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. 2022 Mar 18;17(16):1330–1339. doi: 10.4244/EIJ-D-21-00721

Safety and efficacy of ticagrelor monotherapy according to drug-eluting stent type: the TWILIGHT-STENT study

George Dangas 1, Usman Baber 2,3, Samin Sharma 4, Gennaro Giustino 5, Samantha Sartori 6, Johny Nicolas 7, Ridhima Goel 8, Shamir Mehta 9, David J Cohen 10, Dominick J Angiolillo 11, Zhongjie Zhang 12, Anton Camaj 13, Davide Cao 14, Carlo Briguori 15, Dariusz Dudek 16, Javier Escaned 17, Kurt Huber 18, Timothy Collier 19, Ran Kornowski 20, Vijay Kunadian 21, David J Moliterno 22, E Magnus Ohman 23, Giora Weisz 24, Robert Gil 25, Mitchell W Krucoff 26, Upendra Kaul 27, Keith G Oldroyd 28, Gennaro Sardella 29, Richard Shlofmitz 30, Bernhard Witzenbichler 31, Adnan Kastrati 32, Ya-ling Han 33, Philippe Gabriel Steg 34, Stuart Pocock 35, C Michael Gibson 36, Roxana Mehran 37,*
PMCID: PMC9743248  PMID: 34881696

Abstract

Background

In the TWILIGHT trial, ticagrelor monotherapy after a short course of dual antiplatelet therapy (DAPT) was shown to be a safe bleeding avoidance strategy in high-risk patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES).

Aims

The aim of this study was to evaluate the effects of ticagrelor monotherapy after three-month DAPT in patients undergoing PCI, according to DES type.

Methods

In the current sub-analysis from TWILIGHT, patients were stratified into three groups based on DES type: durable polymer everolimus-eluting stents (DP-EES), durable polymer zotarolimus-eluting stents (DP-ZES), and biodegradable polymer DES (BP-DES). Bleeding and ischaemic outcomes were assessed at one year after randomisation.

Results

Out of 5,769 patients, 3,014 (52.2%) had DP-EES, 1,350 (23.4%) had DP-ZES and 1,405 (24.4%) had BP-DES. Compared with ticagrelor plus aspirin, ticagrelor monotherapy had significantly lower BARC type 2, 3 or 5 bleeding compared with DAPT; DP-EES (3.8% vs 6.7%; HR 0.56, 95% CI: 0.41-0.78), DP-ZES (4.6% vs 6.9%; HR 0.66, 95% CI: 0.42-1.04) and BP-DES (4.2% vs 7.9%; HR 0.52, 95% CI: 0.33-0.81; pinteraction=0.76). Ticagrelor monotherapy resulted in similar rates of death, MI, or stroke: DP-EES (4.2% vs 4.3%; HR 0.97; 95% CI: 0.68-1.37); DP-ZES (4.1% vs 3.1%; HR 1.32; 95% CI: 0.75-2.33); BP-DES (3.9% vs 4.2%; HR 0.92; 95% CI: 0.54-1.55; pinteraction=0.60). In both unadjusted and covariate-adjusted analyses, DES type was not associated with any differences in ischaemic or bleeding complications.

Conclusions

As compared with ticagrelor plus aspirin, ticagrelor monotherapy after a short DAPT duration lowered bleeding complications without increasing the ischaemic risk, irrespective of DES type. We observed no significant differences among DES types.

Introduction

Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12-receptor inhibitor constitutes the standard of care following percutaneous coronary intervention (PCI) with drug-eluting stents (DES) to prevent coronary thrombotic events1. First-generation DES, while more effective than bare metal stents at reducing rates of restenosis, were limited by late and very late thrombosis2. Iterations in DES technologies with refinements in stent design, drug, polymer and alloy as well as more potent P2Y12-receptor inhibitors further improved the safety of PCI by reducing the incidence of early and late thrombotic complications3,4. Prolonged DAPT, while effective in reducing long-term ischaemic events, results in significantly higher rates of major bleeding complications which are in turn associated with increased risk of morbidity and mortality5,6,7,8,9. These observations led to a series of studies evaluating the safety and efficacy of abbreviated DAPT duration consisting of early P2Y12-receptor inhibitor withdrawal following PCI with DES10.

An emerging strategy of early aspirin withdrawal (i.e., 1-3 months post-PCI) with continuation of P2Y12-receptor inhibitor has recently been demonstrated to reduce bleeding risk while preserving ischaemic protection11. Monotherapy with the potent P2Y12-receptor inhibitor ticagrelor following three months of DAPT resulted in a lower incidence of clinically relevant bleeding without increasing the risk of ischaemic events, compared to continuing DAPT up to 15 months post-PCI with DES11. Patients undergoing PCI with different stent types may have variable ischaemic/bleeding risk profiles (i.e., due to large differences in strut thickness, polymer type, eluting drug, etc.) and thus may respond differently to this novel strategy. A prior sub-analysis from the TWILIGHT trial showed the safety and efficacy of ticagrelor monotherapy in patients receiving the SYNERGY biodegradable polymer drug-eluting stents (BP-DES)12. A broader evaluation across various platforms of durable polymer drug-eluting stents (DP-DES) and BP-DES has not been performed. We therefore performed a post hoc analysis of the Ticagrelor with Aspirin or Alone in High-Risk Patients after Coronary Intervention (TWILIGHT) trial evaluating the safety and efficacy of a regimen of ticagrelor monotherapy versus ticagrelor plus aspirin in patients who initially completed three months of DAPT after PCI with different types of new-generation DES.

Methods

Study design

TWILIGHT was an international, multicentre, randomised, placebo-controlled trial conducted in 187 sites across 11 countries, as previously described11,13. The Icahn School of Medicine at Mount Sinai designed and sponsored the trial, which was supported by an investigator-initiated grant from AstraZeneca. National regulatory agencies and institutional review boards or ethics committees of participating centres approved the trial protocol. An independent data and safety monitoring board provided external oversight to ensure the safety of the trial participants.

Study population

Patients who underwent successful PCI with at least one locally approved DES and whom the treating clinician intended to discharge on a regimen of ticagrelor plus aspirin were eligible to participate. Patients also had to have at least one additional clinical feature and one angiographic feature associated with a high risk of ischaemic or bleeding events13. For the present pre-specified analysis, only durable polymer everolimus-eluting stents (DP-EES), durable polymer zotarolimus-eluting stents (DP-ZES) and BP-DES were included (Supplementary Figure 1). Patients who underwent PCI with more than one stent type or with a bare metal stent implanted were excluded. A full list of the commercially approved DES types included in the analysis is provided in Supplementary Table 1. The clinical criteria for high risk were: age ≥65 years, female sex, troponin-positive acute coronary syndrome (ACS), established vascular disease, diabetes mellitus that was being treated with medication (including both oral and parenteral medications), and chronic kidney disease. Angiographic criteria included multivessel coronary artery disease (CAD), a total stent length >30 mm, a thrombotic target lesion, a bifurcation lesion treated with two stents, an obstructive left main or proximal left anterior descending lesion, and a calcified target lesion treated with atherectomy. Key exclusion criteria included presentation with ST-segment elevation myocardial infarction, cardiogenic shock, ongoing long-term treatment with oral anticoagulants, or contraindication to aspirin or ticagrelor.

Study procedures

All enrolled patients received open-label ticagrelor (90 mg twice daily) and enteric-coated aspirin (81 to 100 mg daily) after the index PCI. At the three-month follow-up visit, patients who remained adherent and had not sustained a major bleeding event (defined as a Bleeding Academic Research Consortium [BARC] type 3b or 5 bleed) or a major ischaemic event (stroke, myocardial infarction, or coronary revascularisation) were eligible for randomisation to either aspirin (81 to 100 mg daily) or matching placebo with continuation of open-label ticagrelor (90 mg twice daily) for an additional 12 months. The choice of prolonged potent DAPT in the control group was justified by the heightened ischaemic risk, as reflected by the procedural/angiographic inclusion criteria of the study population11,13. Follow-up was performed by telephone at one month after randomisation and in person at six and 12 months after randomisation. Adherence was assessed with manual pill counts, and non-adherence was classified systematically, as described previously14. After 12 months of protocol-mandated therapy, patients were switched to a standard-of-care antiplatelet regimen at the discretion of their treating physician, followed by a final telephone follow-up three months later.

Endpoints

The primary endpoint of the study was BARC type 2, 3 or 5 bleeding15 between randomisation and the one-year follow-up (i.e., 15 months after the index procedure). The key secondary endpoint was major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of death from any cause, non-fatal myocardial infarction (MI) or non-fatal stroke. Secondary bleeding endpoints included BARC type 3 or 5 bleeding15; Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding16; Global Use of Strategies to open Occluded Arteries (GUSTO) moderate, severe, or life-threatening bleeding17; or major bleeding as defined by the International Society on Thrombosis or Haemostasis (ISTH)18. Other secondary endpoints included death from cardiovascular causes, MI, ischaemic stroke, and definite or probable stent thrombosis (ST). MI was defined according to the third universal definition19, and revascularisation and ST were classified according to the Academic Research Consortium20. The definitions of study endpoints are listed in Supplementary Table 2. All clinical events were adjudicated by an external independent committee, the members of which were unaware of the treatment group assignments.

Statistical analysis

Analyses were performed in the intention-to-treat population for bleeding endpoints and in the per-protocol population for ischaemic endpoints. Baseline characteristics were compared using chi-square or Student’s t-test for categorical or continuous variables, respectively. The cumulative incidence of the primary and secondary endpoints was estimated by the Kaplan-Meier method. Hazard ratios (HR) and 95% confidence intervals (CI) were generated using adjusted Cox proportional hazards models for DES-type comparisons. Clinically relevant variables were included in the adjustment model: body mass index (kg/m2), hypercholesterolaemia, peripheral arterial disease, previous PCI or coronary artery bypass graft surgery, multivessel CAD, indication for PCI (ACS versus stable CAD), total occlusion of target vessel, and total stent length. The consistency of the treatment effect of ticagrelor monotherapy versus ticagrelor plus aspirin between the different stent types (DP-EES, DP-ZES and BP-DES) was evaluated with formal interaction testing. All analyses were performed using Stata version 16.0 (College Station, TX, USA). A p-value <0.05 indicates statistical significance.

Results

A total of 9,006 patients were initially enrolled following PCI, of which 7,119 were randomly assigned three months later to receive ticagrelor plus placebo or ticagrelor plus aspirin. Of these 7,119 patients, 5,769 (81.0%) were included in this analysis. Of these, 3,014 (52.2%) received a DP-EES, 1,350 (23.4%) received a DP-ZES and 1,405 (24.4%) received a BP-DES. The study flow diagram is reported in Supplementary Figure 1. Baseline clinical and procedural characteristics for patients according to type of new-generation DES are reported in Table 1; similarly, baseline characteristics according to treatment arm within each stent type group are reported in Supplementary Table 3. Patients who underwent PCI with a BP-DES had fewer comorbidities and were more likely to present with an ACS. Overall outcomes according to the three types of DES are reported in Figure 1-Figure 3 and Supplementary Table 4; in both univariate analysis and multivariable analyses, DES type was not associated with an increased risk of MACCE, target lesion failure (TLF) or major bleeding complications. One-year rates of stent thrombosis were <1% across all DES platforms.

Table 1. Baseline clinical and procedural characteristics.

New-generation drug-eluting stent DP-EES
N=3,014
(52.2%) 		DP-ZES
N=1,350
(23.4%) 		BP-DES
N=1,405
(24.4%) 		p-value
Age, years 65.3±10.3 65.3±10.2 65.2±10.3 0.96
Female sex 696 (23.1%) 321 (23.8%) 342 (24.3%) 0.65
BMI, kg/m2 29.3±5.9 29.2±5.6 28.4±5.2 <0.001
Diabetes 1,107 (36.7%) 526 (39.0%) 504 (35.9%) 0.21
Diabetes treated with insulin 304 (27.5%) 144 (27.4%) 138 (27.4%) 0.99
Chronic kidney disease 509 (17.6%) 242 (18.4%) 241 (18.1%) 0.78
Anaemia 572 (19.8%) 259 (19.7%) 247 (18.6%) 0.67
Current smoker 617 (20.5%) 287 (21.3%) 317 (22.6%) 0.28
Hypercholesterolaemia 2,076 (68.9%) 965 (71.5%) 814 (57.9%) <0.001
Hypertension 2,273 (75.4%) 1,002 (74.2%) 1,014 (72.2%) 0.07
Peripheral arterial disease 207 (6.9%) 138 (10.2%) 87 (6.2%) <0.001
Previous MI 953 (31.6%) 394 (29.2%) 414 (29.5%) 0.17
Previous PCI 1,333 (44.2%) 644 (47.7%) 604 (43.0%) 0.03
Previous CABG 368 (12.2%) 156 (11.6%) 140 (10.0%) 0.09
Multivessel CAD 1,786 (59.3%) 876 (64.9%) 844 (60.1%) 0.002
Previous major bleed 28 (0.9%) 10 (0.7%) 11 (0.8%) 0.78
Indication for PCI ACS 1,880 (62.4%) 785 (58.2%) 937 (66.7%) <0.001
Stable CAD 1,134 (37.6%) 564 (41.8%) 468 (33.3%)
Target vessel Left main 124 (4.1%) 57 (4.2%) 61 (4.3%) 0.94
LAD 1,619 (53.7%) 714 (52.9%) 802 (57.1%) 0.05
LCx 949 (31.5%) 434 (32.1%) 410 (29.2%) 0.19
RCA 996 (33.0%) 455 (33.7%) 500 (35.6%) 0.25
Number of vessels treated 1.2±0.5 1.2±0.5 1.3±0.5 0.04
Number of lesions treated 1.5±0.7 1.5±0.7 1.5±0.7 0.69
Lesion morphology* Moderate/severe calcification 412 (13.7%) 206 (15.3%) 199 (14.2%) 0.38
Bifurcation 343 (11.4%) 134 (9.9%) 174 (12.4%) 0.12
Total occlusion 155 (5.1%) 42 (3.1%) 113 (8.0%) <0.001
Thrombotic 403 (13.4%) 136 (10.1%) 125 (8.9%) <0.001
Total stent length, mm# 36.2±21.6 36.0±21.5 39.2±23.9 <0.001
Minimum stent diameter, mm 2.9±0.5 2.9±0.5 2.9±0.5 0.38
*Lesion morphology assessed by operators. #Stent length calculated as the addition of individual stent lengths per lesion. ACS: acute coronary syndrome; BMI: body mass index; BP-DES: biodegradable polymer drug-eluting stent; CABG: coronary artery bypass graft; CAD: coronary artery disease; DP-EES: durable polymer everolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; LAD: left anterior descending; LCx: left circumflex; MI: myocardial infarction; PCI: percutaneous coronary intervention; RCA: right coronary artery
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Figure 1. Rates of (A) BARC 2, 3 or 5 bleeding and (B) MACCE among the three DES types evaluated.

Figure 1

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Kaplan–Meier estimates for BARC 2, 3 or 5 bleeding and target lesion failure at 12 months after randomisation (intention-to-treat population) by drug-eluting stent type in patients who underwent percutaneous coronary intervention. BARC: Bleeding Academic Research Consortium; BP-DES: biodegradable polymer drug-eluting stent; DP-EES: durable polymer everolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; Gen: generation; MACCE: major adverse cardiac and cerebral events (all-cause death, myocardial infarction, or stroke)

Figure 3. Rates of BARC 3 or 5 bleeding among the three DES types evaluated.

Figure 3

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Kaplan–Meier estimates for BARC 3 or 5 bleeding at 12 months after randomisation by drug-eluting stent type in patients who underwent percutaneous coronary intervention. BARC: Bleeding Academic Research Consortium; BP-DES: biodegradable polymer drug-eluting stent; DP-EES: durable polymer everolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; Gen: generation

Bleeding outcomes

Bleeding event rates in patients according to randomised treatment assignment (ticagrelor plus placebo versus ticagrelor plus aspirin) and DES type are reported in Table 2. Overall, the reduction in bleeding rates of ticagrelor monotherapy was consistent across DES types. Ticagrelor monotherapy consistently resulted in significantly lower rates of BARC type 2, 3 or 5 bleeding at one year after randomisation among patients treated with DP-EES (3.8% vs 6.7%; absolute risk difference −2.9%; HR: 0.56, 95% CI: 0.41-0.78), DP-ZES (4.6% vs 6.9%; absolute risk difference −2.3%; HR: 0.66, 95% CI: 0.42-1.04) and BP-DES (4.2% vs 7.9%; absolute risk difference −3.7%; HR: 0.52, 95% CI: 0.33-0.81), without statistical interaction (pinteraction=0.76) (Central illustration). These results were also consistent when other bleeding definitions were examined (Table 2).

Table 2. Bleeding and ischaemic events within each stent subgroup one year after randomisation.

no. of events (%) DP-EES (N=3,014) DP-ZES (N=1,350) BP-DES (N=1,405) Interaction p-value*
Tica+
placebo (N=1,525) 		Tica+
aspirin (N=1,489) 		Hazard
ratio
(95% CI) 		Tica+
placebo (N=669) 		Tica+
aspirin (N=681) 		Hazard
ratio
(95% CI) 		Tica+
placebo (N=705) 		Tica+
aspirin (N=700) 		Hazard
ratio
(95% CI)
Bleeding endpoints
BARC 2, 3, or 5 58 (3.8%) 99 (6.7%) 0.56 (0.41-0.78) 30 (4.6%) 46 (6.9%) 0.66 (0.42-1.04) 29 (4.2%) 54 (7.9%) 0.52 (0.33-0.81) 0.76
BARC 3 or 5 10 (0.7%) 25 (1.7%) 0.39 (0.19-0.81) 8 (1.2%) 12 (1.8%) 0.68 (0.28-1.66) 8 (1.2%) 17 (2.5%) 0.46 (0.20-1.07) 0.64
TIMI major 4 (0.3%) 11 (0.7%) 0.35 (0.11-1.11) 7 (1.1%) 5 (0.7%) 1.43 (0.45-4.51) 4 (0.6%) 7 (1.0%) 0.57 (0.17-1.93) 0.22
GUSTO moderate or severe 6 (0.4%) 16 (1.1%) 0.37 (0.14-0.93) 7 (1.1%) 8 (1.2%) 0.89 (0.32-2.46) 8 (1.2%) 10 (1.4%) 0.79 (0.31-2.00) 0.36
ISTH major 11 (0.7%) 27 (1.8%) 0.40 (0.20-0.80) 9 (1.4%) 12 (1.8%) 0.76 (0.32-1.81) 10 (1.4%) 18 (2.6%) 0.55 (0.25-1.18) 0.51
Ischaemic endpoints
MACCE 63 (4.2%) 64 (4.3%) 0.97 (0.68-1.37) 27 (4.1%) 21 (3.1%) 1.32 (0.75-2.33) 27 (3.9%) 29 (4.2%) 0.92 (0.54-1.55) 0.60
Target lesion failure 112 (7.4%) 117 (7.9%) 0.94 (0.72-1.22) 65 (9.9%) 51 (7.6%) 1.31 (0.91-1.89) 54 (7.8%) 48 (7.0%) 1.13 (0.76-1.66) 0.33
Cardiovascular death 10 (0.7%) 20 (1.4%) 0.49 (0.23-1.04) 8 (1.2%) 5 (0.7%) 1.64 (0.54-5.00) 6 (0.9%) 7 (1.0%) 0.85 (0.29-2.52) 0.20
MI 47 (3.1%) 44 (3.0%) 1.05 (0.69-1.58) 19 (2.9%) 16 (2.4%) 1.22 (0.62-2.36) 17 (2.4%) 20 (2.9%) 0.84 (0.44-1.60) 0.73
Ischaemic stroke 7 (0.5%) 1 (0.1%) 6.85 (0.84-55.7) 2 (0.3%) 1 (0.2%) 2.05 (0.19-22.6) 2 (0.3%) 4 (0.6%) 0.49 (0.09-2.70) 0.10
Target vessel revascularisation 57 (3.8%) 54 (3.7%) 1.03 (0.71-1.50) 30 (4.6%) 25 (3.7%) 1.23 (0.72-2.09) 30 (4.3%) 28 (4.1%) 1.07 (0.64-1.78) 0.87
Stent thrombosis (definite/probable) 5 (0.3%) 9 (0.6%) 0.54 (0.18-1.62) 5 (0.8%) 3 (0.4%) 1.71 (0.41-7.14) 3 (0.4%) 6 (0.9%) 0.49 (0.12-1.98) 0.37
NACE 70 (4.6%) 83 (5.6%) 0.82 (0.60-1.13) 33 (5.0%) 31 (4.6%) 1.09 (0.67-1.77) 35 (5.0%) 44 (6.4%) 0.78 (0.50-1.22) 0.57
*P-value is for the test of interaction between randomised treatment assignment and stent type. The percentages mentioned above represent K-M rates at 1 year after randomisation. Hazard ratio comparing ticagrelor+placebo versus ticagrelor+aspirin. Target lesion failure: cardiac death/target vessel MI/clinically indicated revascularisation/definite or probable stent thrombosis. BARC: bleeding academic research consortium; BP-DES: biodegradable polymer drug-eluting stent; CI: confidence interval; DP-EES: durable polymer everolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; ISTH: International Society on Thrombosis and Haemostasis; MACCE: death/MI/stroke; MI: myocardial infarction; NACE: death/MI/stroke/BARC 3 or 5; TIMI: Thrombolysis in Myocardial Infarction; GUSTO: global utilization of streptokinase and TPA for occluded arteries
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Central illustration. Bleeding and ischaemic effects of ticagrelor monotherapy versus ticagrelor plus aspirin after three months of DAPT in patients undergoing PCI with second-generation DES.

Central illustration

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Following three months of adherence to DAPT post-PCI and in the absence of major bleeding or ischaemic events, this post hoc analysis from the TWILIGHT trial assessing clinical outcomes in n=5,769 patients who underwent PCI with a second-generation DES showed that ticagrelor monotherapy, compared with ticagrelor plus aspirin, was associated with a reduction in BARC 2, 3, or 5 bleeding over one year consistently across the three studied DES types. There was no significant difference in the one-year rate of all-cause death, MI, or stroke between the two treatment arms; this was also consistent across the 3 DES types. ASA: aspirin; BARC: Bleeding Academic Research Consortium; BP-DES: biodegradable polymer drug-eluting stent; DP-EES: durable polymer everolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; Gen: generation; MACCE: major adverse cardiac and cerebrovascular events, a composite of death, myocardial infarction or stroke.

Ischaemic outcomes

Ischaemic event rates in patients according to randomised group (ticagrelor plus placebo versus ticagrelor plus aspirin) and stent type are reported in Table 2. There were no significant differences in MACCE between ticagrelor monotherapy and ticagrelor plus aspirin among patients treated with DP-EES (4.2% vs 4.3%; absolute risk difference −0.1%; HR: 0.97, 95% CI: 0.68-1.37), DP-ZES (4.1% vs 3.1%; absolute risk difference 1.0%; HR: 1.32, 95% CI: 0.75-2.33) and BP-DES (3.9% vs 4.2%; absolute risk difference −0.3%; HR: 0.92, 95% CI: 0.54-1.55), without statistical interaction (pinteraction=0.597). Additionally, there were no significant differences among groups regarding the individual ischaemic endpoints (Central illustration, Table 2). The rates of DES thrombosis were <1% and not influenced by the randomised treatment assignment to ticagrelor monotherapy or DAPT.

Discussion

The key findings of the present, post hoc analysis from the TWILIGHT trial, in which we examined the effect of aspirin withdrawal on a background of potent P2Y12-receptor inhibition with ticagrelor after three months of DAPT according to stent type, include: (i) ticagrelor monotherapy compared with ticagrelor plus aspirin resulted in significantly lower major bleeding complications, a finding that was consistent across new-generation DES types; (ii) ticagrelor monotherapy compared to ticagrelor plus aspirin was not associated with increased risk of ischaemic events irrespective of the type of new-generation DES; and (iii) there were no significant differences in MACCEs across DES types in the overall population; notably, rates of DES thrombosis were uniformly low and not influenced by the randomised treatment assignment.

Iteration in DES technologies including improved drug release kinetics, polymer biocompatibility, and endothelialisation patterns of new-generation DES significantly overcame the limitations observed with early-generation DES4,10. In the era of first-generation DES, an extended period of DAPT (≥1 year) using aspirin and a P2Y12-receptor inhibitor was considered necessary in order to reduce the risk of DES-related thrombotic events10. While extended DAPT has been shown to reduce the risk of DES-related and non-DES-related ischaemic events, it may also result in higher risk of haemorrhagic complications which are strongly associated with increased risk of morbidity, mortality and healthcare costs5,21,22. New-generation DES platforms have been associated with lower risk of DES-related thrombotic events compared to first-generation DESs therefore obviating the need for mandatory prolonged DAPT10,23. In a previous large meta-analysis of randomised controlled trials investigating the efficacy and safety of longer versus shorter DAPT, the risk for ST was significantly higher using short-term DAPT in patients who received a first-generation DES (OR 3.94, 95% CI: 2.20-7.05) compared with those who received a new-generation DES (OR 1.54, 95% CI: 0.96-2.47; pinteraction=0.008)10.

In the current analysis from the TWILIGHT trial, we extended prior knowledge by evaluating the safety and efficacy of a strategy of abbreviated DAPT using aspirin and ticagrelor followed by ticagrelor monotherapy among high-risk patients undergoing PCI with different types of new-generation DESs. Overall, DP-EES, DP-ZES and BP-DES were associated with very low rates of late DES thrombosis (between three and 15 months post-PCI). Among randomised patients, a strategy of ticagrelor monotherapy did not result in increased rates of MACCE nor stent thrombosis irrespective of the type of DES implanted compared to continuing DAPT. The bleeding avoidance benefits of ticagrelor monotherapy versus DAPT were not influenced by the type of DES. These findings are overall consistent with the main results of the TWILIGHT trial as well as with prior trials evaluating a strategy of P2Y12-receptor monotherapy following abbreviated DAPT using clopidogrel11. For example, in the Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt Chromium Stent (STOPDAPT 2) trial in which 3,009 patients who underwent PCI with a cobalt-chromium EES and were randomised to one month of DAPT followed by clopidogrel monotherapy versus 12 months of DAPT with aspirin and clopidogrel, the former regimen resulted in lower rates of bleeding complications and similar rates of ischaemic events compared with one-year DAPT24. In the GLOBAL LEADERS trial, a randomised, open-label superiority trial of all-comers undergoing PCI with a bioresorbable polymer biolimus A9-eluting DES (N=15,968), aspirin plus ticagrelor was tested for one month followed by 23 months of ticagrelor monotherapy and also resulted in similar rates of ischaemic events compared to 12 months of DAPT (aspirin plus clopidogrel in those with stable CAD or 12 months of aspirin plus ticagrelor in those with ACS) followed by 12 months of aspirin monotherapy25. Hence, the totality of evidence supports the efficacy and safety of a strategy of P2Y12-receptor monotherapy following an initial short period of DAPT when using a latest-generation DES after PCI in patients with high-risk clinical or anatomic characteristics26. Furthermore, P2Y12-receptor monotherapy has recently gained attention within the context of chronic maintenance therapy (i.e., beyond one year) after PCI. Indeed, the recently published HOST-EXAM randomised trial revealed a significant decrease in net adverse events (composite of all-cause death, MI, stroke, and BARC bleeding type 3 or greater) with clopidogrel versus aspirin monotherapy at 24-month follow-up among patients who were maintained on DAPT and remained event free for six to 18 months following PCI27. Whether ticagrelor monotherapy could similarly extend its benefits beyond the period tested in our trial warrants further investigation11.

Improvements in DES design continue to strive for biocompatibility; allowing enthothelialisation after the implantation-induced arterial trauma is a key process in coronary devices adherence to the arterial wall28. Strut material, thickness and metallic mesh configuration, polymer type and properties as well as drug type, dose and elution kinetics are all important. Notably, the TWILIGHT-pharmacodynamic study supported the rationale for safety of aspirin withdrawal, and the present study concurs that aspirin can be withdrawn relatively safely after an initial three-month DAPT treatment after the index PCI, irrespective of DES type29.

Limitations

Our findings should be considered in the light of the following limitations. First, as a subgroup analysis from a randomised controlled trial, the current findings can only be considered hypothesis generating and should be further tested in adequately-powered studies for individual stent types. Second, the three DES groups were not individually powered to draw definitive conclusions on the effect of ticagrelor monotherapy versus DAPT within each DES type; for the same reason, we could not perform landmark analyses assessing the time-dependent effect of ticagrelor monotherapy according to stent type. Nonetheless, the magnitude and direction of the effects were largely consistent with the overall trial findings. Third, due to absence of statistical correction for multiple comparisons, the chance findings related to multiple testing should be considered by the readers. Fourth, these results are not generalisable to all patients who undergo PCI due to the inclusion and exclusion criteria of our trial. The observed treatment effects are applicable only to patients who tolerated an initial three months of DAPT with ticagrelor plus aspirin without any major adverse events. Whether these findings across different new-generation DES types are generalisable to a regimen of clopidogrel or prasugrel monotherapy remains unknown. Finally, treatment with a specific type of DES was not randomly assigned. Therefore, these comparisons can be subject to residual confounding despite multivariable adjustment.

Conclusions

Among high-risk patients who underwent PCI, a regimen of ticagrelor monotherapy (after an initial three months of DAPT with ticagrelor plus aspirin) resulted in significantly lower clinically relevant bleeding without increasing the risk of ischaemic events compared to continuing DAPT regardless of the type of new-generation DES implanted. There were no significant differences in the rates of MACCE among types of DES between three and 15 months. Rates of stent thrombosis were low (<1%) and not influenced by the randomised assignment to ticagrelor monotherapy or DAPT.

Impact on daily practice

Owing to significant advances in DES technologies and antithrombotic therapies, initiation of ticagrelor monotherapy after three-month DAPT reduced bleeding without increasing ischaemic events as compared with 12-month DAPT across different DES types. Further studies are warranted to investigate whether shorter DAPT durations (i.e., <3 months) with ticagrelor monotherapy are a safe bleeding avoidance strategy in patients receiving different types of newer-generation DES.

Supplementary data

Supplementary Table 1

Types of drug-eluting stents.

Supplementary Table 2

Definitions of study endpoints.

Supplementary Table 3

Baseline clinical and procedural characteristics within each stent group.

Supplementary Table 4

Outcomes associated with DES types one year after randomisation.

Supplementary Figure 1

Study flow diagram.

Figure 2. Rates of target lesion failure among the three DES types evaluated.

Figure 2

Open in a new tab

Kaplan-Meier estimates for target lesion failure at 12 months after randomisation (intention-to-treat population) by drug-eluting stent type in patients who underwent percutaneous coronary intervention. BP-DES: biodegradable polymer drug-eluting stent; DP-EES: durable polymer everolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; Gen: generation

Acknowledgments

Funding

Investigator-initiated grant from AstraZeneca; TWILIGHT ClinicalTrials.gov number, NCT02270242.

Conflict of interest statement

G. Dangas reports receiving consulting fees and advisory board fees from AstraZeneca, consulting fees from Biosensors, and previously holding stock in Medtronic. U. Baber reports speaker honoraria from AstraZeneca and Boston Scientific. S. Sharma has received consulting fees or honoraria from Abbott, Boston Scientific, Abiomed, and Cardiovascular Systems, Inc. S. Mehta has received research grants to the institution from AstraZeneca, Abbott, Boston Scientific, and Sanofi; and has received honoraria for consultancy from AstraZeneca, Bayer, Biosensors, and Sanofi. D. Cohen reports receiving grant support, paid to his institution, and consulting fees from AstraZeneca, Medtronic, Abbott Vascular, and Boston Scientific. D. Angiolillo has received payment as an individual for: a) Consulting fee or honorarium from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; b) participation in review activities from CeloNova, and St. Jude Medical. He has also received institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead Sciences, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, RenalGuard Solutions, and the Scott R. MacKenzie Foundation. J. Escaned reports receiving consulting fees and lecture fees from Abbott, Philips, Boston Scientific, and Medtronic, and lecture fees from Abiomed, Terumo, and Biosensors. K. Huber reports receiving lecture fees from AstraZeneca and Bayer. V. Kunadian has received personal fees/honoraria from Bayer, Astra Zeneca, Abbott, Amgen, and Daichii Sankyo. D. Moliterno reports grants from AstraZeneca, during the conduct of the study. M. Ohman reports research grants from Abiomed and Chiesi, and consulting fees from AstraZeneca, Cara Therapeutics, Faculty Connection, Imbria, Impulse Medical, Janssen Pharmaceuticals, Milestone Pharmaceuticals, Xylocor, and Zoll Medical. G. Weisz reports receiving grant support and advisory board fees from and holding equity in Corindus, advisory board fees from and holding equity in Filterlex, serving on an advisory board for and holding options in Trisol, and receiving grant support from Abbott, CSI, and RenalGuard Solutions. M. Krucoff reports grants and/or personal fees from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Medtronic, OrbusNeich, and Terumo. K. Oldroyd reports receiving grant support and lecture fees from AstraZeneca; and is employed by Biosensors. G. Sardella reports receiving consulting fees from Abbott, Shockwave, Boston Scientific, and Balmed, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbott, Alvimedica, Shockwave, Medtronic, Biosensors. P.G. Steg reports receiving research grants from Amarin, Bayer, Sanofi, and Servier; compensation for work in clinical trials from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Idorsia, Novartis, Pfizer, Sanofi, and Servier; receiving fees for consulting or speaking from Amgen, BMS/Myokardia, Novo-Nordisk, and Regeneron; and being a Senior Associate Editor at Circulation. M. Gibson reports receiving grant support and consulting fees from Angel Medical, Bayer, CSL Behring, Janssen Pharmaceuticals, Johnson & Johnson, and Portola Pharmaceuticals; consulting fees from the Medicines Company, Eli Lilly, Gilead Sciences, Novo Nordisk, WebMD, UpToDate Cardiovascular Medicine, Amarin Pharma, Amgen, Boehringer Ingelheim, Chiesi, Merck, PharmaMar, Sanofi, Somahlution, Verreseon Corporation, Boston Scientific, Impact Bio, MedImmume, Medtelligence, MicroPort, PERT Consortium, and GE Healthcare, holding equity in Nference; serving as chief executive officer of Baim Institute; and receiving grant support, paid to Baim Institute, from Bristol-Myers Squibb. R. Mehran reports institutional research grants from Abbott, Abiomed, Applied Therapeutics, Arena, AstraZeneca, Bayer, Biosensors, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CellAegis, CERC, Chiesi, Concept Medical, CSL Behring, DSI, Insel Gruppe AG, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Philips, Transverse Medical, and Zoll; personal fees from ACC, Boston Scientific, California Institute for Regenerative Medicine (CIRM), Cine-Med Research, Janssen, WebMD, SCAI; consulting fees paid to the institution from Abbott, Abiomed, AM-Pharma, Alleviant Medical, Bayer, Beth Israel Deaconess, CardiaWave, CeloNova, Chiesi, Concept Medical, DSI, Duke University, Idorsia Pharmaceuticals, Medtronic, Novartis, and Philips; equity <1% in Applied Therapeutics, Elixir Medical, STEL, and CONTROLRAD (spouse); being on the scientific advisory board for AMA, and Biosensors (spouse). The other authors have no conflicts of interest to declare.

Abbreviations

BARC

Bleeding Academic Research Consortium

CAD

coronary artery disease

DAPT

dual antiplatelet therapy

DES

drug-eluting stent

GUSTO

Global Use of Strategies to open Occluded Arteries

ISTH

International Society of Thrombosis or Haemostasis

MI

myocardial infarction

PCI

percutaneous coronary intervention

ST

stent thrombosis

TIMI

Thrombolysis in Myocardial Infarction

Contributor Information

George Dangas, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Usman Baber, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Cardiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Samin Sharma, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Gennaro Giustino, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Samantha Sartori, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Johny Nicolas, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ridhima Goel, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Shamir Mehta, Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada.

David J. Cohen, St. Francis Hospital, Roslyn NY and Cardiovascular Research Foundation, New York, NY, USA.

Dominick J. Angiolillo, Division of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA.

Zhongjie Zhang, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Anton Camaj, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Davide Cao, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Carlo Briguori, Mediterranea Cardiocentro, Naples, Italy.

Dariusz Dudek, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland.

Javier Escaned, Hospital Clínico San Carlos IDISCC, Complutense University of Madrid, Madrid, Spain.

Kurt Huber, 3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, and Sigmund Freud University, Medical Faculty, Vienna, Austria.

Timothy Collier, Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Ran Kornowski, Cardiology Department, Rabin Medical Center, Petach Tikva, Israel.

Vijay Kunadian, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University and Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.

David J. Moliterno, University of Kentucky, Lexington, KY, USA.

E. Magnus Ohman, Duke University Medical Center-Duke Clinical Research Institute, Durham, NC, USA.

Giora Weisz, New York Presbyterian Hospital, Columbia University Medical Center, NY, USA.

Robert Gil, Center of Postgraduate Medical Education, Central Clinical Hospital of the Ministry of Interior and Administration, Warsaw, Poland.

Mitchell W. Krucoff, Duke University Medical Center-Duke Clinical Research Institute, Durham, NC, USA.

Upendra Kaul, Batra Hospital and Medical Research Center, New Delhi, India.

Keith G. Oldroyd, West of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, United Kingdom.

Gennaro Sardella, Department of Cardiology, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

Richard Shlofmitz, St. Francis Hospital, Roslyn, NY, USA.

Bernhard Witzenbichler, Department of Cardiology and Pneumology, Helios Amper-Klinikum, Dachau, Germany.

Adnan Kastrati, Department of Cardiology, Deutsches Herzzentrum Munchen, Munchen, Germany.

Ya-ling Han, Department of Cardiology, Shenyang North Hospital, Shenyang Shi, China.

Philippe Gabriel Steg, Department of Cardiology, Groupe Hospitalier Bichat-Claude-Bernard, Paris, France.

Stuart Pocock, Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom.

C. Michael Gibson, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Roxana Mehran, The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

References

  1. Capodanno D, Alfonso F, Levine GN, Valgimigli M, Angiolillo DJ. ACC/AHA Versus ESC Guidelines on Dual Antiplatelet Therapy: JACC Guideline Comparison. J Am Coll Cardiol. 2018;72:2915–31. doi: 10.1016/j.jacc.2018.09.057. [DOI] [PubMed] [Google Scholar]
  2. Galløe AM, Kelbæk H, Thuesen L, Hansen HS, Ravkilde J, Hansen PR, Christiansen EH, Abildgaard U, Stephansen G, Lassen JF, Engstrøm T, Jensen JS, Jeppesen JL, Bligaard N SORT OUT II Investigators. 10-Year Clinical Outcome After Randomization to Treatment by Sirolimus-or Paclitaxel-Eluting Coronary Stents. J Am Coll Cardiol. 2017;69:616–24. doi: 10.1016/j.jacc.2016.11.055. [DOI] [PubMed] [Google Scholar]
  3. Giustino G, Harari R, Baber U, Sartori S, Stone GW, Leon MB, Windecker S, Serruys PW, Kastrati A, Von Birgelen, Kimura T, Stefanini GG, Dangas GD, Wijns W, Steg PG, Morice MC, Camenzind E, Weisz G, Smits PC, Sorrentino S, Sharma M, Farhan S, Faggioni M, Kandzari D, Galatius S, Jeger RV, Valgimigli M, Itchhaporia D, Mehta L, Kim HS, Chieffo A, Mehran R. Long-term Safety and Efficacy of New-Generation Drug-Eluting Stents in Women With Acute Myocardial Infarction: From the Women in Innovation and Drug-Eluting Stents (WIN-DES) Collaboration. JAMA Cardiol. 2017;2:855–62. doi: 10.1001/jamacardio.2017.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Madhavan MV, Kirtane AJ, Redfors B, Généreux P, Ben-Yehuda O, Palmerini T, Benedetto U, Biondi-Zoccai G, Smits PC, von Birgelen, Mehran R, McAndrew T, Serruys PW, Leon MB, Pocock SJ, Stone GW. Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention. J Am Coll Cardiol. 2020;75:590–604. doi: 10.1016/j.jacc.2019.11.058. [DOI] [PubMed] [Google Scholar]
  5. Généreux P, Giustino G, Witzenbichler B, Weisz G, Stuckey TD, Rinaldi MJ, Neumann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Yadav M, Francese DP, Palmerini T, Kirtane AJ, Litherland C, Mehran R, Stone GW. Incidence, Predictors, and Impact of Post-Discharge Bleeding After Percutaneous Coronary Intervention. J Am Coll Cardiol. 2015;66:1036–45. doi: 10.1016/j.jacc.2015.06.1323. [DOI] [PubMed] [Google Scholar]
  6. Baber U, Dangas G, Chandrasekhar J, Sartori S, Steg PG, Cohen DJ, Giustino G, Ariti C, Witzenbichler B, Henry TD, Kini AS, Krucoff MW, Gibson CM, Chieffo A, Moliterno DJ, Weisz G, Colombo A, Pocock S, Mehran R. Time-Dependent Associations Between Actionable Bleeding, Coronary Thrombotic Events, and Mortality Following Percutaneous Coronary Intervention: Results From the PARIS Registry. JACC Cardiovasc Interv. 2016;9:1349–57. doi: 10.1016/j.jcin.2016.04.009. [DOI] [PubMed] [Google Scholar]
  7. Yeh RW, Secemsky EA, Kereiakes DJ, Normand SL, Gershlick AH, Cohen DJ, Spertus JA, Steg PG, Cutlip DE, Rinaldi MJ, Camenzind E, Wijns W, Apruzzese PK, Song Y, Massaro JM, Mauri L DAPT Study Investigators. Development and Validation of a Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention. JAMA. 2016;315:1735–49. doi: 10.1001/jama.2016.3775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Costa F, van Klaveren, James S, Heg D, Räber L, Feres F, Pilgrim T, Hong MK, Kim HS, Colombo A, Steg PG, Zanchin T, Palmerini T, Wallentin L, Bhatt DL, Stone GW, Windecker S, Steyerberg EW, Valgimigli M PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet. 2017;389:1025–34. doi: 10.1016/S0140-6736(17)30397-5. [DOI] [PubMed] [Google Scholar]
  9. Valgimigli M, Costa F, Lokhnygina Y, Clare RM, Wallentin L, Moliterno DJ, Armstrong PW, White HD, Held C, Aylward PE, Van de, Harrington RA, Mahaffey KW, Tricoci P. Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial. Eur Heart J. 2017;38:804–10. doi: 10.1093/eurheartj/ehw525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Giustino G, Baber U, Sartori S, Mehran R, Mastoris I, Kini AS, Sharma SK, Pocock SJ, Dangas GD. Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2015;65:1298–310. doi: 10.1016/j.jacc.2015.01.039. [DOI] [PubMed] [Google Scholar]
  11. 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. doi: 10.1056/NEJMoa1908419. [DOI] [PubMed] [Google Scholar]
  12. Baber U, Chandiramani R, Mehta SR, Sartori S, Zhang Z, Claessen BE, Briguori C, Sharma S, Dangas G, Mehran R. Safety and efficacy of the bioabsorbable polymer everolimus‐eluting stent versus durable polymer drug‐eluting stents in high‐risk patients undergoing PCI: TWILIGHT‐SYNERGY. Catheter Cardiovasc Interv. 2021;97:63–71. doi: 10.1002/ccd.28995. [DOI] [PubMed] [Google Scholar]
  13. Baber U, Dangas G, Cohen DJ, Gibson CM, Mehta SR, Angiolillo DJ, Pocock SJ, Krucoff MW, Kastrati A, Ohman EM, Steg PG, Badimon J, Zafar MU, Chandrasekhar J, Sartori S, Aquino M, Mehran R. Ticagrelor with aspirin or alone in high-risk patients after coronary intervention: Rationale and design of the TWILIGHT study. Am Heart J. 2016;182:125–34. doi: 10.1016/j.ahj.2016.09.006. [DOI] [PubMed] [Google Scholar]
  14. Mehran R, Baber U, Steg PG, Ariti C, Weisz G, Witzenbichler B, Henry TD, Kini AS, Stuckey T, Cohen DJ, Berger PB, Iakovou I, Dangas G, Waksman R, Antoniucci D, Sartori S, Krucoff MW, Hermiller JB, Shawl F, Gibson CM, Chieffo A, Alu M, Moliterno DJ, Colombo A, Pocock S. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet. 2013;382:1714–22. doi: 10.1016/S0140-6736(13)61720-1. [DOI] [PubMed] [Google Scholar]
  15. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736–47. doi: 10.1161/CIRCULATIONAHA.110.009449. [DOI] [PubMed] [Google Scholar]
  16. Bovill EG, Terrin ML, Stump DC, Berke AD, Frederick M, Collen D, Feit F, Gore JM, Hillis LD, Lambrew CT, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI), phase II trial. Ann Intern Med. 1991;115:256–65. doi: 10.7326/0003-4819-115-4-256. [DOI] [PubMed] [Google Scholar]
  17. GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329:673–82. doi: 10.1056/NEJM199309023291001. [DOI] [PubMed] [Google Scholar]
  18. Kaatz S, Ahmad D, Spyropoulos A, Schulman S Subcommittee on Control of Anticoagulation. Definition of clinically relevant non‐major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non‐surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13:2119–26. doi: 10.1111/jth.13140. [DOI] [PubMed] [Google Scholar]
  19. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction; Authors/Task Force Members Chairpersons, Thygesen K, Alpert JS, White HD; Biomarker Subcommittee, Jaffe AS, Katus HA, Apple FS, Lindahl B, Morrow DA; ECG Subcommittee, Chaitman BR, Clemmensen PM, Johanson P, Hod H; Imaging Subcommittee, Underwood R, Bax JJ, Bonow JJ, Pinto F, Gibbons RJ; Classification Subcommittee, Fox KA, Atar D, Newby LK, Galvani M, Hamm CW; Intervention Subcommittee, Uretsky BF, Steg PG, Wijns W, Bassand JP, Menasche P, Ravkilde J; Trials & Registries Subcommittee, Ohman EM, Antman EM, Wallentin LC, Armstrong PW, Simoons ML; Trials & Registries Subcommittee, Januzzi JL, Nieminen MS, Gheorghiade M, Filippatos G; Trials & Registries Subcommittee, Luepker RV, Fortmann SP, Rosamond WD, Levy D, Wood D; Trials & Registries Subcommittee, Smith SC, Hu D, Lopez-Sendon JL, Robertson RM, Weaver D, Tendera M, Bove AA, Parkhomenko AN, Vasilieva EJ, Mendis S; ESC Committee for Practice Guidelines (CPG), Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S; Document Reviewers, Morais J, Aguiar C, Almahmeed W, Arnar DO, Barili F, Bloch KD, Bolger AF, Botker HE, Bozkurt B, Bugiardini R, Cannon C, de Lemos J, Eberli FR, Escobar E, Hlatky M, James S, Kern KB, Moliterno DJ, Mueller C, Neskovic AN, Pieske BM, Schulman SP, Storey RF, Taubert KA, Vranckx P, Wagner DR. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581–98. [Google Scholar]
  20. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115:2344–51. doi: 10.1161/CIRCULATIONAHA.106.685313. [DOI] [PubMed] [Google Scholar]
  21. Sorrentino S, Sartori S, Baber U, Claessen BE, Giustino G, Chandrasekhar J, Chandiramani R, Cohen DJ, Henry TD, Guedeney P, Ariti C, Dangas G, Gibson CM, Krucoff MW, Moliterno DJ, Colombo A, Vogel B, Chieffo A, Kini AS, Witzenbichler B, Weisz G, Steg PG, Pocock S, Urban P, Mehran R. Bleeding Risk, Dual Antiplatelet Therapy Cessation, and Adverse Events After Percutaneous Coronary Intervention: The PARIS Registry. Circ Cardiovasc Interv. 2020;13:e008226. doi: 10.1161/CIRCINTERVENTIONS.119.008226. [DOI] [PubMed] [Google Scholar]
  22. Sorrentino S, Baber U, Claessen BE, Camaj A, Vogel B, Sartori S, Guedeney P, Chandrasekhar J, Farhan S, Barman N, Sweeny J, Giustino G, Dangas G, Kini A, Sharma S, Mehran R. Determinants of Significant Out-Of-Hospital Bleeding in Patients Undergoing Percutaneous Coronary Intervention. Thromb Haemost. 2018;118:1997–2005. doi: 10.1055/s-0038-1673687. [DOI] [PubMed] [Google Scholar]
  23. Palmerini T, Sangiorgi D, Valgimigli M, Biondi-Zoccai G, Feres F, Abizaid A, Costa RA, Hong MK, Kim BK, Jang Y, Kim HS, Park KW, Mariani A, Della Riva, Genereux P, Leon MB, Bhatt DL, Bendetto U, Rapezzi C, Stone GW. Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis. J Am Coll Cardiol. 2015;65:1092–102. doi: 10.1016/j.jacc.2014.12.046. [DOI] [PubMed] [Google Scholar]
  24. 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. doi: 10.1001/jama.2019.8145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Vranckx P, Valgimigli M, Jüni P, Hamm C, Steg PG, Heg D, van Es, McFadden EP, Onuma Y, van Meijeren, Chichareon P, Benit E, Möllmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns, 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. doi: 10.1016/S0140-6736(18)31858-0. [DOI] [PubMed] [Google Scholar]
  26. 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. doi: 10.1016/j.jacc.2020.03.011. [DOI] [PubMed] [Google Scholar]
  27. Koo BK, Kang J, Park KW, Rhee TM, Yang HM, Won KB, Rha SW, Bae JW, Lee NH, Hur SH, Yoon J, Park TH, Kim BS, Lim SW, Cho YH, Jeon DW, Kim SH, Han JK, Shin ES, Kim HS HOST-EXAM investigators. Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial. Lancet. 2021;397:2487–96. doi: 10.1016/S0140-6736(21)01063-1. [DOI] [PubMed] [Google Scholar]
  28. Torii S, Jinnouchi H, Sakamoto A, Kutyna M, Cornelissen A, Kuntz S, Guo L, Mori H, Harari E, Paek KH, Fernandez R, Chahal D, Romero ME, Kolodgie FD, Gupta A, Virmani R, Finn AV. Drug-eluting coronary stents: insights from preclinical and pathology studies. Nat Rev Cardiol. 2020;17:37–51. doi: 10.1038/s41569-019-0234-x. [DOI] [PubMed] [Google Scholar]
  29. Baber U, Zafar MU, Dangas G, Escolar G, Angiolillo DJ, Sharma SK, Kini AS, Sartori S, Joyce L, Vogel B, Farhan S, Gurbel P, Gibson CM, Fuster V, Mehran R, Badimon JJ. Ticagrelor With or Without Aspirin After PCI: The TWILIGHT Platelet Substudy. J Am Coll Cardiol. 2020;75:578–86. doi: 10.1016/j.jacc.2019.11.056. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1

Types of drug-eluting stents.

EIJ-D-21-00721_Dangas_SD.pdf (311.3KB, pdf)
Supplementary Table 2

Definitions of study endpoints.

EIJ-D-21-00721_Dangas_SD.pdf (311.3KB, pdf)
Supplementary Table 3

Baseline clinical and procedural characteristics within each stent group.

EIJ-D-21-00721_Dangas_SD.pdf (311.3KB, pdf)
Supplementary Table 4

Outcomes associated with DES types one year after randomisation.

EIJ-D-21-00721_Dangas_SD.pdf (311.3KB, pdf)
Supplementary Figure 1

Study flow diagram.

EIJ-D-21-00721_Dangas_SD.pdf (311.3KB, pdf)

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