State-of-the-Art

DOI: 10.4244/EIJ-D-24-00992

Antithrombotic therapy in complex percutaneous coronary intervention

Domenico Simone Castiello1, MD; Angelo Oliva2, MD; Giuseppe Andò3, MD, PhD; Giampaolo Niccoli4, MD, PhD; Francesco Pelliccia5, MD, PhD; Elisabetta Moscarella6,7, MD, PhD; Rocco Antonio Montone8, MD, PhD; Felice Gragnano6,7, MD, PhD; Italo Porto9,10, MD, PhD; Paolo Calabrò6,7, MD, PhD; Salvatore De Rosa11, MD, PhD; Carmen Anna Maria Spaccarotella1, MD, PhD; Enrico Fabris12, MD, PhD; Giovanni Esposito1, MD, PhD; Ciro Indolfi13, MD, PhD; Gianfranco Sinagra12, MD, PhD; Pasquale Perrone Filardi1, MD, PhD; Raffaele Piccolo1, MD, PhD; on behalf of the Working Group of Interventional Cardiology of the Italian Society of Cardiology

Abstract

Abstract: Over the past decades, percutaneous coronary intervention (PCI) has become the most common modality for myocardial revascularisation, and it is increasingly used in patients with advanced coronary artery disease. Antithrombotic therapy, including antiplatelet and anticoagulant drugs, plays a key role and should be part of the optimal revascularisation strategy in the early phase as well as in the long-term prevention of ischaemic events. An antithrombotic therapy regimen of increased intensity and/or duration may mitigate part of the ischaemic burden associated with complex PCI. However, patients undergoing complex PCI are often at increased bleeding risk, challenging, therefore, the decision-making process. In this setting, the optimal antithrombotic treatment is still a matter of debate and has become a field of intensive research. In this state-of-the-art review, we analyse the evidence related to the different approaches regarding the periprocedural and long-term antithrombotic management of patients undergoing complex PCI. Since a “one-size-fits-all” approach cannot be justified in this clinical setting, our aim is to tailor the antithrombotic strategy to each patient’s profile and PCI complexity. We discuss the type and duration of antithrombotic regimens that can be selected for patients undergoing complex PCI, with a focus on prolonged dual antiplatelet therapy, P2Y12 receptor inhibitor monotherapy, and dual pathway inhibition. We also address antithrombotic management in specific scenarios (left main disease, coronary bifurcations, chronic total occlusion) and in patients undergoing complex PCI who require oral anticoagulant therapy.

In approximately 30% of cases, percutaneous coronary intervention (PCI) features a certain level of technical or anatomical complexity1. Antithrombotic therapy in the setting of PCI has the following aims: (i) to minimise thrombus burden and prevent the no-reflow phenomenon in patients with acute coronary syndrome (ACS); (ii) to reduce thrombotic complications secondary to the mechanical damage derived from coronary intervention (such as distal embolisation, plaque rupture, iatrogenic dissection, and occlusion of side branches); (iii) to prevent stent thrombosis; and (iv) to prevent ischaemic events outside the stented coronary segments23.

In this state-of-the-art review, we summarise the currently available antithrombotic strategies in patients undergoing complex PCI and highlight the results of randomised clinical trials that have tested antithrombotic regimens in this setting (Figure 1).

Figure 1. Timeline of randomised trials testing antithrombotic strategies in complex percutaneous coronary intervention. The duration is shown only for trials comparing short-term versus long-term DAPT. The publication year refers to the substudies performed in a complex PCI setting. ACS: acute coronary syndrome; DAPT: dual antiplatelet therapy; OAC: oral anticoagulant; PCI: percutaneous coronary intervention

Methods

We searched MEDLINE (from its inception to October 2024). We used the search terms “complex” or “complexity” in combination with the terms “percutaneous coronary intervention” or “PCI” or “revascularisation”. We selected publications from the past 10 years but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Review articles are cited to provide readers with more details.

Complex PCI

Despite the lack of a universal definition, criteria for complex PCI generally include one of the following characteristics: treatment of 3 vessels or ≥3 lesions, implantation of ≥3 stents, treatment of bifurcation with a 2-stent technique, total stent length ≥60 mm, or a chronic total occlusion (CTO) as the target lesion4. Additional criteria, such as treatment of the left main (LM) or a saphenous vein graft (SVG), lesion length ≥30 mm, thrombus-containing lesions, the use of an atherectomy device for severely calcified lesions, or bifurcation lesions with a side branch diameter ≥2.5 mm, have also been reported (Figure 2)56. The concept of complex PCI differs from complex high-risk indicated PCI (CHIP-PCI), as the latter considers patient-related factors (e.g., elderly status, frailty, severe left ventricular dysfunction, or chronic kidney disease) and procedure-related factors (e.g., mechanical circulatory support)7.

Patients undergoing complex PCI tend to have more comorbidities and incur a higher risk of both early and late ischaemic events compared to those undergoing non-complex PCI, particularly in the presence of multiple complexity features124689. Factors such as longer procedural time, more extensive coronary manipulation, the presence of severe calcifications that hinder proper stent expansion, and an increased incidence of periprocedural complications contribute to an elevated early ischaemic risk. Conversely, incomplete revascularisation, the higher likelihood of stent failure, and accelerated disease progression play a greater role in late ischaemic events. Despite potentially being effective, antithrombotic therapy is invariably associated with an increased bleeding risk, which might override the ischaemic risk in certain populations510. Notably, major bleeding complications may portend a similar prognostic impact compared with thrombotic events11. While the link between complex PCI and ischaemic events is generally recognised, the impact of complex PCI on bleeding events is more controversial41213. Since antithrombotic therapy can mitigate the risk of both stent-related and non-stent-related events, the selection of an antithrombotic regimen based on its efficacy and safety profiles may significantly influence the outcomes of patients undergoing complex PCI. Although recommendations on alternative antithrombotic regimens in current European Society of Cardiology (ESC) guidelines refer to patients with high ischaemic risk, several technical aspects are potential criteria for complex PCI (≥3 stents implanted, treatment of ≥3 lesions, total stent length >60 mm, LM PCI, treatment of bifurcation with a 2-stent technique, CTO PCI)1415.

Figure 2. Principal and additional criteria for complex percutaneous coronary intervention. PCI: percutaneous coronary intervention

Antithrombotic therapy before PCI

In patients with unknown coronary anatomy, anticipating complex PCI is highly unlikely. However, not all patients undergo ad hoc PCI, and in several instances the decision to proceed with PCI is delayed (e.g., after Heart Team evaluation). In patients with chronic coronary syndrome (CCS), the prior recommendation to pretreat with clopidogrel for at least 5 days is no longer present in the current ESC guidelines on CCS1415161718. From a clinical standpoint, in patients scheduled for complex PCI and deemed at low bleeding risk based on their risk score (e.g., Academic Research Consortium for High Bleeding Risk [ARC-HBR])10 and procedural aspects (e.g., radial access), pretreatment is a valuable option. In other cases, a loading dose of P2Y12 inhibitors can be safely administered around the time of PCI141518.

In the setting of ACS, routine pretreatment with P2Y12 inhibitors is no longer recommended for patients with non-ST-segment elevation ACS (NSTE-ACS) undergoing early invasive assessment within 24 hours (Class III, Level of Evidence A) and is weakly recommended for ST-segment elevation myocardial infarction (STEMI; Class IIb, Level of Evidence B)14.

An intravenous bolus of unfractionated heparin (UFH) is recommended at the time of diagnosis in patients with STEMI (Class I, Level of Evidence C)14. Data from observational studies showed that pretreatment with UFH in patients with STEMI is associated with higher patency of the infarct-related artery at baseline angiography1920, and these data have been recently confirmed by a randomised trial21.

In patients with NSTE-ACS, fondaparinux is recommended when an invasive strategy within 24 hours is not anticipated (Class I, Level of Evidence B)14.

Antithrombotic therapy during PCI

Periprocedural antithrombotic therapy is mandatory during PCI to avoid thrombus formation on the surface of the intravascular equipment and at the site of local plaque rupture or dissection caused by balloon angioplasty and stent implantation2. Complex PCI is linked to a heightened risk of bleeding at the access site, particularly when using femoral access, larger sheath sizes, or mechanical circulatory support devices. Hence, determining the ideal periprocedural antithrombotic approach remains a subject of ongoing debate.

1. Anticoagulant therapy

Parenteral anticoagulant therapy with intravenous UFH is the standard of care in patients undergoing PCI by virtue of its low cost, the immediate onset of action, the ease of periprocedural monitoring using activated clotting time (ACT) with the opportunity to titrate the infusion in order to deepen the antithrombotic effect, and the possibility of being rapidly antagonisable by protamine sulphate22. Bivalirudin and intravenous enoxaparin are two alternatives to UFH, based on data from randomised trials showing a decreased risk of major bleeding232425. The rapid onset and stable antithrombotic effect of bivalirudin, with no need for repeated monitoring, are significant advantages for the use of bivalirudin in long, technically complex coronary procedures, even though the absence of a selective antagonist remains a concern for its use. Data on bivalirudin are more controversial in view of the increased risk of stent thrombosis and myocardial infarction (MI) reported by early trials26272829, findings not confirmed by the three most recent trials303132. Evidence interpretation about bivalirudin is also challenged by the variable use of glycoprotein IIb/IIIa inhibitors (GPI) in the control arms and the non-standardised scheme of bivalirudin infusion after PCI. Considering the shorter half-life of bivalirudin (25 min) compared with heparin (60-90 min), continuing a full dose of bivalirudin infusion for up to 2-4 h post-PCI may mitigate the early increased ischaemic risk after PCI, mainly driven by stent thrombosis, observed in previous trials. This hypothesis, initially supported by a post hoc analysis of the EUROMAX trial33, was recently confirmed in a patient-level meta-analysis of six randomised trials with 15,254 patients34. Bivalirudin reduced the risk of all-cause mortality, cardiac mortality and major bleeding, although with an increase in reinfarction and stent thrombosis compared with UFH. However, in four trials with a 2- to 4-hour high-dose post-PCI infusion regimen, bivalirudin reduced cardiac mortality and major bleeding, without increasing the risk of reinfarction or stent thrombosis34. Of interest, a prolonged infusion of bivalirudin after PCI reduced procedural myocardial injury severity without increasing the risk of bleeding in patients with CCS in the Safety and Efficacy of Prolonged Use of Bivalirudin 4 Hours After elective PCI (COBER) study35. In approximately 20% of patients included in the CHAMPION PHOENIX trial, bivalirudin was used as the anticoagulant during PCI. Of interest, the decreased risk of ischaemic complications without bleeding liability was retained in patients receiving cangrelor and bivalirudin36. Hence, even if there is still a lack of data in patients undergoing complex PCI, bivalirudin might counterbalance the possibly higher risk of bleeding associated with the use of more potent P2Y12 inhibitors and cangrelor.

Despite the lack of data regarding complex PCI, in a large meta-analysis of 23 randomised and non-randomised trials including 30,966 patients, enoxaparin (both intravenous and subcutaneous) significantly reduced mortality, MI, and the composite endpoint of death or MI compared with UFH, particularly in patients with STEMI undergoing primary PCI. Of note, major bleeding was reduced only with the intravenous route, a finding not observed in studies that used subcutaneous enoxaparin25.

To summarise, although there are no specific data regarding the optimal periprocedural anticoagulant management in the complex PCI setting, UFH is widely used and remains the default strategy for anticoagulant therapy. However, bivalirudin and enoxaparin represent valuable alternatives for complex PCI, especially in patients at high risk of periprocedural bleeding events (Central illustration).

However, when UFH is used, in some complex procedures (e.g., retrograde CTO PCI), achieving a higher ACT (>350 seconds) may be considered37. The results of several studies on ACT monitoring during PCI are conflicting. A post hoc analysis of the Treatment of Acute Coronary Syndromes With Otamixaban (TAO) trial represents, to date, the largest cohort with systematic blinded ACT monitoring38. In this cohort of patients with NSTE-ACS treated with UFH plus GPI undergoing PCI, there was no evidence of an ACT threshold predicting ischaemic complications, whereas peak procedural ACTs ≥250 seconds for femoral access and ≥290 seconds by radial approach were associated with increased bleeding risk38.

Central illustration. Antithrombotic strategies for patients undergoing complex percutaneous coronary intervention. The algorithm shows periprocedural and long-term antithrombotic strategies based on bleeding risk. All patients undergoing complex PCI are assumed to be at high ischaemic risk. Patients requiring OACs are assumed by default to be at HBR. ACS: acute coronary syndrome; CCS: chronic coronary syndrome; HBR: high bleeding risk; NOAC: non-vitamin K antagonist oral anticoagulant; OAC: oral anticoagulant; P2Y12-i: P2Y12 inhibitor; PCI: percutaneous coronary intervention; UFH: unfractionated heparin

2. Antiplatelet therapy

Periprocedural aspirin use, along with P2Y12 inhibitor administration, is the mainstay in patients undergoing PCI and is also standard in complex PCI. Clopidogrel is usually the default P2Y12 inhibitor in the setting of elective PCI, whereas ticagrelor or prasugrel are preferred in patients with ACS and may be considered in patients with CCS at high ischaemic risk (Class IIb, Level of Evidence C)141518. Clopidogrel has been extensively used and remains the P2Y12 inhibitor of choice in patients with CCS, even in complex PCI1539, although its use is limited by delayed antiplatelet efficacy and high variability in the antiplatelet effect. As of yet, there is no reason to replace clopidogrel with more potent P2Y12 inhibitors to prevent periprocedural events in patients undergoing elective, complex PCI. Two randomised trials, Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS) and Strategies of Loading With Prasugrel Versus Clopidogrel in PCI-Treated Biomarker Negative Angina (SASSICAIA), failed to demonstrate the superiority of more potent P2Y12 inhibition using ticagrelor or prasugrel, respectively, compared with clopidogrel. These trials aimed to decrease periprocedural and cardiovascular events in patients with CCS undergoing high-risk PCI4041. Consistently, in the ALPHEUS substudy, randomisation to ticagrelor versus clopidogrel did not decrease periprocedural or 30-day cardiovascular events in patients with CCS undergoing complex PCI42.

Cangrelor is an intravenous P2Y12 inhibitor that acts as a direct reversible P2Y12 receptor antagonist, with rapid onset and offset after infusion discontinuation36. It is currently approved (Class IIb, Level of Evidence A) for oral P2Y12 inhibitor-naïve patients presenting with ACS undergoing PCI14. Compared to clopidogrel, cangrelor achieves faster and more potent platelet inhibition, and this finding has been confirmed in patients undergoing complex PCI43. In a pooled analysis of three trials, including 24,910 patients, cangrelor significantly reduced the risk of early ischaemic events at 48 hours after PCI compared with clopidogrel44. Although there was no significant difference in terms of the primary safety endpoint, the risk of major bleeding based on other criteria was significantly increased in patients randomised to cangrelor. Because the risk of periprocedural MI is significantly higher in patients undergoing complex compared to non-complex PCI, even using multiple definitions8, cangrelor may represent a valid alternative in patients naïve to P2Y12 inhibitors who are not at high bleeding risk (HBR). In this respect, the greatest absolute risk reduction in ischaemic events with cangrelor has been reported in patients with the highest number of high-risk features45.

GPI are potent intravenous antiplatelet agents, which were routinely added to UFH in patients with ACS in the early era of PCI. However, in view of the increased risk of major bleeding, GPI are currently indicated only as a bailout strategy in case of no-reflow or thrombotic complications during PCI. Recent ESC guidelines on ACS indicate the potential use of GPI in patients undergoing high-risk PCI and naïve to P2Y12 inhibitors14.

Antithrombotic therapy after PCI

1. Dual antiplatelet therapy

In patients undergoing PCI, a variable duration of dual antiplatelet therapy (DAPT), consisting of a combination of aspirin and a P2Y12 inhibitor, is recommended for all patients and still remains the cornerstone of secondary prevention.

In real-world clinical practice, 20-40% of patients continue DAPT beyond 1 year after revascularisation, and complex PCI is a major independent predictor of DAPT persistence46. In a patient-level meta-analysis including nearly 9,500 patients from 6 randomised trials, long-term DAPT (≥12 months), compared with short-term DAPT (3-6 months), yielded a significant reduction of major adverse cardiovascular events in the complex PCI group, a finding not observed in the non-complex PCI stratum (p for interaction=0.01). Moreover, the benefit associated with long-term DAPT gradually increased with the number of complex PCI features. However, long-term DAPT was associated with a significantly higher risk of major bleeding, both in complex PCI and in non-complex PCI strata4. A subsequent meta-analysis combined the risk of bleeding with PCI complexity in 8 trials and showed that in patients undergoing complex PCI without HBR features, prolonging DAPT (12 or 24 months) was associated with a decreased absolute risk of ischaemic events without bleeding liability, compared with short DAPT (3 or 6 months). In patients undergoing complex PCI and at HBR, prolonging DAPT increased the risk of bleeding without a parallel ischaemic benefit13. In a post hoc analysis of the DAPT trial, long-term DAPT (12-30 months), mainly with clopidogrel and prasugrel, was associated with a reduction of MI and stent thrombosis rates at the expense of an increased bleeding rate, a finding that was similar for patients with and without anatomical complexity6. Consistently, in a prespecified subanalysis of the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, extended DAPT with ticagrelor significantly reduced the risk of cardiovascular death, MI, or stroke, whereas it increased the risk of major bleeding, as compared to aspirin plus placebo, irrespective of multivessel coronary artery disease angiographic evidence47. Taken together, these data (Table 1) support a strategy of DAPT prolongation beyond 1 year after PCI in patients undergoing complex PCI when the thrombotic risk is prevalent (e.g., patients with ACS) and the bleeding risk is low (Central illustration). Extended DAPT (beyond 12 months) should be considered in patients without HBR and with high ischaemic risk, including those presenting with complex PCI (Class IIa, Level of Evidence A) according to current ESC guidelines on the management of ACS and CCS1415.

Table 1. Studies comparing short-term versus long-term DAPT strategies in patients undergoing complex PCI.

Study - year Complex PCI patients ACS patients Follow-up Complex PCI criteria Short-term DAPT Long-term
DAPT		 Results
Patient-level meta-analysis of 6 RCTs4 -2016 17.5%(1,680/9,577) 43.7%(4,189/9,577) 12 months* ≥1 of the following: 3 to 6 months of DAPT (aspirin and clopidogrel) ≥12 months of DAPT (aspirin and clopidogrel) Long-term DAPT yielded a significant reduction in MACE in the complex PCI group versus the non-complex PCI group
3 vessels treated,

≥3 stents implanted,

≥3 lesions treated,

bifurcation with 2 stents implanted,

total stent length >60 mm,
CTO PCI
DAPTtrial6-2017 32.2%(3,730/11,554) 46.3%(5,359/11,554) 30 months ≥1 of the following: 12 months of DAPT (aspirin and clopidogrel or prasugrel) 30 months of DAPT (aspirin and clopidogrel or prasugrel) Long-term DAPT reduced ischaemic events, irrespective of the presence of anatomically complex lesions, but increased moderate/severe bleeding
unprotected LM,

≥2 lesions per vessel,

lesion length ≥30 mm,

bifurcation lesion with side branch ≥2.5 mm,

saphenous vein graft,

thrombotic lesions
EXCEL trial-2018 100%(633/633) 38.7%(245/633) 36 months LM PCI 12 months of DAPT (aspirin and clopidogrel, prasugrel or ticagrelor) 36 months of DAPT (aspirin and clopidogrel or ticagrelor) Long-term DAPT was not associated with improved event-free survival in complex PCI patients
PEGASUS-TIMI 54 trial4786-2018 59.4%(12,558/21,162) 0%(0/21,162) 36 months† Multivessel CAD 12 months of DAPT (aspirin and ticagrelor) 36 months of DAPT (aspirin and ticagrelor) Long-term DAPT reduced ischaemic events, but increased TIMI major bleeding (not ICH or fatal bleeding) in multivessel PCI patients
Patient-level meta-analysis of 8 RCTs13 -2019 20.8%(3,118/14,963) 55.5%(8,312/14,963) 24 months ≥1 of the following: 3 to 6 months of DAPT (aspirin and clopidogrel, prasugrel or ticagrelor) 12 to 24 months of DAPT (aspirin and clopidogrel, prasugrel or ticagrelor) Long-term DAPT in non-HBR patients reduced ischaemic events in both complex and non-complex PCI groups, but not among HBR patients, regardless of PCI complexity
3 vessels treated,

≥3 stents implanted,

≥3 lesions treated,

bifurcation with 2 stents implanted,

total stent length >60 mm,
CTO PCI
IDEAL-LM trial87-2022 100%(818/818) 40.4%(331/818) 24 months LM PCI 4 months of DAPT (aspirin and clopidogrel, prasugrel or ticagrelor) 12 months of DAPT (aspirin and clopidogrel, prasugrel or ticagrelor) 4 months of DAPT was non-inferior to 12 months of DAPT with respect to the ischaemic composite endpoint in LM PCI patients
*Median follow-up time: 392 days. †Median follow-up time: 33 months. ACS: acute coronary syndrome; CAD: coronary artery disease; CTO: chronic total occlusion; DAPT: dual antiplatelet therapy; HBR: high bleeding risk; ICH: intracranial haemorrhage; LM: left main; MACE: major adverse cardiovascular events; PCI: percutaneous coronary intervention; RCT: randomised clinical trial; TIMI: Thrombolysis in Myocardial Infarction

2. P2Y12 inhibitor monotherapy

P2Y12 inhibitor monotherapy from PCI to 1 year

Different types of P2Y12 inhibitors and varying timings of aspirin discontinuation (e.g., 1-3 months after PCI) have been tested in randomised trials, showing a satisfactory safety and efficacy profile overall (Table 2)48.

Clopidogrel monotherapy was investigated in three trials495051. Across these studies, clopidogrel monotherapy reduced major bleeding rates without increasing ischaemic events as compared with standard 12-month DAPT, regardless of PCI complexity525354. However, in a pooled analysis of nearly 6,000 patients, clopidogrel monotherapy after 1-month DAPT, compared with 12 months of DAPT, was associated with a numerical increase in cardiovascular events among patients with ACS, but not in patients with CCS, suggesting a possible safety issue with clopidogrel monotherapy in patients with ACS55.

In the “Comparative effectiveness of 1 month of ticagrelor plus aspirin followed by ticagrelor monotherapy versus a current-day intensive dual antiplatelet therapy in all-comers patients undergoing percutaneous coronary intervention with bivalirudin and BioMatrix family drug-eluting stent use” (GLOBAL LEADERS) trial, 23-month ticagrelor monotherapy after 1-month DAPT was compared with 12-month DAPT with ticagrelor or clopidogrel followed by aspirin monotherapy among 15,968 patients undergoing PCI56. In a post hoc analysis of the study, ticagrelor monotherapy significantly reduced the risk of the primary endpoint, a composite of all-cause death or new Q-wave MI, in patients with complex PCI but not in those with non-complex PCI features (p for interaction=0.015), a benefit that was mainly driven by a significant interaction for treatment effect in patients presenting with ACS; moreover, no significant difference in bleeding was shown57. Ticagrelor monotherapy after 3-month DAPT was evaluated in 7,119 high-risk patients enrolled in the Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT) trial and in 3,056 patients presenting with ACS in the Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome (TICO) trial5859. In the TWILIGHT-COMPLEX substudy, a total of 2,342 patients underwent complex PCI and, in line with the parental trial, ticagrelor monotherapy was associated with a significant reduction of major bleeding and similar ischaemic risk compared with ticagrelor plus aspirin, irrespective of periprocedural complexity60. In the TICO trial, when the clinical characteristics (e.g., diabetes and chronic kidney disease) were combined with procedural complexity criteria, no significant interaction was evident for ticagrelor monotherapy after 3-month DAPT compared with 12-month DAPT with ticagrelor61. More recently, in a pooled analysis including 7,529 patients with ACS from the TICO and TWILIGHT trials, ticagrelor monotherapy significantly reduced major bleeding, without increasing adverse events, with no evidence of interaction according to PCI complexity62.

Prasugrel monotherapy was investigated in the recent Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-3 (STOPDAPT-3) trial. In 1,230 patients with ACS or HBR undergoing complex PCI, low-dose prasugrel (3.75 mg/day) monotherapy showed similar ischaemic and bleeding outcomes at 1 month compared with low-dose prasugrel-based DAPT63. However, it should be noted that there was an excess of unplanned revascularisation and subacute definite or probable stent thrombosis in the aspirin-free group6364.

Two recent meta-analyses showed a consistent reduction in the risk of major bleeding during P2Y12 inhibitor monotherapy in patients undergoing complex PCI, without an increased risk of ischaemic events6566. Despite the accumulated evidence, the current guidelines recommend P2Y12 inhibitor monotherapy only in patients with ACS at high bleeding risk (Class IIb, Level of Evidence B) or in patients with CCS at high ischaemic risk in the absence of HBR features (Class IIb, Level of Evidence C) (Central illustration)1415.

Table 2. Studies comparing P2Y12 inhibitor monotherapy versus DAPT in patients undergoing complex PCI.

Study - year Complex PCI patients ACS patients Follow-up Complex PCI criteria P2Y12 inhibitor monotherapy regimen DAPT regimen Results
GLOBAL LEADERStrial57 -2019 28.6%(4,570/15,968) 45.4%(7,260/15,968) 24 months ≥1 of the following: 23-month ticagrelor monotherapy following 1-month DAPT (aspirin and ticagrelor) 12-month aspirin monotherapy following 12-month DAPT (aspirin and ticagrelor or clopidogrel) Ticagrelor monotherapy significantly reduced the risk of the primary ischaemic endpoint in complex PCI patients, but not in the non-complex PCI group
3 vessels treated,
≥3 stents implanted,
≥3 lesions treated,
bifurcation with 2 stents implanted,
total stent length >60 mm
TWILIGHTtrial60 -2020 32.8%(2,342/7,119) 64.8%(4,614/7,119) 15 months ≥1 of the following: 12-month ticagrelor monotherapy following 3-month DAPT (aspirin and ticagrelor) 12-month DAPT (aspirin and ticagrelor) Ticagrelor monotherapy significantly reduced the risk of the primary bleeding endpoint in complex PCI patients without an increased risk of ischaemic events
3 vessels treated,
≥3 lesions treated,
bifurcation with 2 stents implanted,
total stent length >60 mm,
CTO PCI,
atherectomy device use,
LM PCI,
surgical bypass graft PCI
TICOtrial61 -2021 13.3%(409/3,056)* 100%(3,056/3,056) 12 months ≥1 of the following†: 9-month ticagrelor monotherapy following 3-month DAPT (aspirin and ticagrelor) 12-month DAPT (aspirin and ticagrelor) Ticagrelor monotherapy after short-duration DAPT was not associated with an increased risk of ischaemic or bleeding events in high-ischaemic risk patients
≥3 stents implanted,
total stent length >60 mm,
bifurcation with 2 stents implanted,
LM PCI,
CTO PCI,
history of DM or CKD
SMART-CHOICEtrial52 -2021 16.6%(498/2,993) 100%(2,993/2,993) 12 months ≥1 of the following: 9-month P2Y12 inhibitor monotherapy (mostly clopidogrel) following 3-month DAPT (aspirin and mostly clopidogrel) 12-month DAPT (aspirin and mostly clopidogrel) P2Y12 inhibitor monotherapy, mostly clopidogrel, after short-duration DAPT was not associated with an increased risk of ischaemic events in complex PCI patients
3 vessels treated,
≥3 stents implanted,
≥3 lesions treated,
bifurcation with 2 stents implanted,
total stent length >60 mm
Pooled population of STOPDAPT-253 -2021andSTOPDAPT-2 ACS trials54 -2023 16.7%‡(999/5,997) 68.9%§(4,136/5,997) 12 months ≥1 of the following: 11-month clopidogrel monotherapy following 1-month DAPT (aspirin and clopidogrel) 12-month DAPT (aspirin and clopidogrel) Clopidogrel monotherapy after short-duration DAPT showed comparable ischaemic and bleeding outcomes compared to 12-month DAPT in complex PCI patients
3 vessels treated,
≥3 stents implanted,
≥3 lesions treated,
bifurcation with 2 stents implanted,
total stent length >60 mm,
CTO PCI
STOPDAPT-3 trial63 -2024 20.6%(1,228/5,966) 75%(4,474/5,966) 12 months ≥1 of the following: Low-dose prasugrel monotherapy 1-month DAPT (aspirin and low-dose prasugrel) Low-dose prasugrel monotherapy showed comparable ischaemic and bleeding outcomes compared to 1-month DAPT in the complex PCI cohort. However, an excess of unplanned revascularisation and subacute definite or probable stent thrombosis was found in the no-aspirin group
3 vessels treated,
≥3 stents implanted,
≥3 lesions treated,
bifurcation with 2 stents implanted,
total stent length >60 mm,
CTO PCI
*Complex PCI patients: 409; non-complex PCI patients: 2,647. †Information for the post hoc analysis of the TICO trial refers to patients defined as at high ischaemic risk, which included those undergoing complex PCI, having chronic kidney disease, or diabetes mellitus. ‡Complex PCI patients from the STOPDAPT-2 cohort: 509 (16.9%); complex PCI patients from STOPDAPT-2 ACS: 490 (16.3%). §ACS patients from the STOPDAPT-2 cohort: 1,148 (38.1%); ACS patients from STOPDAPT-2 ACS: 2,988 (100%). ACS: acute coronary syndrome; CKD: chronic kidney disease; CTO: chronic total occlusion; DAPT: dual antiplatelet therapy; DM: diabetes mellitus; HBR: high bleeding risk; LM: left main; PCI: percutaneous coronary intervention

P2Y12 inhibitor monotherapy after 1 year

Although aspirin remains the treatment of choice for long-term secondary prevention after PCI, P2Y12 inhibitor monotherapy is emerging as a novel strategy (Table 2, Table 3). A recent patient-level meta-analysis of 7 randomised trials compared P2Y12 inhibitor monotherapy versus aspirin monotherapy for long-term secondary prevention in patients with established coronary artery disease. P2Y12 inhibitor monotherapy was superior to aspirin monotherapy in terms of ischaemic outcomes, whereas the rate of major bleeding was similar between the two strategies67. In the Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-EXtended Antiplatelet Monotherapy (HOST-EXAM) trial, clopidogrel monotherapy was associated with lower risks of both thrombotic and bleeding events compared with aspirin among more than 5,000 patients. A subgroup analysis of PCI complexity showed consistent benefit of clopidogrel monotherapy with no significant interaction68. A landmark analysis of the GLOBAL LEADERS trial at 12-month follow-up showed that ticagrelor versus aspirin monotherapy significantly reduced ischaemic events (all-cause death, any MI, or any stroke), although it numerically increased the risk of bleeding. This result was consistent in patients undergoing both complex and non-complex PCI69. Of note, clopidogrel monotherapy has been endorsed by ESC guidelines on CCS as a safe and effective alternative to aspirin for long-term post-PCI secondary prevention (Class I, Level of Evidence A)15.

Table 3. Studies comparing other antithrombotic strategies versus a standard strategy in patients undergoing complex PCI.

Study - year Complex PCI patients ACS patients Follow-up Complex PCI criteria Antithrombotic experimental regimen Standard regimen Results
CHAMPION PHOENIXtrial45 -2018 83.3%(9,037/10,854) 41.6%(4,518/10,854) 48 hours ≥1 of the following: Cangrelor (30 µg/kg i.v. bolus followed by a 4 µg/kg/min infusion i.v.) Clopidogrel (loading dose of 600 mg or 300 mg) Cangrelor reduced MACE within 48 hours after PCIin both CCS and ACS, compared to an LD of clopidogrel in ADP receptor inhibitor-naïve patients
long lesions,
LM lesions,
bifurcation lesions,
thrombotic lesions,
calcified lesions,
multilesion PCI
COMPASStrial84 -2020 38.0%(3,775/9,862) 0%(0/9,862) 24 months Multivessel PCI (patientswith previous PCI) DPI with rivaroxaban (2.5 mg twice a day) and aspirin Aspirin monotherapy DPI reduced MACE and mortality compared with aspirin, but increased major bleeding in CCS patients with multivessel PCI
HOST REDUCE POLYTECHtrial76 -2022 31.0%(705/2,271) 100%(2,271/2,271) 12 months ≥1 of the following: DAPT with prasugrel dose de-escalation (5 mg once a day) following 1-month DAPT with the conventional prasugrel dose 12-month DAPT with the conventional prasugrel dose(10 mg once a day) Prasugrel dose de-escalation DAPT did not increase the risk of MACE, but decreased bleeding events compared with the conventional dose
≥3 stents implanted,
≥3 lesions treated,
bifurcation PCI
total stent length ≥60 mm,
LM PCI
heavily calcified lesions
HOST-EXAMtrial68 -2022 3%(152/4,717) 0%(0/4,717) 72 months* 1 of the following: Clopidogrel monotherapy following 12±6 months of DAPT with clopidogrel Aspirin monotherapy following 12±6 months of DAPT with clopidogrel Clopidogrel monotherapy showed a lower risk of both thrombotic and bleeding events compared with aspirin monotherapy
3 vessels treated,
≥3 stents implanted,
≥3 lesions treated,
bifurcation with 2 stents implanted,
total stent length >60 mm,
CTO PCI
TALOS-AMItrial77 -2024 29.2%(788/2,697)†‡ 100%(2,697/2,697) 12 months ≥1 of the following: 11-month clopidogrel-based DAPT (aspirin and clopidogrel) following 1 month of ticagrelor-based DAPT (aspirin and ticagrelor) 12-month ticagrelor-based DAPT (aspirin and ticagrelor) An unguided de-escalation strategy to clopidogrel-based DAPT reduced bleeding events withouta significant difference in ischaemic outcomes, regardless of the presence of high ischaemic risk features
history of DM or CKD,
multivessel PCI,
≥3 lesions treated,
total stent length >60 mm,
≥3 stents implanted,
LM PCI,
bifurcation with 2 stents implanted
ALPHEUStrial42 -2024 48.3%(910/1,866) 0%(0/1,866) 1 month ≥1 of the following: Ticagrelor-based DAPT (aspirin and ticagrelor) Clopidogrel-based DAPT (aspirin and clopidogrel) Ticagrelor-based DAPT did not reduce periprocedural MI and ischaemic events compared with clopidogrel in CCS patients undergoing complex PCI
total stent length >60 mm,
bifurcation with 2 stents implanted,
LM PCI,
bypass graft PCI,
CTO PCI,
use of atherectomy,
multiple stents implanted
*Median follow-up time: 5.8 years. †Complex PCI patients: 788; non-complex PCI patients: 1,909. ‡Information for the post hoc analysis of the TALOS-AMI trial refers to patients defined as at high ischaemic risk, which included those undergoing complex PCI, and having a history of diabetes mellitus or chronic kidney disease. ACS: acute coronary syndrome; ADP: adenosine diphosphate; CCS: chronic coronary syndrome; CKD: chronic kidney disease; CTO: chronic total occlusion; DAPT: dual antiplatelet therapy; DM: diabetes mellitus; DPI: dual pathway inhibition; LD: loading dose; LM: left main; MACE: major adverse cardiovascular events; MI: myocardial infarction; PCI: percutaneous coronary intervention

3. Switching, escalation and de-escalation of antithrombotic therapies

Switching between antithrombotic drugs can involve both anticoagulant and antiplatelet agents. As a general approach, switching between anticoagulants should be avoided unless fondaparinux has been used before PCI14.

Switching between P2Y12 inhibitors can involve switching between two oral P2Y12 inhibitors (escalation, de-escalation, or change) or can involve an intravenous P2Y12 inhibitor (bridge or transition). Both escalation and de-escalation approaches can be guided or unguided, according to whether genetic tests to identify carriers of CYP2C19 loss-of-function alleles or platelet function tests are performed or not, respectively. In general, switching between oral P2Y12 inhibitors should occur with the administration of a loading dose in the setting of ACS, whereas reloading is not required in the context of CCS, with the exception of ticagrelor70. Despite the lack of data on complex PCI, a meta-analysis of both randomised and non-randomised trials showed that guided escalation is associated with a decreased risk of ischaemic events without a trade-off in bleeding71. In this respect, an expert consensus statement supported the use of platelet-function testing to escalate P2Y12 inhibitors in patients undergoing complex PCI (multivessel PCI, ≥3 stents implanted, bifurcation PCI with 2 stents, total stent length >60 mm, CTO PCI)72.

A de-escalation strategy has been tested exclusively in patients with ACS across 6 trials (2 functional-guided, 1 genotype-guided, 3 unguided trials)73. Except for one trial74, all the studies met their primary endpoint and showed significant reductions of net adverse clinical events and major bleeding, without increasing ischaemic events. Recently, four of these trials were pooled in an individual patient-data meta-analysis of 10,133 patients75. Guided or unguided de-escalation provided consistent results and was associated with both decreased ischaemic and bleeding endpoints. There was no interaction for either ischaemic or bleeding outcomes in patients undergoing multivessel versus single-vessel PCI nor in those undergoing PCI with ≥3 versus <3 implanted stents, which are considered proxies for complex PCI. Consistently, there was no interaction according to PCI complexity for both ischaemic and bleeding outcomes in the Harmonizing Optimal Strategy for Treatment of Coronary Artery Diseases Trial - Comparison of REDUCTION of prasugrEl Dose & POLYmer TECHnology in ACS Patients (HOST REDUCE POLYTECH) and TicAgrelor Versus CLOpidogrel in Stabilized Patients With Acute Myocardial Infarction (TALOS-AMI) trials, which showed reduced bleeding events with unguided prasugrel or ticagrelor de-escalation, respectively (Table 3)7677. Current ESC guidelines on ACS recommend a de-escalation strategy after 30 days to prevent bleeding (Class IIb, Level of Evidence A)14.

A transition from cangrelor to clopidogrel or prasugrel should occur at the end of cangrelor infusion, or 30 minutes before the cangrelor infusion is stopped when prasugrel is used. Transition from cangrelor to ticagrelor is not affected by drug-drug interaction and therefore can occur at any time during PCI707879.

4. Dual pathway inhibition

Dual pathway inhibition (DPI) consists of a simultaneous inhibition of both platelet activity and coagulation cascade by the administration of an antiplatelet agent combined with an anticoagulant drug. This strategy is aimed to target the residual cardiovascular ischaemic risk in patients who present with ACS and/or undergo coronary revascularisation80. The Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial showed that among patients with ACS with high-risk clinical features (44% treated with PCI), the addition of a full dose of apixaban (5 mg twice daily) to DAPT increased the risk of major bleeding without a significant reduction in ischaemic events as compared with standard DAPT81. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome 2–Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2–TIMI 51) trial tested rivaroxaban on a background of single or dual antiplatelet therapy in patients with recent ACS and showed a significant reduction of ischaemic events and mortality with low-dose rivaroxaban (2.5 mg twice daily) as compared to placebo, counterbalanced by an increase of major bleeding82. Similarly, in the Cardiovascular OutcoMes for People Using Anticoagulation StrategieS (COMPASS) trial, a low dose of rivaroxaban (2.5 mg twice daily) on top of aspirin decreased the rates of major adverse cardiovascular events and cardiovascular mortality, at the expense of bleeding events, in patients with CCS (60% with a clinical history of MI or peripheral artery disease)83. This benefit was preserved in a prespecified subgroup analysis including patients with CCS treated with PCI, of whom a substantial proportion (38%) underwent complex, multilesion PCI84. Based on the available evidence (Table 3), a DPI strategy with rivaroxaban in addition to aspirin should be considered for extended long-term (beyond 12 months) prevention in patients without HBR and with high ischaemic risk, including those presenting with complex PCI (Class IIa, Level of Evidence A) according to current ESC guidelines on the management of ACS (Central illustration)14.

Specific settings

Some complexity features, such as LM, bifurcation and CTO lesions, have been associated with worse prognostic impact and increased rates of ischaemic events. For this reason, some studies have evaluated the optimal antithrombotic therapy in these subsets of patients5. On the other hand, patients with a chronic indication to oral anticoagulation undergoing complex PCI represent a unique cohort with a higher bleeding risk.

1. Left main disease

LM PCI represents one of the most challenging scenarios in view of the large area of myocardium at risk with a potentially catastrophic impact of thrombotic complications related to LM stenting. Indeed, unprotected LM disease can substantially affect myocardial supply and has a critical role in long-term outcomes in patients undergoing PCI, with a higher long-term risk of ischaemic events85. In a post hoc analysis of the Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial, continuation of DAPT beyond 1 year was not associated with improved outcomes, and trends toward harm were noted with extended DAPT after propensity adjustment86. In the randomised Improved Drug-Eluting stent for All-comers Left Main (IDEAL-LM) study, among 818 patients undergoing PCI of the LM, a biodegradable-polymer everolimus-eluting stent followed by 4 months of DAPT resulted in non-inferior outcomes compared to a durable-polymer everolimus-eluting stent followed by 12 months of DAPT. However, major adverse cardiovascular events and its individual components trended numerically higher in the biodegradable-polymer stent with the 4-month DAPT group87. Along the same line, in a prospective observational study enrolling 3,865 patients undergoing LM PCI and at low bleeding risk, a longer duration (>12 months) of DAPT was associated with a significant reduction of ischaemic events without a concomitant increase in clinically relevant bleeding as compared with ≤12-month DAPT88. Interestingly, in a large retrospective analysis including 700 patients undergoing LM PCI, the rate of target lesion failure in patients treated with a two-stent technique was significantly higher than in the one-stent group only when DAPT was interrupted before 1 year89. Given the available evidence (Table 1), even if LM PCI does not appear to be a treatment modifier for oral antithrombotic therapy, it is well recognised as a procedural risk enhancer for ischaemic events. For this reason, LM PCI is considered an ischaemic risk condition, allowing for extended antithrombotic therapy (with DAPT or DPI) beyond 6 and 12 months in patients with CCS and ACS, respectively (Class IIa, Level of Evidence A)1415. In patients with CCS undergoing complex LM PCI, potent P2Y12 inhibitors may be an alternative to clopidogrel in selected cases (Class IIb, Level of Evidence C)15.

2. Bifurcation PCI

Bifurcation lesions have a critical prognostic impact on ischaemic outcomes with a 2-year major adverse cardiovascular events rate of 10% and a higher risk of stent thrombosis4585. Bifurcation stenting is considered an ischaemic risk criterion, justifying the recommendation of extended antithrombotic therapy (with both DAPT or DPI) beyond 6 and 12 months in patients with CCS and ACS, respectively (Class IIa, Level of Evidence A), and the opportunity to replace clopidogrel with potent P2Y12 inhibitors in patients with CCS (Class IIb, Level of Evidence C)1415. In 2,082 patients who underwent bifurcation stenting in the Coronary Bifurcation Stenting (COBIS) II registry and who were event-free at 12 months, prolonged DAPT was associated with a reduced incidence of all-cause death, MI and stent thrombosis at 4-year follow-up compared with a short-term strategy (<12 months). Interestingly, the beneficial role of prolonged DAPT was not significantly affected by lesion location or stenting technique90. Similarly, in the European Bifurcation Club registry, prolonged DAPT was associated with a significantly lower risk of ischaemic events as compared with both the short-term DAPT group (<6 months) and standard DAPT group (6-12 months) at 2-year follow-up. Furthermore, event-free survival was significantly lower in the group of DAPT duration <6 months91. However, the currently available evidence about antithrombotic therapy in bifurcation PCI is not derived from major dedicated trials, and observational studies may be inexorably biased. A decision-making algorithm for DAPT duration based primarily on the clinical presentation, the baseline bleeding risk, the stenting strategy, and the possible use of intracoronary imaging in patients who are not candidates for anticoagulant therapy has recently been proposed and may inform clinician decisions92.

3. CTO PCI

As previously described, patients with a CTO are considered at increased ischaemic risk. Notably, extensive calcification, a common CTO lesion feature, hinders stent expansion and leads to a higher risk of both acute and late stent thrombosis. Most of the time, CTO PCI is performed as a scheduled intervention in patients with CCS; thus, aspirin and clopidogrel are the standard DAPT regimen, even if ticagrelor or prasugrel may be considered (Class IIb, Level of Evidence C). Regarding the DAPT duration, prolonged DAPT (>6 months) should be considered according to European guidelines (Class IIa, Level of Evidence A)1415. Lee et al compared ≤12-month with >12-month DAPT in 512 patients undergoing CTO PCI. In a propensity score-matched population, the rate of ischaemic events was similar between the two groups93. More recently, Sachdeva et al found that prolonged DAPT (>12 months) was associated with a lower incidence of death or MI without an increase in bleeding rate in 1,069 patients undergoing CTO PCI94. Further dedicated prospective studies are required to assess the optimal antithrombotic strategy in this distinct subgroup.

4. SVG PCI

PCI of SVG disease represents a technical challenge considering that the pathophysiological mechanisms are distinct from those of native coronary artery disease. Despite their poor mid- and long-term patency rates, venous grafts are still commonly used in patients undergoing surgical myocardial revascularisation95. SVG PCI is frequently performed in the setting of ACS. Among 8,582 patients enrolled in the ADAPT-DES study, 405 (4.7%) underwent SVG PCI. In this cohort, patients who underwent SVG PCI had a higher risk of ischaemic events compared with patients undergoing PCI of native coronary arteries. For this reason, SVG PCI is considered, in some cases, a complex PCI criterion; prolonged antithrombotic therapy therefore provides potential benefits96. However, further studies are warranted to investigate this particular cohort, and, to date, no specific recommendations are available.

5. Patients with atrial fibrillation requiring oral anticoagulation

Patients with atrial fibrillation (AF) requiring oral anticoagulants (OACs) undergoing PCI are at increased risk for thromboembolic and bleeding events. Current guidelines recommend triple antithrombotic therapy (TAT) consisting of DAPT with clopidogrel plus an OAC agent for a short peri-interventional 1-week time frame, followed by dual antithrombotic therapy (DAT) with clopidogrel plus OAC for up to 6 or 12 months after PCI for patients with CCS and ACS, respectively (Class I, Level of Evidence A)141597. This recommendation largely relies on four major trials comparing DAT, mainly based on non-vitamin K antagonist oral anticoagulants (NOACs), with vitamin K antagonist (VKA)-based TAT in patients with AF presenting with ACS and/or undergoing PCI9899100. Across these trials, DAT was associated with a significant reduction of major bleeding, a similar incidence of ischaemic stroke, numerically higher risks of MI and stent thrombosis, and an overall neutral effect on all-cause mortality. A post hoc analysis of Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) and Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL PCI) showed consistent risk estimates between a DAT and/or NOAC-based strategy as compared with VKA-based TAT regardless of PCI complexity101102. However, the individual trials were underpowered for ischaemic outcomes, and two large meta-analyses found a significant association between DAT and the risk of stent thrombosis occurrence103104. For this reason, when the ischaemic risk outweighs the bleeding risk, TAT can be extended up to 1 month after PCI in patients with CCS (Class IIa, Level of Evidence B) and ACS (Class IIa, Level of Evidence C). ESC guidelines on both ACS and CCS provide several high ischaemic risk criteria for extended treatment with TAT that include complex PCI characteristics: diffuse multivessel disease, implantation of ≥3 stents, treatment of ≥3 lesions, total stent length >60 mm, bifurcation with two stents implanted, and treatment of a CTO1415. Furthermore, European guidelines on ACS indicate that continuation with one antiplatelet agent (aspirin or clopidogrel) beyond 1 year after ACS may be considered for patients having high-risk features of stent-driven recurrent ischaemic events. A similar approach is endorsed by the North American consensus recommending long-term continuation of single antiplatelet therapy only for selected patients at high risk for ischaemic recurrence and low bleeding risk14105. These recommendations should be interpreted, however, in view of recent trials showing a reduced risk of major bleeding with sole continuation of the OAC agent in the longstanding phase of coronary artery disease106.

Future perspectives

As the landscape of antithrombotic therapy continues to evolve, several innovative agents and strategies are poised to enhance the outcomes of patients undergoing complex PCI. The development of subcutaneous, self-administered P2Y12 inhibitors like selatogrel, currently being tested in the SOS-AMI trial (ClinicalTrials.gov: NCT04957719), and the novel subcutaneously administered GPI zalunfiban (RUC-4), being evaluated in the CELEBRATE trial (NCT04825743), represents a shift towards more accessible, rapid-acting therapies for acute MI, which may revolutionise early intervention for patients with complex coronary artery disease.

Tailored antithrombotic strategies are also being explored specifically for high-risk complex PCI populations, such as switching from ticagrelor- to clopidogrel-based DAPT at 6 months (TAILORED-CHIP; ClinicalTrials.gov: NCT03465644), utilising low-dose prasugrel or low-dose ticagrelor DAPT (E5TION; NCT04734353), prolonging DAPT with aspirin and prasugrel (ATTEMPT; NCT04014803), and comparing long-term clopidogrel and aspirin monotherapy (SMART-CHOICE3; NCT04418479). Additionally, the advent of factor XIa inhibitors promises to target residual thrombotic risk while decoupling haemostasis and thrombosis, mirroring the benefits of DPI, but with a potentially lower risk of bleeding. Among the factor XIa inhibitors in development, milvexian is currently being tested in the phase III LIBREXIA-ACS trial (NCT05754957), enrolling patients with ACS undergoing PCI3. As these novel strategies continue to be validated through clinical trials, they have the potential to transform the standard of care for complex PCI, offering more personalised, safer, and more effective treatment options for high-risk patients. Furthermore, these studies could be helpful to better define the profile and unique definition of patients undergoing complex PCI.

Conclusions

As complex PCI is associated with a higher ischaemic risk, adjunctive antithrombotic therapy plays a key role and should be part of the optimal revascularisation strategy. Some very high-risk patients may derive clinical benefit from extending DAPT beyond the period mandated by clinical guidelines, but bleeding risk status should always be considered in the decision. New strategies including early aspirin withdrawal followed by monotherapy with a potent P2Y12 inhibitor or implementation of DPI have shown promising results and may be attractive strategies in this setting, particularly in patients at high bleeding or ischaemic risk, respectively. To summarise, in patients undergoing complex PCI, the evaluation of bleeding risk is pivotal: in patients with HBR features, ticagrelor or clopidogrel monotherapy, after a short course of DAPT, should be the antithrombotic strategy of choice; conversely, in patients without bleeding concerns, prolonged DAPT represents the gold standard antithrombotic therapy, even if P2Y12 inhibitor monotherapy or DPI are promising strategies in this setting. Hence, we have proposed an algorithm to guide antithrombotic therapy strategies integrating bleeding risk and indication to oral anticoagulation after complex PCI (Central illustration). However, a standardised definition of complex PCI is still lacking, which partly hampers the comparability of previous studies. Moreover, it is important to acknowledge that the available evidence on the safety and efficacy profiles of antithrombotic strategies in complex PCI, as well as in specific subsets, is derived from subgroup analyses of randomised trials, which might be underpowered to assess heterogeneity in the treatment effect between patients undergoing complex and non-complex PCI. Although the definition of complex PCI is increasingly becoming “prespecified” in trial protocols, the presence of subgroup phenomena can bias the interpretation of results. Finally, it is also important to recognise that some PCI criteria for complexity are unplanned or might not become evident upon PCI completion. Even if this aspect poses challenges, dedicated randomised trials for patients undergoing complex PCI are warranted to find the optimal antithrombotic strategy in this specific population and, in this way, optimise outcomes.

Acknowledgements

D.S. Castiello, A. Oliva, G. Andò, G. Niccoli, and F. Pelliccia conceived and designed the project. R. Piccolo, E. Moscarella, R.A. Montone, F. Gragnano, and I. Porto supervised the project. P. Calabrò, S. De Rosa, E. Fabris, and G. Sinagra contributed to the acquisition, analysis and interpretation of data. D.S. Castiello, A. Oliva, and R. Piccolo drafted the manuscript. C.A.M. Spaccarotella, G. Esposito, C. Indolfi, and P.P. Filardi critically revised the manuscript for important intellectual content and the final approval of the version to be published. All authors have read and agreed to the published version of the manuscript.

Funding

This work is supported by a research grant from the Italian Ministry of Education (PRIN PNRR P2022RJS7X and PRIN 2022497RZ4 to R. P.).

Conflict of interest statement

The authors have no conflicts of interest to declare that could have appeared to influence the work reported in this paper.

References

1. Mohamed MO, Polad J, Hildick-Smith D, Bizeau O, Baisebenov RK, Roffi M, Íñiguez-Romo A, Chevalier B, von Birgelen C, Roguin A, Aminian A, Angioi M, Mamas MA. Impact of coronary lesion complexity in percutaneous coronary intervention: one-year outcomes from the large, multicentre e-Ultimaster registry. EuroIntervention. 2020;16:603-12.
2. Cao D, Chandiramani R, Chiarito M, Claessen BE, Mehran R. Evolution of antithrombotic therapy in patients undergoing percutaneous coronary intervention: a 40-year journey. Eur Heart J. 2021;42:339-51.
3. Angiolillo DJ, Galli M, Collet JP, Kastrati A, O’Donoghue ML. Antiplatelet therapy after percutaneous coronary intervention. EuroIntervention. 2022;17:e1371-96.
4. Giustino G, Chieffo A, Palmerini T, Valgimigli M, Feres F, Abizaid A, Costa RA, Hong MK, Kim BK, Jang Y, Kim HS, Park KW, Gilard M, Morice MC, Sawaya F, Sardella G, Genereux P, Redfors B, Leon MB, Bhatt DL, Stone GW, Colombo A. Efficacy and Safety of Dual Antiplatelet Therapy After Complex PCI. J Am Coll Cardiol. 2016;68:1851-64.
5. Généreux P, Giustino G, Redfors B, Palmerini T, Witzenbichler B, Weisz G, Stuckey TD, Maehara A, Mehran R, Kirtane AJ, Stone GW. Impact of percutaneous coronary intervention extent, complexity and platelet reactivity on outcomes after drug-eluting stent implantation. Int J Cardiol. 2018;268:61-7.
6. Yeh RW, Kereiakes DJ, Steg PG, Cutlip DE, Croce KJ, Massaro JM, Mauri L; DAPT Study Investigators. Lesion Complexity and Outcomes of Extended Dual Antiplatelet Therapy After Percutaneous Coronary Intervention. J Am Coll Cardiol. 2017;70:2213-23.
7. Protty M, Sharp ASP, Gallagher S, Farooq V, Spratt JC, Ludman P, Anderson R, McEntegart MM, Hanratty C, Walsh S, Curzen N, Smith E, Mamas M, Kinnaird T. Defining Percutaneous Coronary Intervention Complexity and Risk: An Analysis of the United Kingdom BCIS Database 2006-2016. JACC Cardiovasc Interv. 2022;15:39-49.
8. Piccolo R, Leone A, Simonetti F, Avvedimento M, Angellotti D, Manzi L, Verde N, Spaccarotella CAM, Di Serafino L, Cirillo P, Gargiulo G, Fortunato G, Franzone A, Esposito G. Periprocedural myocardial infarction in patients undergoing complex versus noncomplex percutaneous coronary intervention. Catheter Cardiovasc Interv. 2023;102:212-20.
9. Stefanini GG, Serruys PW, Silber S, Khattab AA, van Geuns RJ, Richardt G, Buszman PE, Kelbæk H, van Boven AJ, Hofma SH, Linke A, Klauss V, Wijns W, Macaya C, Garot P, Di Mario C, Manoharan G, Kornowski R, Ischinger T, Bartorelli AL, Gobbens P, Windecker S. The impact of patient and lesion complexity on clinical and angiographic outcomes after revascularization with zotarolimus- and everolimus-eluting stents: a substudy of the RESOLUTE All Comers Trial (a randomized comparison of a zotarolimus-eluting stent with an everolimus-eluting stent for percutaneous coronary intervention). J Am Coll Cardiol. 2011;57:2221-32.
10. Urban P, Mehran R, Colleran R, Angiolillo DJ, Byrne RA, Capodanno D, Cuisset T, Cutlip D, Eerdmans P, Eikelboom J, Farb A, Gibson CM, Gregson J, Haude M, James SK, Kim HS, Kimura T, Konishi A, Laschinger J, Leon MB, Magee PFA, Mitsutake Y, Mylotte D, Pocock S, Price MJ, Rao SV, Spitzer E, Stockbridge N, Valgimigli M, Varenne O, Windhoevel U, Yeh RW, Krucoff MW, Morice MC. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Eur Heart J. 2019;40:2632-53.
11. Piccolo R, Oliva A, Avvedimento M, Franzone A, Windecker S, Valgimigli M, Esposito G, Jüni P. Mortality after bleeding versus myocardial infarction in coronary artery disease: a systematic review and meta-analysis. EuroIntervention. 2021;17:550-60.
12. Yamamoto K, Shiomi H, Morimoto T, Takeji Y, Yoshikawa Y, Natsuaki M, Watanabe H, Tada T, Tazaki J, Yamaji K, Tamura T, Ando K, Kadota K, Furukawa Y, Nakagawa Y, Kimura T. Ischemic and bleeding risk after complex percutaneous coronary intervention in patients with or without high bleeding risk. Catheter Cardiovasc Interv. 2021;97:E758-70.
13. Costa F, Van Klaveren D, Feres F, James S, Räber L, Pilgrim T, Hong MK, Kim HS, Colombo A, Steg PG, Bhatt DL, Stone GW, Windecker S, Steyerberg EW, Valgimigli M; PRECISE-DAPT Study Investigators. Dual Antiplatelet Therapy Duration Based on Ischemic and Bleeding Risks After Coronary Stenting. J Am Coll Cardiol. 2019;73:741-54.
14. Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, Claeys MJ, Dan GA, Dweck MR, Galbraith M, Gilard M, Hinterbuchner L, Jankowska EA, Jüni P, Kimura T, Kunadian V, Leosdottir M, Lorusso R, Pedretti RFE, Rigopoulos AG, Rubini Gimenez M, Thiele H, Vranckx P, Wassmann S, Wenger NK, Ibanez B; ESC Scientific Document Group. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44:3720-826.
15. Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, Banning AP, Budaj A, Buechel RR, Chiariello GA, Chieffo A, Christodorescu RM, Deaton C, Doenst T, Jones HW, Kunadian V, Mehilli J, Milojevic M, Piek JJ, Pugliese F, Rubboli A, Semb AG, Senior R, Ten Berg JM, Van Belle E, Van Craenenbroeck EM, Vidal-Perez R, Winther S; ESC Scientific Document Group. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024;45:3415-537.
16. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41:407-77.
17. Bates ER, Lau WC, Bleske BE. Loading, pretreatment, and interindividual variability issues with clopidogrel dosing. Circulation. 2005;111:2557-9.
18. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Jüni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39:213-60.
19. Rakowski T, Dudek D, Dziewierz A, Yu J, Witzenbichler B, Guagliumi G, Kornowski R, Hartmann F, Lansky AJ, Brener SJ, Mehran R, Stone GW. Impact of infarct-related artery patency before primary PCI on outcome in patients with ST-segment elevation myocardial infarction: the HORIZONS-AMI trial. EuroIntervention. 2013;8:1307-14.
20. Emilsson OL, Bergman S, Mohammad MA, Olivecrona GK, Götberg M, Erlinge D, Koul S. Pretreatment with heparin in patients with ST-segment elevation myocardial infarction: a report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). EuroIntervention. 2022;18:709-18.
21. Chen J, Xu C, Qiu L, Li B, Yao W, Wu H, Hu Z, Yang S, Luo D, Liu J, Wang M, Yang J, Jiang H. TCT-934 Early Administration of Heparin at First Medical Contact Versus in the Cath Lab for STEMI Patients Undergoing Primary Percutaneous Coronary Intervention (HELP-PCI): A Multicenter, Randomized Trial. JACC. 2024;84:B398.
22. Choi JH, Chun KJ, Jung SM, Lee SY, Chon MK, Lee SH, Hwang KW, Kim JS, Park YH, Kim JH. Safety and efficacy of immediate heparin reversal with protamine after complex percutaneous coronary intervention. BMC Cardiovasc Disord. 2022;22:207.
23. Vlachakis PK, Varlamos C, Benetou DR, Kanakakis I, Alexopoulos D. Periprocedural Antithrombotic Treatment in Complex Percutaneous Coronary Intervention. J Cardiovasc Pharmacol. 2022;79:407-19.
24. Bikdeli B, Erlinge D, Valgimigli M, Kastrati A, Han Y, Steg PG, Stables RH, Mehran R, James SK, Frigoli E, Goldstein P, Li Y, Shahzad A, Schüpke S, Mehdipoor G, Chen S, Redfors B, Crowley A, Zhou Z, Stone GW. Bivalirudin Versus Heparin During PCI in NSTEMI: Individual Patient Data Meta-Analysis of Large Randomized Trials. Circulation. 2023;148:1207-19.
25. Silvain J, Beygui F, Barthélémy O, Pollack C Jr, Cohen M, Zeymer U, Huber K, Goldstein P, Cayla G, Collet JP, Vicaut E, Montalescot G. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.
26. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358:2218-30.
27. Steg PG, van ‘t Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, Ten Berg J, Van Grunsven P, Eggink GJ, Nibbe L, Zeymer U, Campo dell’ Orto M, Nef H, Steinmetz J, Soulat L, Huber K, Deliargyris EN, Bernstein D, Schuette D, Prats J, Clayton T, Pocock S, Hamon M, Goldstein P; EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369:2207-17.
28. Shahzad A, Kemp I, Mars C, Wilson K, Roome C, Cooper R, Andron M, Appleby C, Fisher M, Khand A, Kunadian B, Mills JD, Morris JL, Morrison WL, Munir S, Palmer ND, Perry RA, Ramsdale DR, Velavan P, Stables RH; HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;384:1849-58.
29. Valgimigli M, Frigoli E, Leonardi S, Rothenbühler M, Gagnor A, Calabrò P, Garducci S, Rubartelli P, Briguori C, Andò G, Repetto A, Limbruno U, Garbo R, Sganzerla P, Russo F, Lupi A, Cortese B, Ausiello A, Ierna S, Esposito G, Presbitero P, Santarelli A, Sardella G, Varbella F, Tresoldi S, de Cesare N, Rigattieri S, Zingarelli A, Tosi P, van ‘t Hof A, Boccuzzi G, Omerovic E, Sabaté M, Heg D, Jüni P, Vranckx P; MATRIX Investigators. Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med. 2015;373:997-1009.
30. Li Y, Liang Z, Qin L, Wang M, Wang X, Zhang H, Liu Y, Li Y, Jia Z, Liu L, Zhang H, Luo J, Dong S, Guo J, Zhu H, Li S, Zheng H, Liu L, Wu Y, Zhong Y, Qiu M, Han Y, Stone GW. Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet. 2022;400:1847-57.
31. Han Y, Guo J, Zheng Y, Zang H, Su X, Wang Y, Chen S, Jiang T, Yang P, Chen J, Jiang D, Jing Q, Liang Z, Liu H, Zhao X, Li J, Li Y, Xu B, Stone GW; BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015;313:1336-46.
32. Erlinge D, Koul S, Eriksson P, Scherstén F, Omerovic E, Linder R, Östlund OP, Wallentin L, Fröbert O, James S. Bivalirudin versus heparin in non-ST and ST-segment elevation myocardial infarction-a registry-based randomized clinical trial in the SWEDEHEART registry (the VALIDATE-SWEDEHEART trial). Am Heart J. 2016;175:36-46.
33. Clemmensen P, Wiberg S, Van’t Hof A, Deliargyris EN, Coste P, Ten Berg J, Cavallini C, Hamon M, Dudek D, Zeymer U, Tabone X, Kristensen SD, Bernstein D, Anthopoulos P, Prats J, Steg PG. Acute stent thrombosis after primary percutaneous coronary intervention: insights from the EUROMAX trial (European Ambulance Acute Coronary Syndrome Angiography). JACC Cardiovasc Interv. 2015;8:214-20.
34. Stone GW, Valgimigli M, Erlinge D, Han Y, Steg PG, Stables RH, Frigoli E, James SK, Li Y, Goldstein P, Mehran R, Mehdipoor G, Crowley A, Chen S, Redfors B, Snyder C, Zhou Z, Bikdeli B. Bivalirudin vs Heparin Anticoagulation in STEMI: Confirmation of the BRIGHT-4 Results. J Am Coll Cardiol. 2024;84:1512-24.
35. Wu Z, Meng P, Guo Y, You W, Wu X, Ye F. Prolonged infusion of bivalirudin after elective percutaneous coronary intervention protects against procedural myocardial injury (a COBER study)-a randomized trial. Sci Rep. 2023;13:6667.
36. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, Price MJ, Leonardi S, Gallup D, Bramucci E, Radke PW, Widimský P, Tousek F, Tauth J, Spriggs D, McLaurin BT, Angiolillo DJ, Généreux P, Liu T, Prats J, Todd M, Skerjanec S, White HD, Harrington RA; CHAMPION PHOENIX Investigators. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303-13.
37. De Luca L, Valgimigli M. Unravelling the puzzle of antithrombotic therapies for complex percutaneous coronary intervention. Eur Heart J Cardiovasc Pharmacother. 2021;7:352-9.
38. Dillinger JG, Ducrocq G, Elbez Y, Cohen M, Bode C, Pollack C Jr, Nicolau JC, Henry P, Kedev S, Wiviott SD, Sabatine MS, Mehta SR, Steg PG. Activated Clotting Time to Guide Heparin Dosing in Non-ST-Segment-Elevation Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention and Treated With IIb/IIIa Inhibitors: Impact on Ischemic and Bleeding Outcomes: Insights From the TAO Trial. Circ Cardiovasc Interv. 2018;11:e006084.
39. Lawton JS, Tamis-Holland JE, Bangalore S, Bates ER, Beckie TM, Bischoff JM, Bittl JA, Cohen MG, DiMaio JM, Don CW, Fremes SE, Gaudino MF, Goldberger ZD, Grant MC, Jaswal JB, Kurlansky PA, Mehran R, Metkus TS Jr, Nnacheta LC, Rao SV, Sellke FW, Sharma G, Yong CM, Zwischenberger BA. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145:e4-17.
40. Silvain J, Lattuca B, Beygui F, Rangé G, Motovska Z, Dillinger JG, Boueri Z, Brunel P, Lhermusier T, Pouillot C, Larrieu-Ardilouze E, Boccara F, Labeque JN, Guedeney P, El Kasty M, Laredo M, Dumaine R, Ducrocq G, Collet JP, Cayla G, Blanchart K, Kala P, Vicaut E, Montalescot G; ALPHEUS investigators. Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial. Lancet. 2020;396:1737-44.
41. Mehilli J, Baquet M, Hochholzer W, Mayer K, Tesche C, Aradi D, Xu Y, Thienel M, Gschwendtner S, Zadrozny M, Jochheim D, Sibbing D, Schüpke S, Mansmann U, Hoffmann E, Kastrati A, Neumann FJ, Massberg S. Randomized Comparison of Intensified and Standard P2Y12-Receptor-Inhibition Before Elective Percutaneous Coronary Intervention: The SASSICAIA Trial. Circ Cardiovasc Interv. 2020;13:e008649.
42. Lattuca B, Mazeau C, Cayla G, Ducrocq G, Guedeney P, Laredo M, Dumaine R, El Kasty M, Kala P, Nejjari M, Hlinomaz O, Morel O, Varenne O, Leclercq F, Payot L, Spaulding C, Beygui F, Rangé G, Motovska Z, Portal JJ, Vicaut E, Collet JP, Montalescot G, Silvain J; ALPHEUS Investigators. Ticagrelor vs Clopidogrel for Complex Percutaneous Coronary Intervention in Chronic Coronary Syndrome. JACC Cardiovasc Interv. 2024;17:359-70.
43. Gargiulo G, Marenna A, Sperandeo L, Manzi L, Avvedimento M, Simonetti F, Canonico ME, Paolillo R, Spinelli A, Borgia F, Diserafino L, Franzone A, Stabile E, Piccolo R, Cirillo P, Valgimigli M, Esposito G. Pharmacodynamic effects of cangrelor in elective complex PCI: insights from the POMPEII Registry. EuroIntervention. 2023;18:1266-8.
44. Steg PG, Bhatt DL, Hamm CW, Stone GW, Gibson CM, Mahaffey KW, Leonardi S, Liu T, Skerjanec S, Day JR, Iwaoka RS, Stuckey TD, Gogia HS, Gruberg L, French WJ, White HD, Harrington RA; CHAMPION Investigators. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet. 2013;382:1981-92.
45. Stone GW, Généreux P, Harrington RA, White HD, Gibson CM, Steg PG, Hamm CW, Mahaffey KW, Price MJ, Prats J, Deliargyris EN, Bhatt DL. Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10 854 patients from the CHAMPION PHOENIX trial. Eur Heart J. 2018;39:4112-21.
46. De Luca L, Piscione F, Colivicchi F, Lucci D, Mascia F, Marinoni B, Cirillo P, Grosseto D, Mauro C, Calabrò P, Nardi F, Rossini R, Geraci G, Gabrielli D, Di Lenarda A, Gulizia MM; EYESHOT Post-MI Investigators. Contemporary management of patients referring to cardiologists one to three years from a myocardial infarction: The EYESHOT Post-MI study. Int J Cardiol. 2018;273:8-14.
47. Bansilal S, Bonaca MP, Cornel JH, Storey RF, Bhatt DL, Steg PG, Im K, Murphy SA, Angiolillo DJ, Kiss RG, Parkhomenko AN, Lopez-Sendon J, Isaza D, Goudev A, Kontny F, Held P, Jensen EC, Braunwald E, Sabatine MS, Oude Ophuis AJ. Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease. J Am Coll Cardiol. 2018;71:489-96.
48. Andò G, De Santis GA, Greco A, Pistelli L, Francaviglia B, Capodanno D, De Caterina R, Capranzano P. P2Y12 Inhibitor or Aspirin Following Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Network Meta-Analysis. JACC Cardiovasc Interv. 2022;15:2239-49.
49. Hahn JY, Song YB, Oh JH, Chun WJ, Park YH, Jang WJ, Im ES, Jeong JO, Cho BR, Oh SK, Yun KH, Cho DK, Lee JY, Koh YY, Bae JW, Choi JW, Lee WS, Yoon HJ, Lee SU, Cho JH, Choi WG, Rha SW, Lee JM, Park TK, Yang JH, Choi JH, Choi SH, Lee SH, Gwon HC; SMART-CHOICE Investigators. Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial. JAMA. 2019;321:2428-37.
50. Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T, Ohya M, Suwa S, Takagi K, Nanasato M, Hata Y, Yagi M, Suematsu N, Yokomatsu T, Takamisawa I, Doi M, Noda T, Okayama H, Seino Y, Tada T, Sakamoto H, Hibi K, Abe M, Kawai K, Nakao K, Ando K, Tanabe K, Ikari Y, Hanaoka KI, Morino Y, Kozuma K, Kadota K, Furukawa Y, Nakagawa Y, Kimura T; STOPDAPT-2 Investigators. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019;321:2414-27.
51. Watanabe H, Morimoto T, Natsuaki M, Yamamoto K, Obayashi Y, Ogita M, Suwa S, Isawa T, Domei T, Yamaji K, Tatsushima S, Watanabe H, Ohya M, Tokuyama H, Tada T, Sakamoto H, Mori H, Suzuki H, Nishikura T, Wakabayashi K, Hibi K, Abe M, Kawai K, Nakao K, Ando K, Tanabe K, Ikari Y, Morino Y, Kadota K, Furukawa Y, Nakagawa Y, Kimura T; STOPDAPT-2 ACS Investigators. Comparison of Clopidogrel Monotherapy After 1 to 2 Months of Dual Antiplatelet Therapy With 12 Months of Dual Antiplatelet Therapy in Patients With Acute Coronary Syndrome: The STOPDAPT-2 ACS Randomized Clinical Trial. JAMA Cardiol. 2022;7:407-17.
52. Roh JW, Hahn JY, Oh JH, Chun WJ, Park YH, Jang WJ, Im ES, Jeong JO, Cho BR, Oh SK, Yun KH, Cho DK, Lee JY, Koh YY, Bae JW, Choi JW, Lee WS, Yoon HJ, Lee SU, Cho JH, Choi WG, Rha SW, Kim HY, Lee JM, Park TK, Yang JH, Choi JH, Choi SH, Lee SH, Gwon HC, Kim DB, Song YB. P2Y12 inhibitor monotherapy in complex percutaneous coronary intervention: A post-hoc analysis of SMART-CHOICE randomized clinical trial. Cardiol J. 2021;28:855-63.
53. Yamamoto K, Watanabe H, Morimoto T, Domei T, Ohya M, Ogita M, Takagi K, Suzuki H, Nikaido A, Ishii M, Fujii S, Natsuaki M, Yasuda S, Kaneko T, Tamura T, Tamura T, Abe M, Kawai K, Nakao K, Ando K, Tanabe K, Ikari Y, Igarashi Hanaoka K, Morino Y, Kozuma K, Kadota K, Furukawa Y, Nakagawa Y, Kimura T; STOPDAPT-2 Investigators. Very Short Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Patients Who Underwent Complex Percutaneous Coronary Intervention: Insight From the STOPDAPT-2 Trial. Circ Cardiovasc Interv. 2021;14:e010384.
54. Yamamoto K, Watanabe H, Morimoto T, Obayashi Y, Natsuaki M, Domei T, Yamaji K, Suwa S, Isawa T, Watanabe H, Yoshida R, Sakamoto H, Akao M, Hata Y, Morishima I, Tokuyama H, Yagi M, Suzuki H, Wakabayashi K, Suematsu N, Inada T, Tamura T, Okayama H, Abe M, Kawai K, Nakao K, Ando K, Tanabe K, Ikari Y, Morino Y, Kadota K, Furukawa Y, Nakagawa Y, Kimura T; STOPDAPT-2 and STOPDAPT-2 ACS Investigators. Clopidogrel Monotherapy After 1-Month DAPT in Patients With High Bleeding Risk or Complex PCI. JACC Asia. 2023;3:31-46.
55. Obayashi Y, Watanabe H, Morimoto T, Yamamoto K, Natsuaki M, Domei T, Yamaji K, Suwa S, Isawa T, Watanabe H, Yoshida R, Sakamoto H, Akao M, Hata Y, Morishima I, Tokuyama H, Yagi M, Suzuki H, Wakabayashi K, Suematsu N, Inada T, Tamura T, Okayama H, Abe M, Kawai K, Nakao K, Ando K, Tanabe K, Ikari Y, Morino Y, Kadota K, Furukawa Y, Nakagawa Y, Kimura T; STOPDAPT-2 and STOPDAPT-2 ACS Investigators. Clopidogrel Monotherapy After 1-Month Dual Antiplatelet Therapy in Percutaneous Coronary Intervention: From the STOPDAPT-2 Total Cohort. Circ Cardiovasc Interv. 2022;15:e012004.
56. Vranckx P, Valgimigli M, Jüni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E, Möllmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns RJ, Huber K, Slagboom T, Serruys PW, Windecker S; GLOBAL LEADERS Investigators. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018;392:940-9.
57. Serruys PW, Takahashi K, Chichareon P, Kogame N, Tomaniak M, Modolo R, Chang CC, Komiyama H, Soliman O, Wykrzykowska JJ, de Winter RJ, Ferrario M, Dominici M, Buszman P, Bolognese L, Tumscitz C, Benit E, Stoll HP, Hamm C, Steg PG, Onuma Y, Jüni P, Windecker S, Vranckx P, Colombo A, Valgimigli M. Impact of long-term ticagrelor monotherapy following 1-month dual antiplatelet therapy in patients who underwent complex percutaneous coronary intervention: insights from the Global Leaders trial. Eur Heart J. 2019;40:2595-604.
58. Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha JY, Collier T, Dangas G, Dudek D, Džavík V, Escaned J, Gil R, Gurbel P, Hamm CW, Henry T, Huber K, Kastrati A, Kaul U, Kornowski R, Krucoff M, Kunadian V, Marx SO, Mehta SR, Moliterno D, Ohman EM, Oldroyd K, Sardella G, Sartori S, Shlofmitz R, Steg PG, Weisz G, Witzenbichler B, Han YL, Pocock S, Gibson CM. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019;381:2032-42.
59. Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, Cho JY, Her AY, Cho S, Jeon DW, Yoo SY, Cho DK, Hong BK, Kwon H, Ahn CM, Shin DH, Nam CM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y; TICO Investigators. Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020;323:2407-16.
60. Dangas G, Baber U, Sharma S, Giustino G, Mehta S, Cohen DJ, Angiolillo DJ, Sartori S, Chandiramani R, Briguori C, Dudek D, Escaned J, Huber K, Collier T, Kornowski R, Kunadian V, Kaul U, Oldroyd K, Sardella G, Shlofmitz R, Witzenbichler B, Ya-Ling H, Pocock S, Gibson CM, Mehran R. Ticagrelor With or Without Aspirin After Complex PCI. J Am Coll Cardiol. 2020;75:2414-24.
61. Lee SJ, Lee YJ, Kim BK, Hong SJ, Ahn CM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y. Ticagrelor Monotherapy Versus Ticagrelor With Aspirin in Acute Coronary Syndrome Patients With a High Risk of Ischemic Events. Circ Cardiovasc Interv. 2021;14:e010812.
62. Baber U, Jang Y, Oliva A, Cao D, Vogel B, Dangas G, Sartori S, Spirito A, Smith KF, Branca M, Collier T, Pocock S, Valgimigli M, Kim BK, Hong MK, Mehran R. Safety and Efficacy of Ticagrelor Monotherapy in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: An Individual Patient Data Meta-Analysis of TWILIGHT and TICO Randomized Trials. Circulation. 2024;149:574-84.
63. Yamamoto K, Natsuaki M, Watanabe H, Morimoto T, Obayashi Y, Nishikawa R, Ando K, Suwa S, Isawa T, Takenaka H, Ishikawa T, Tamura T, Kawahatsu K, Hayashi F, Akao M, Serikawa T, Mori H, Kawamura T, Hagikura A, Shibata N, Ono K, Kimura T; STOPDAPT-3 Investigators. An Aspirin-Free Strategy for Immediate Treatment Following Complex Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2024;17:1119-30.
64. Natsuaki M, Watanabe H, Morimoto T, Yamamoto K, Obayashi Y, Nishikawa R, Ando K, Domei T, Suwa S, Ogita M, Isawa T, Takenaka H, Yamamoto T, Ishikawa T, Hisauchi I, Wakabayashi K, Onishi Y, Hibi K, Kawai K, Yoshida R, Suzuki H, Nakazawa G, Kusuyama T, Morishima I, Ono K, Kimura T. An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial. Circulation. 2024;149:585-600.
65. Oliva A, Castiello DS, Franzone A, Condorelli G, Colombo A, Esposito G, Stefanini GG, Piccolo R. P2Y12 Inhibitors Monotherapy in Patients Undergoing Complex vs Non-Complex Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Trials. Am Heart J. 2023;255:71-81.
66. Gragnano F, Mehran R, Branca M, Franzone A, Baber U, Jang Y, Kimura T, Hahn JY, Zhao Q, Windecker S, Gibson CM, Kim BK, Watanabe H, Song YB, Zhu Y, Vranckx P, Mehta S, Hong SJ, Ando K, Gwon HC, Calabrò P, Serruys PW, Dangas GD, McFadden EP, Angiolillo DJ, Heg D, Valgimigli M; Single Versus Dual Antiplatelet Therapy (Sidney-2) Collaboration. P2Y12 Inhibitor Monotherapy or Dual Antiplatelet Therapy After Complex Percutaneous Coronary Interventions. J Am Coll Cardiol. 2023;81:537-52.
67. Gragnano F, Cao D, Pirondini L, Franzone A, Kim HS, von Scheidt M, Pettersen AR, Zhao Q, Woodward M, Chiarito M, McFadden EP, Park KW, Kastrati A, Seljeflot I, Zhu Y, Windecker S, Kang J, Schunkert H, Arnesen H, Bhatt DL, Steg PG, Calabrò P, Pocock S, Mehran R, Valgimigli M; PANTHER Collaboration. P2Y12 Inhibitor or Aspirin Monotherapy for Secondary Prevention of Coronary Events. J Am Coll Cardiol. 2023;82:89-105.
68. Kang J, Park KW, Lee H, Hwang D, Yang HM, Rha SW, Bae JW, Lee NH, Hur SH, Han JK, Shin ES, Koo BK, Kim HS. Aspirin Versus Clopidogrel for Long-Term Maintenance Monotherapy After Percutaneous Coronary Intervention: The HOST-EXAM Extended Study. Circulation. 2023;147:108-17.
69. Ono M, Hara H, Kawashima H, Gao C, Wang R, Wykrzykowska JJ, Piek JJ, Garg S, Hamm C, Steg PG, Valgimigli M, Windecker S, Vranckx P, Onuma Y, Serruys PW. Ticagrelor monotherapy versus aspirin monotherapy at 12 months after percutaneous coronary intervention: a landmark analysis of the GLOBAL LEADERS trial. EuroIntervention. 2022;18:e377-88.
70. Angiolillo DJ, Rollini F, Storey RF, Bhatt DL, James S, Schneider DJ, Sibbing D, So DYF, Trenk D, Alexopoulos D, Gurbel PA, Hochholzer W, De Luca L, Bonello L, Aradi D, Cuisset T, Tantry US, Wang TY, Valgimigli M, Waksman R, Mehran R, Montalescot G, Franchi F, Price MJ. International Expert Consensus on Switching Platelet P2Y12 Receptor-Inhibiting Therapies. Circulation. 2017;136:1955-75.
71. Galli M, Benenati S, Capodanno D, Franchi F, Rollini F, D’Amario D, Porto I, Angiolillo DJ. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet. 2021;397:1470-83.
72. Sibbing D, Aradi D, Alexopoulos D, Ten Berg J, Bhatt DL, Bonello L, Collet JP, Cuisset T, Franchi F, Gross L, Gurbel P, Jeong YH, Mehran R, Moliterno DJ, Neumann FJ, Pereira NL, Price MJ, Sabatine MS, So DYF, Stone GW, Storey RF, Tantry U, Trenk D, Valgimigli M, Waksman R, Angiolillo DJ. Updated Expert Consensus Statement on Platelet Function and Genetic Testing for Guiding P2Y12 Receptor Inhibitor Treatment in Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2019;12:1521-37.
73. Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol. 2016;13:11-27.
74. Cayla G, Cuisset T, Silvain J, Leclercq F, Manzo-Silberman S, Saint-Etienne C, Delarche N, Bellemain-Appaix A, Range G, El Mahmoud R, Carrié D, Belle L, Souteyrand G, Aubry P, Sabouret P, du Fretay XH, Beygui F, Bonnet JL, Lattuca B, Pouillot C, Varenne O, Boueri Z, Van Belle E, Henry P, Motreff P, Elhadad S, Salem JE, Abtan J, Rousseau H, Collet JP, Vicaut E, Montalescot G; ANTARCTIC investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet. 2016;388:2015-22.
75. Kang J, Rizas KD, Park KW, Chung J, van den Broek W, Claassens DMF, Choo EH, Aradi D, Massberg S, Hwang D, Han JK, Yang HM, Kang HJ, Chang K, Ten Berg JM, Sibbing D, Koo BK, Kim HS. Dual antiplatelet therapy de-escalation in acute coronary syndrome: an individual patient meta-analysis. Eur Heart J. 2023;44:1360-70.
76. Hwang D, Lim YH, Park KW, Chun KJ, Han JK, Yang HM, Kang HJ, Koo BK, Kang J, Cho YK, Hong SJ, Kim S, Jo SH, Kim YH, Kim W, Lee SY, Kim YD, Oh SK, Lee JH, Kim HS; HOST-RP-ACS investigators. Prasugrel Dose De-escalation Therapy After Complex Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome: A Post Hoc Analysis From the HOST-REDUCE-POLYTECH-ACS Trial. JAMA Cardiol. 2022;7:418-26.
77. Lee M, Byun S, Lim S, Choo EH, Lee KY, Moon D, Choi IJ, Hwang BH, Kim CJ, Park MW, Choi YS, Kim HY, Yoo KD, Jeon DS, Yim HW, Chang K; TALOS-AMI Investigators. Dual Antiplatelet Therapy De-Escalation in Stabilized Myocardial Infarction With High Ischemic Risk: Post Hoc Analysis of the TALOS-AMI Randomized Clinical Trial. JAMA Cardiol. 2024;9:125-33.
78. Franchi F, Ortega-Paz L, Rollini F, Galli M, Been L, Ghanem G, Shalhoub A, Ossi T, Rivas A, Zhou X, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Reiter B, Jilma B, Angiolillo DJ. Cangrelor in Patients With Coronary Artery Disease Pretreated With Ticagrelor: The Switching Antiplatelet (SWAP)-5 Study. JACC Cardiovasc Interv. 2023;16:36-46.
79. Franchi F, Rollini F, Ortega-Paz L, Been L, Giordano S, Galli M, Ghanem G, Garabedian H, Al Saleh T, Uzunoglu E, Rivas A, Pineda AM, Suryadevara S, Soffer D, Zenni MM, Mahowald M, Reiter B, Jilma B, Angiolillo DJ. Switching From Cangrelor to Prasugrel in Patients Undergoing Percutaneous Coronary Intervention: The Switching Antiplatelet-6 (SWAP-6) Study. JACC Cardiovasc Interv. 2023;16:2528-39.
80. Capodanno D, Bhatt DL, Eikelboom JW, Fox KAA, Geisler T, Michael Gibson C, Gonzalez-Juanatey JR, James S, Lopes RD, Mehran R, Montalescot G, Patel M, Steg PG, Storey RF, Vranckx P, Weitz JI, Welsh R, Zeymer U, Angiolillo DJ. Dual-pathway inhibition for secondary and tertiary antithrombotic prevention in cardiovascular disease. Nat Rev Cardiol. 2020;17:242-57.
81. APPRAISE Steering Committee and Investigators; Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, Fox KA, Goodman SG, Harrington RA, Huber K, Husted S, Lewis BS, Lopez-Sendon J, Mohan P, Montalescot G, Ruda M, Ruzyllo W, Verheugt F, Wallentin L. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation. 2009;119:2877-85.
82. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9-19.
83. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O’Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Störk S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377:1319-30.
84. Bainey KR, Welsh RC, Connolly SJ, Marsden T, Bosch J, Fox KAA, Steg PG, Vinereanu D, Connolly DL, Berkowitz SD, Foody JM, Probstfield JL, Branch KR, Lewis BS, Diaz R, Muehlhofer E, Widimsky P, Yusuf S, Eikelboom JW, Bhatt DL; COMPASS Investigators. Rivaroxaban Plus Aspirin Versus Aspirin Alone in Patients With Prior Percutaneous Coronary Intervention (COMPASS-PCI). Circulation. 2020;141:1141-51.
85. Benetou DR, Andreou I, Varlamos C, Alexopoulos D. Tailoring Dual Antiplatelet Therapy for the Complex PCI Patient: Current Status and Perspectives. Cardiovasc Drugs Ther. 2020;34:697-706.
86. Brener SJ, Serruys PW, Morice MC, Mehran R, Kappetein AP, Sabik JF 3rd, Liu Y, Dressler O, Ben-Yehuda O, Stone GW. Optimal Duration of Dual Antiplatelet Therapy After Left Main Coronary Stenting. J Am Coll Cardiol. 2018;72:2086-7.
87. van Geuns RJ, Chun-Chin C, McEntegart MB, Merkulov E, Kretov E, Lesiak M, O’Kane P, Hanratty CG, Bressollette E, Silvestri M, Wlodarczak A, Barragan P, Anderson R, Protopopov A, Peace A, Menown I, Rocchiccioli P, Onuma Y, Oldroyd KG. Bioabsorbable polymer drug-eluting stents with 4-month dual antiplatelet therapy versus durable polymer drug-eluting stents with 12-month dual antiplatelet therapy in patients with left main coronary artery disease: the IDEAL-LM randomised trial. EuroIntervention. 2022;17:1467-76.
88. Wang HY, Dou KF, Guan C, Xie L, Huang Y, Zhang R, Yang W, Wu Y, Yang Y, Qiao S, Gao R, Xu B. New Insights Into Long- Versus Short-Term Dual Antiplatelet Therapy Duration in Patients After Stenting for Left Main Coronary Artery Disease: Findings From a Prospective Observational Study. Circ Cardiovasc Interv. 2022;15:e011536.
89. Rhee TM, Park KW, Kim CH, Kang J, Han JK, Yang HM, Kang HJ, Koo BK, Kim HS. Dual Antiplatelet Therapy Duration Determines Outcome After 2- But Not 1-Stent Strategy in Left Main Bifurcation Percutaneous Coronary Intervention. JACC Cardiovasc Interv. 2018;11:2453-63.
90. Jang WJ, Ahn SG, Song YB, Choi SH, Chun WJ, Oh JH, Cho SW, Kim BS, Yoon JH, Koo BK, Yu CW, Jang YS, Tahk SJ, Kim HS, Gwon HC, Lee SY, Hahn JY. Benefit of Prolonged Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stent for Coronary Bifurcation Lesions: Results From the Coronary Bifurcation Stenting Registry II. Circ Cardiovasc Interv. 2018;11:e005849.
91. Cirillo P, DI Serafino L, Gamra H, Zimarino M, Barbato E, Briguori C, Amat-Santos IJ, Chieffo A, Erglis A, Gil RJ, Kedev SA, Petrov I, Radico F, Niglio T, Nakamura S, Costa RA, Kanic V, Perfetti M, Pellicano M, Maric K, Tesorio T, Vukcevic V, Esposito G, Stankovic G; EuroBifurcation Club. Impact of dual antiplatelet therapy duration on clinical outcome after coronary bifurcation stenting: results from the EuroBifurcation Club registry. Panminerva Med. 2023;65:1-12.
92. Zimarino M, Angiolillo DJ, Dangas G, Capodanno D, Barbato E, Hahn JY, Giustino G, Watanabe H, Costa F, Cuisset T, Rossini R, Sibbing D, Burzotta F, Louvard Y, Shehab A, Renda G, Kimura T, Gwon HC, Chen SL, Costa RA, Koo BK, Storey RF, Valgimigli M, Mehran R, Stankovic G. Antithrombotic therapy after percutaneous coronary intervention of bifurcation lesions. EuroIntervention. 2021;17:59-66.
93. Lee SH, Yang JH, Choi SH, Park TK, Jang WJ, Song YB, Hahn JY, Choi JH, Gwon HC. Duration of dual antiplatelet therapy in patients treated with percutaneous coronary intervention for coronary chronic total occlusion. PLoS One. 2017;12:e0176737.
94. Sachdeva A, Hung YY, Solomon MD, McNulty EJ. Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention for Chronic Total Occlusion. Am J Cardiol. 2020;132:44-51.
95. Lichtenwalter C, de Lemos JA, Roesle M, Obel O, Holper EM, Haagen D, Saeed B, Iturbe JM, Shunk K, Bissett JK, Sachdeva R, Voudris VV, Karyofillis P, Kar B, Rossen J, Fasseas P, Berger P, Banerjee S, Brilakis ES. Clinical presentation and angiographic characteristics of saphenous vein graft failure after stenting: insights from the SOS (stenting of saphenous vein grafts) trial. JACC Cardiovasc Interv. 2009;2:855-60.
96. Redfors B, Généreux P, Witzenbichler B, McAndrew T, Diamond J, Huang X, Maehara A, Weisz G, Mehran R, Kirtane AJ, Stone GW. Percutaneous Coronary Intervention of Saphenous Vein Graft. Circ Cardiovasc Interv. 2017;10:e004953.
97. Van Gelder IC, Rienstra M, Bunting KV, Casado-Arroyo R, Caso V, Crijns HJGM, De Potter TJR, Dwight J, Guasti L, Hanke T, Jaarsma T, Lettino M, Løchen ML, Lumbers RT, Maesen B, Mølgaard I, Rosano GMC, Sanders P, Schnabel RB, Suwalski P, Svennberg E, Tamargo J, Tica O, Traykov V, Tzeis S, Kotecha D; ESC Scientific Document Group. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2024;45:3314-414.
98. Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T, Maeng M, Merkely B, Zeymer U, Gropper S, Nordaby M, Kleine E, Harper R, Manassie J, Januzzi JL, Ten Berg JM, Steg PG, Hohnloser SH; RE-DUAL PCI Steering Committee and Investigators. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377:1513-24.
99. Hijazi Z, Alexander JH, Li Z, Wojdyla DM, Mehran R, Granger CB, Parkhomenko A, Bahit MC, Windecker S, Aronson R, Berwanger O, Halvorsen S, de Waha-Thiele S, Sinnaeve P, Darius H, Storey RF, Lopes RD. Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial. Circulation. 2021;143:1215-23.
100. Vranckx P, Valgimigli M, Eckardt L, Tijssen J, Lewalter T, Gargiulo G, Batushkin V, Campo G, Lysak Z, Vakaliuk I, Milewski K, Laeis P, Reimitz PE, Smolnik R, Zierhut W, Goette A. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet. 2019;394:1335-43.
101. Kerneis M, Gibson CM, Chi G, Mehran R, AlKhalfan F, Talib U, Pahlavani S, Mir M, Bode C, Halperin JL, Nafee T, Peterson ED, Verheugt FWA, Wildgoose P, van Eickels M, Lip GYH, Fox KAA, Cohen M. Effect of Procedure and Coronary Lesion Characteristics on Clinical Outcomes Among Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention: Insights From the PIONEER AF-PCI Trial. JACC Cardiovasc Interv. 2018;11:626-34.
102. Berry NC, Mauri L, Steg PG, Bhatt DL, Hohnloser SH, Nordaby M, Miede C, Kimura T, Lip GYH, Oldgren J, Ten Berg JM, Cannon CP. Effect of Lesion Complexity and Clinical Risk Factors on the Efficacy and Safety of Dabigatran Dual Therapy Versus Warfarin Triple Therapy in Atrial Fibrillation After Percutaneous Coronary Intervention: A Subgroup Analysis From the REDUAL PCI Trial. Circ Cardiovasc Interv. 2020;13:e008349.
103. Gargiulo G, Goette A, Tijssen J, Eckardt L, Lewalter T, Vranckx P, Valgimigli M. Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur Heart J. 2019;40:3757-67.
104. Potpara TS, Mujovic N, Proietti M, Dagres N, Hindricks G, Collet JP, Valgimigli M, Heidbuchel H, Lip GYH. Revisiting the effects of omitting aspirin in combined antithrombotic therapies for atrial fibrillation and acute coronary syndromes or percutaneous coronary interventions: meta-analysis of pooled data from the PIONEER AF-PCI, RE-DUAL PCI, and AUGUSTUS trials. Europace. 2020;22:33-46.
105. Angiolillo DJ, Bhatt DL, Cannon CP, Eikelboom JW, Gibson CM, Goodman SG, Granger CB, Holmes DR, Lopes RD, Mehran R, Moliterno DJ, Price MJ, Saw J, Tanguay JF, Faxon DP. Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention: A North American Perspective: 2021 Update. Circulation. 2021;143:583-96.
106. Cho MS, Kang DY, Ahn JM, Yun SC, Oh YS, Lee CH, Choi EK, Lee JH, Kwon CH, Park GM, Choi HO, Park KH, Park KM, Hwang J, Yoo KD, Cho YR, Kim JH, Hwang KW, Jin ES, Kwon O, Kim KH, Park SJ, Park DW, Nam GB; EPIC-CAD Investigators. Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease. N Engl J Med. 2024;391:2075-86.
Volume 21 Number 18
Sep 15, 2025
Volume 21 Number 18
View full issue

Key metrics

Suggested by Cory

10.4244/EIJV15I11A174 • Dec 6, 2019
Antiplatelet strategies for complex PCI
Capodanno D
free

Clinical research

10.4244/EIJ-D-20-00361 • Sep 18, 2020
Impact of coronary lesion complexity in percutaneous coronary intervention: one-year outcomes from the large, multicentre e-Ultimaster registry
Mohamed M et al
free

• May 25, 2010
Rationale and use of antiplatelet and antithrombotic drugs during cardiovascular interventions: May 2010 update
Cuisset T et al
free

Expert review

10.4244/EIJ-D-20-00885 • May 16, 2021
Antithrombotic therapy after percutaneous coronary intervention of bifurcation lesions
Zimarino M et al
free

10.4244/EIJV13I12A222 • Dec 8, 2017
Endeavours to define optimal antithrombotic therapy after percutaneous coronary intervention
Kimura T
free

Research correspondence

10.4244/EIJ-D-22-00594 • Mar 20, 2023
Pharmacodynamic effects of cangrelor in elective complex PCI: insights from the POMPEII Registry
Gargiulo G et al
free

10.4244/EIJV15I12A192 • Dec 20, 2019
GLOBAL LEADERS: looking now at the bigger picture
Guedeney P and Montalescot G
free

10.4244/EIJV14I4A68 • Jul 20, 2018
Navigating the complexity of percutaneous coronary intervention in patients at high risk for bleeding
Giustino G and Mehran R
free

State-of-the-Art Review

10.4244/EIJ-D-21-00904 • Apr 1, 2022
Antiplatelet therapy after percutaneous coronary intervention
Angiolillo D et al
free
Trending articles
76.3

State-of-the-Art

10.4244/EIJ-D-23-00840 • Sep 2, 2024
Aortic regurgitation: from mechanisms to management
Baumbach A et al
free
64.5

Trial design

10.4244/EIJ-D-23-00125 • Jul 17, 2023
P2Y12 inhibitor monotherapy versus dual antiplatelet therapy in patients with acute coronary syndromes undergoing coronary stenting: rationale and design of the NEOMINDSET Trial
Guimarães PO et al
free
64.25

Original Research

10.4244/EIJ-D-24-00055 • Sep 16, 2024
Vascular response following implantation of the third-generation drug-eluting resorbable coronary magnesium scaffold: an intravascular imaging analysis of the BIOMAG-I first-in-human study
Seguchi M et al
56.1

Original Research

10.4244/EIJ-D-25-00331 • May 21, 2025
One-month dual antiplatelet therapy followed by prasugrel monotherapy at a reduced dose: the 4D-ACS randomised trial
Jang Y et al
open access
56.1

Original Research

10.4244/EIJ-D-25-00331 • Jul 21, 2025
One-month dual antiplatelet therapy followed by prasugrel monotherapy at a reduced dose: the 4D-ACS randomised trial
Jang Y et al
open access
46.75

Trial design

10.4244/EIJ-D-22-01006 • Jun 19, 2023
A prospective study comparing short versus standard dual antiplatelet therapy in patients with acute myocardial infarction: design and rationale of the TARGET-FIRST trial
Tarantini G et al
free
31.1

Expert Review

10.4244/EIJ-D-24-00535 • May 5, 2025
Catheter-based techniques for pulmonary embolism treatment
Costa F et al
28.25

Clinical research

10.4244/EIJ-D-19-01006 • Aug 7, 2020
Coronary collaterals and myocardial viability in patients with chronic total occlusions
Schumacher S et al
free
25.1

SHORT REPORT

10.4244/EIJ-D-18-00201 • Sep 20, 2018
International LAMPOON: first European experience with laceration of the anterior mitral valve leaflet prior to transseptal transcatheter mitral valve implantation
Kasel AM et al
free
24.6

CLINICAL RESEARCH

10.4244/EIJ-D-18-00344 • Aug 3, 2018
Left atrial appendage occlusion with the AMPLATZER Amulet device: one-year follow-up from the prospective global Amulet observational registry
Landmesser U et al
free
23.95

Original Research

10.4244/EIJ-D-25-00826 • Aug 30, 2025
Effect of beta blocker withholding or withdrawal after myocardial infarction without reduced ejection fraction on ischaemic events: a post hoc analysis from the REBOOT trial
Rossello X et al
open access
X
PCR
Readers
Current issue
Archives
Subscriptions
Authors
Submit your paper
Instructions
Services
Advertise
Reprints / ePrints
Rights and permissions
Textbooks
The PCR Textbook
The history of angioplasty
Percutaneous cardiac interventions
About the journal
Editorial team
Disclaimer
Privacy policy
Cookie Management
Follow us
Facebook
X
Instagram
LinkedIn
YouTube
Impact factor: 9.5
2024 Journal Citation Reports®
Science Edition (Clarivate Analytics, 2025)
Online ISSN 1969-6213 - Print ISSN 1774-024X
© 2005-2025 Europa Group - All rights reserved