel while noncarriers with clo­
pidogrel. The disadvantage of relying solely on genetic testing is that the
pharmacodynamic effects of clopidogrel as measured by PFT depend
on multiple factors and not solely on CYP2C19 genotypes.91 To this
extent, integrating genetic data with clinical variables, such as in the
ABCD-GENE (Age, Body Mass Index, Chronic Kidney Disease,
Diabetes, and Genotyping) score has shown to enhance the accuracy
in identifying patients with impaired clopidogrel response.92 Although
retrospective assessments have shown the ability of the
ABCD-GENE score to identify patients at increased ischemic risk, pro­
spective validation of this score is still warranted.93,94
Antiplatelet therapies,
personalised strategies under
clinical testing, and unmet needs
The challenge for new antiplatelet drugs for CAD is to exhibit less
bleeding without reducing antithrombotic potency. Some of these de­
velopments may include new formulations of already available drugs,
such as a phospholipid-aspirin complex which is designed to reduce
gastro-intestinal injury and readily absorbed to ensure antithrombotic
efficacy.95 Other drugs include novel experimental agents aimed at
new targets. Potential new therapeutics are in advanced preclinical de­
velopment or have already entered the clinical development phase.96 It
remains to be seen how these new agents will fit within current para­
digms of antiplatelet therapy and whether they will lead to safer com­
binations in clinical practice.
The value of risk stratification tools to guide clinical decisions is typ­
ically assessed by means of c-statistics indicating their discrimination
ability. However, whether a risk score is helpful in improving clinical
outcomes requires an intervention-based randomized clinical study.
Trials of personalised duration of antiplatelet therapy based on the
DAPT score (NCT04135989) and the PRECISE-DAPT score
(NCT05732701, NCT03848572) are underway. Several ongoing ran­
domized clinical trials are also addressing the role of PFT-guided strat­
egies of antiplatelet therapy modulation in patients with ACS
(NCT04755387, NCT04718025, NCT04240834, NCT04937699,
NCT04338919, NCT05262803) and genotype-guided strategies in pa­
tients undergoing PCI (NCT03783351).
There are a number of unmet needs that may be stimulating for fu­
ture studies. In fact, de-escalation strategies have used DAPT as a com­
parator and there is limited data comparing the different approaches.
For example, there are no direct comparisons of de-escalation strat­
egies involving aspirin withdrawal (i.e. P2Y12 inhibitor monotherapy)
vs. switch guided by PFT or genotype testing. Additionally, most of
the trials and evidence cited in this review investigated clinical outcomes
over a relatively short time interval (i.e. 1 to 3 years). While strategies
for long-term secondary prevention are also evolving rapidly, it is un­
clear which patients may be ideally suited for long-term DAPT vs.
dual pathway inhibition the low-dose direct oral anticoagulants (i.e. riv­
aroxaban) vs. P2Y12 inhibitor monotherapy.
Guidelines
The ESC guidelines for myocardial revascularization97 and those for
ACS22 include a low-grade recommendation (i.e. class IIb) for de-
3069
escalation by switch of P2Y12 receptor inhibitor treatment (e.g. from
prasugrel or ticagrelor to clopidogrel), or de-escalation by dose
reduction, as an alternative DAPT strategy ‘especially for ACS patients
deemed unsuitable for potent platelet inhibition’. Also, the recommenda­
tion states that de-escalation by switch ‘may be done unguided based on
clinical judgment or guided by PFT or CYP2C19 genotyping, depending on
patient’s risk profile and availability of respective assays’. The level of evi­
dence for this recommendation is A, with the TOPIC,
TROPICAL-ACS, and POPULAR GENETICS trials used as supporting
references. The phrasing of the recommendation, referring to patients
‘unsuitable for potent platelet inhibition’, implies that these approaches
for now are best suited to patients at high bleeding risk, a population
that was actually understudied in the abovementioned trials, while
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the application of a strategy should reflect the types of patients enrolled
in the respective trials. No recommendation for de-escalation by switch
has been issued by the recent American guidelines for myocardial
revascularization.4
The ESC guidelines also include class IIa recommendations for de-
escalation by discontinuation of the P2Y12 inhibitor at 3 months (level
of evidence B, in patients at high bleeding risk as define by the
PRECISE-DAPT score or by the ARC-HBR criteria) or aspirin at 3–6
months (level of evidence A, ‘depending on the balance between the ische­
mic and bleeding risk’). In the American guidelines, the recommendation
for P2Y12 inhibitor discontinuation at 6 months is class 2b (for patients
at ‘high bleeding risk or overt bleeding on DAPT’) and the recommendation
for aspirin at 1–3 months discontinuation is 2a (potentially for any
patient).
Additionally, the ESC guidelines include recommendations for escal­
ation by ‘add-on’ of a P2Y12 inhibitor (class IIa, level of evidence A for
patients ‘with a high risk of ischemic events and without increased risk of
major or life-threatening bleeding’ and class IIb, level of evidence A for pa­
tients ‘with a moderate risk of ischemic events and without increased risk of
major or life-threatening bleeding’). In the American guidelines, this ap­
proach is recommended with class 2b for patients ‘with no high risk of
bleeding and no significant overt bleeding on DAPT’.
Conclusions
Personalised antiplatelet therapy has emerged as a crucial approach in
optimizing the balance between efficacy and safety by customizing anti­
platelet therapy to individual patient’s needs and risk profile. Accurate
risk stratification for both bleeding and thrombosis based on multiple
factors can aid in selecting the appropriate antiplatelet therapy and pre­
vent serious and life-threatening outcomes. With the introduction of
PFT and rapid genotype characterization, personalised antiplatelet ther­
apy is becoming more feasible and accessible. The comprehensive un­
derstanding of personalised antiplatelet therapy presented in this
review can help clinicians make informed clinical decisions and tailor
cardiovascular disease management.
Declarations
Disclosure of Interest
D.C. reports speaker’s or consulting fees from Amgen, Arena,
Chiesi, Daiichi Sankyo, Sanofi, Terumo, and institutional fees from
Medtronic. D.J.A. declares that he has received consulting fees or hon­
oraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors,
Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli
Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma,
3070
Pfizer, Sanofi, and Vectura, outside the present work; D.J.A. also de­
clares that his institution has received research grants from Amgen,
AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring,
Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical
Industry Co., Merck, Novartis, Osprey Medical, Renal Guard
Solutions, and Scott R. MacKenzie Foundation.
Data Availability
No new data were generated or analysed for this manuscript.
Funding
The research leading to this review has received funding from the
European Union—NextGenerationEU through the Italian Ministry of
University and Research under PNRR—M4C2-I1.3 Project
PE_00000019 ‘HEAL ITALIA’ to Davide Capodanno, CUP
E63C22002080006 of University of Catania. The views and opinions
expressed are those of the authors only and do not necessarily reflect
those of the European Union or the European Commission. Neither
the European Union nor the European Commission can be held re­
sponsible for them.
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