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 | Acute Coronary Syndromes | JAMA | JAMA Network
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Visual Abstract. 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.
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.
Figure 1.  Participant Flow in the TICO Randomized Clinical Trial
Participant Flow in the TICO Randomized Clinical Trial

aStudy sites were not required to provide screening logs. Data regarding reasons for ineligibility are not available.

bOutcomes of patients who were lost to follow-up or withdrew consent were included to the point of final contact. Their time-to-event measure was censored at the last contact date.

Figure 2.  Time-to-Event Curves for the Primary Outcome and Landmark Analysis at 3 Months
Time-to-Event Curves for the Primary Outcome and Landmark Analysis at 3 Months

A net adverse clinical event was defined as a composite of major bleeding by the Thrombolysis in Myocardial Infarction criteria or major adverse cardiac and cerebrovascular event. Between 3 and 12 months, the hazard ratio (HR) was 0.41 (95% CI, 0.25-0.68; P = .001). Reported HRs are for the patients with ticagrelor monotherapy after 3-month dual antiplatelet therapy (DAPT). The median observation periods were 365 days (interquartile range, 365-365) for both study groups.

Figure 3.  Subgroup Analyses for the Primary Outcome
Subgroup Analyses for the Primary Outcome

Numbers and percentages shown are number of patients with event/number of patients at risk and incidences at 1 year. NSTEMI indicates non–ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

aP values for interaction were calculated using interaction terms in a Cox proportional hazard model.

bChronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 of body surface area.

cCalculated as weight in kilograms divided by height in meters squared.

Table 1.  Patient, Lesion, and Procedural Characteristics
Patient, Lesion, and Procedural Characteristics
Table 2.  Clinical Outcomes at 1 Year
Clinical Outcomes at 1 Year
1.
Levine  GN, Bates  ER, Bittl  JA,  et al.  2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.   J Am Coll Cardiol. 2016;68(10):1082-1115. doi:10.1016/j.jacc.2016.03.513PubMedGoogle ScholarCrossref
2.
Valgimigli  M, Bueno  H, Byrne  RA,  et al; 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(3):213-260. doi:10.1093/eurheartj/ehx419PubMedGoogle ScholarCrossref
3.
Wiviott  SD, Braunwald  E, McCabe  CH,  et al; TRITON-TIMI 38 Investigators.  Prasugrel versus clopidogrel in patients with acute coronary syndromes.   N Engl J Med. 2007;357(20):2001-2015. doi:10.1056/NEJMoa0706482PubMedGoogle ScholarCrossref
4.
Wallentin  L, Becker  RC, Budaj  A,  et al; PLATO Investigators.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes.   N Engl J Med. 2009;361(11):1045-1057. doi:10.1056/NEJMoa0904327PubMedGoogle ScholarCrossref
5.
Park  DW, Kwon  O, Jang  JS,  et al; TICAKOREA Investigators.  Clinically significant bleeding with ticagrelor versus clopidogrel in Korean patients with acute coronary syndromes intended for invasive management: a randomized clinical trial.   Circulation. 2019;140(23):1865-1877. doi:10.1161/CIRCULATIONAHA.119.041766PubMedGoogle ScholarCrossref
6.
Antman  EM, Wiviott  SD, Murphy  SA,  et al.  Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis.   J Am Coll Cardiol. 2008;51(21):2028-2033. doi:10.1016/j.jacc.2008.04.002PubMedGoogle ScholarCrossref
7.
Becker  RC, Bassand  JP, Budaj  A,  et al.  Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial.   Eur Heart J. 2011;32(23):2933-2944. doi:10.1093/eurheartj/ehr422PubMedGoogle ScholarCrossref
8.
Capodanno  D, Mehran  R, Valgimigli  M,  et al.  Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention.   Nat Rev Cardiol. 2018;15(8):480-496. doi:10.1038/s41569-018-0049-1PubMedGoogle ScholarCrossref
9.
Vranckx  P, Valgimigli  M, Jüni  P,  et al; 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(10151):940-949. doi:10.1016/S0140-6736(18)31858-0PubMedGoogle ScholarCrossref
10.
Mehran  R, Baber  U, Sharma  SK,  et al.  Ticagrelor with or without aspirin in high-risk patients after PCI.   N Engl J Med. 2019;381(21):2032-2042. doi:10.1056/NEJMoa1908419PubMedGoogle ScholarCrossref
11.
Kim  C, Hong  SJ, Shin  DH,  et al.  Randomized evaluation of ticagrelor monotherapy after 3-month dual-antiplatelet therapy in patients with acute coronary syndrome treated with new-generation sirolimus-eluting stents: TICO trial rationale and design.   Am Heart J. 2019;212:45-52. doi:10.1016/j.ahj.2019.02.015PubMedGoogle ScholarCrossref
12.
Mehran  R, Rao  SV, Bhatt  DL,  et al.  Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.   Circulation. 2011;123(23):2736-2747. doi:10.1161/CIRCULATIONAHA.110.009449PubMedGoogle ScholarCrossref
13.
Thygesen  K, Alpert  JS, Jaffe  AS,  et al; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction.  Third universal definition of myocardial infarction.   Circulation. 2012;126(16):2020-2035. doi:10.1161/CIR.0b013e31826e1058PubMedGoogle ScholarCrossref
14.
Cutlip  DE, Windecker  S, Mehran  R,  et al; Academic Research Consortium.  Clinical end points in coronary stent trials: a case for standardized definitions.   Circulation. 2007;115(17):2344-2351. doi:10.1161/CIRCULATIONAHA.106.685313PubMedGoogle ScholarCrossref
15.
Sacco  RL, Kasner  SE, Broderick  JP,  et al; American Heart Association Stroke Council, Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; Council on Peripheral Vascular Disease; Council on Nutrition, Physical Activity and Metabolism.  An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association.   Stroke. 2013;44(7):2064-2089. doi:10.1161/STR.0b013e318296aecaPubMedGoogle ScholarCrossref
16.
Kim  BK, Hong  MK, Shin  DH,  et al; RESET Investigators.  A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).   J Am Coll Cardiol. 2012;60(15):1340-1348. doi:10.1016/j.jacc.2012.06.043PubMedGoogle ScholarCrossref
17.
Kaul  S, Diamond  GA.  Making sense of noninferiority: a clinical and statistical perspective on its application to cardiovascular clinical trials.   Prog Cardiovasc Dis. 2007;49(4):284-299. doi:10.1016/j.pcad.2006.10.001PubMedGoogle ScholarCrossref
18.
Palmerini  T, Benedetto  U, Bacchi-Reggiani  L,  et al.  Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.   Lancet. 2015;385(9985):2371-2382. doi:10.1016/S0140-6736(15)60263-XPubMedGoogle ScholarCrossref
19.
Feres  F, Costa  RA, Abizaid  A,  et al; OPTIMIZE Trial Investigators.  Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.   JAMA. 2013;310(23):2510-2522. doi:10.1001/jama.2013.282183PubMedGoogle Scholar
20.
Hong  SJ, Shin  DH, Kim  JS,  et al; IVUS-XPL Investigators.  6-Month versus 12-month dual-antiplatelet therapy following long everolimus-eluting stent implantation: the IVUS-XPL randomized clinical trial.   JACC Cardiovasc Interv. 2016;9(14):1438-1446. doi:10.1016/j.jcin.2016.04.036PubMedGoogle ScholarCrossref
21.
Hahn  JY, Song  YB, Oh  JH,  et al; SMART-DATE Investigators.  6-Month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial.   Lancet. 2018;391(10127):1274-1284. doi:10.1016/S0140-6736(18)30493-8PubMedGoogle ScholarCrossref
22.
De Luca  G, Damen  SA, Camaro  C,  et al; Collaborators.  Final results of the randomised evaluation of short-term dual antiplatelet therapy in patients with acute coronary syndrome treated with a new-generation stent (REDUCE trial).   EuroIntervention. 2019;15(11):e990-e998. doi:10.4244/EIJ-D-19-00539PubMedGoogle ScholarCrossref
23.
Kedhi  E, Fabris  E, van der Ent  M,  et al.  Six months versus 12 months dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): randomised, multicentre, non-inferiority trial.   BMJ. 2018;363:k3793. doi:10.1136/bmj.k3793PubMedGoogle ScholarCrossref
24.
Watanabe  H, Domei  T, Morimoto  T,  et al; 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(24):2414-2427. doi:10.1001/jama.2019.8145PubMedGoogle ScholarCrossref
25.
Hahn  JY, Song  YB, Oh  JH,  et al; 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(24):2428-2437. doi:10.1001/jama.2019.8146PubMedGoogle ScholarCrossref
26.
Lee  SY, Hong  MK, Shin  DH,  et al.  Association between duration of dual antiplatelet therapy and angiographic multivessel disease on outcomes in patients treated with newer-generation drug-eluting stents.   Circ Cardiovasc Interv. 2016;9(11):e004256. doi:10.1161/CIRCINTERVENTIONS.116.004256PubMedGoogle Scholar
27.
Kandzari  DE, Mauri  L, Koolen  JJ,  et al; BIOFLOW V Investigators.  Ultrathin, bioresorbable polymer sirolimus-eluting stents versus thin, durable polymer everolimus-eluting stents in patients undergoing coronary revascularisation (BIOFLOW V): a randomised trial.   Lancet. 2017;390(10105):1843-1852. doi:10.1016/S0140-6736(17)32249-3PubMedGoogle ScholarCrossref
28.
Iglesias  JF, Muller  O, Heg  D,  et al.  Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial.   Lancet. 2019;394(10205):1243-1253. doi:10.1016/S0140-6736(19)31877-XPubMedGoogle ScholarCrossref
Original Investigation
June 16, 2020

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

Author Affiliations
  • 1Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, South Korea
  • 2Myongji Hospital, Hanyang University College of Medicine, Goyang, South Korea
  • 3Wonkwang University Hospital, Iksan, South Korea
  • 4Kangwon National University School of Medicine, Chuncheon, South Korea
  • 5Dankook University Hospital, Dankook University College of Medicine, Cheonan, South Korea
  • 6National Health Insurance Service Ilsan Hospital, Goyang-City, South Korea
  • 7Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, South Korea
  • 8Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea
  • 9Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
  • 10Department of Preventive Medicine and Biostatistics, Yonsei University College of Medicine, Seoul, South Korea
JAMA. 2020;323(23):2407-2416. doi:10.1001/jama.2020.7580
Visual Abstract. 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.
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.
Key Points

Question  Does switching to ticagrelor monotherapy after 3 months of dual antiplatelet therapy reduce net adverse clinical events (a composite of major bleeding and major adverse cardiac and cerebrovascular events) among patients with acute coronary syndrome treated with drug-eluting stents?

Findings  In this randomized clinical trial that included 3056 patients with acute coronary syndrome, ticagrelor monotherapy after 3 months of dual antiplatelet therapy, compared with ticagrelor-based 12-month dual antiplatelet therapy, significantly reduced net adverse clinical events at 1 year (3.9% vs 5.9%).

Meaning  Among patients with acute coronary syndrome treated with new-generation drug-eluting stents, use of ticagrelor monotherapy after 3 months of dual antiplatelet therapy resulted in a modest but statistically significant reduction in a composite outcome of major bleeding and adverse cardiac and cerebrovascular events at 1 year.

Abstract

Importance  Discontinuing aspirin after short-term dual antiplatelet therapy (DAPT) was evaluated as a bleeding reduction strategy. However, the strategy of ticagrelor monotherapy has not been exclusively evaluated in patients with acute coronary syndromes (ACS).

Objective  To determine whether switching to ticagrelor monotherapy after 3 months of DAPT reduces net adverse clinical events compared with ticagrelor-based 12-month DAPT in patients with ACS treated with drug-eluting stents.

Design, Setting, and Participants  A randomized multicenter trial was conducted in 3056 patients with ACS treated with drug-eluting stents between August 2015 and October 2018 at 38 centers in South Korea. Follow-up was completed in October 2019.

Interventions  Patients were randomized to receive ticagrelor monotherapy (90 mg twice daily) after 3-month DAPT (n = 1527) or ticagrelor-based 12-month DAPT (n = 1529).

Main Outcomes and Measures  The primary outcome was a 1-year net adverse clinical event, defined as a composite of major bleeding and adverse cardiac and cerebrovascular events (death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization). Prespecified secondary outcomes included major bleeding and major adverse cardiac and cerebrovascular events.

Results  Among 3056 patients who were randomized (mean age, 61 years; 628 women [20%]; 36% ST-elevation myocardial infarction), 2978 patients (97.4%) completed the trial. The primary outcome occurred in 59 patients (3.9%) receiving ticagrelor monotherapy after 3-month DAPT and in 89 patients (5.9%) receiving ticagrelor-based 12-month DAPT (absolute difference, −1.98% [95% CI, −3.50% to −0.45%]; hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.92]; P = .01). Of 10 prespecified secondary outcomes, 8 showed no significant difference. Major bleeding occurred in 1.7% of patients with ticagrelor monotherapy after 3-month DAPT and in 3.0% of patients with ticagrelor-based 12-month DAPT (HR, 0.56 [95% CI, 0.34 to 0.91]; P = .02). The incidence of major adverse cardiac and cerebrovascular events was not significantly different between the ticagrelor monotherapy after 3-month DAPT group (2.3%) vs the ticagrelor-based 12-month DAPT group (3.4%) (HR, 0.69 [95% CI, 0.45 to 1.06]; P = .09).

Conclusions and Relevance  Among patients with acute coronary syndromes treated with drug-eluting stents, ticagrelor monotherapy after 3 months of dual antiplatelet therapy, compared with ticagrelor-based 12-month dual antiplatelet therapy, resulted in a modest but statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year. The study population and lower than expected event rates should be considered in interpreting the trial.

Trial Registration  ClinicalTrials.gov Identifier: NCT02494895

Introduction

Quiz Ref IDPatients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) with drug-eluting stents are currently recommended dual antiplatelet therapy (DAPT), consisting of aspirin with a P2Y12 inhibitor for 12 months using a potent antiplatelet agent such as ticagrelor or prasugrel.1-4 However, this strategy increases bleeding risk even in patients with a high thrombotic risk of ACS.5-7 Although aspirin has proven benefits and has become the cornerstone for the antiplatelet therapy in secondary prevention of cardiovascular disease, discontinuing aspirin while maintaining administration of a P2Y12 inhibitor after DAPT was introduced to reduce the risk of bleeding.8 Recent randomized trials also evaluated the aspirin-free strategies with ticagrelor monotherapy.9,10 However, an investigation of ticagrelor monotherapy after short-term DAPT focusing on the patients with ACS including ST-elevation myocardial infarction who underwent PCI with newer-generation drug-eluting stents has not been performed.

Therefore, the trial of Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus-eluting Stent for Acute Coronary Syndrome (TICO) was performed to evaluate whether switching to ticagrelor monotherapy after 3 months of DAPT would reduce net adverse clinical events compared with ticagrelor-based 12-month DAPT among patients with ACS treated with drug-eluting stents.

Methods
Study Design

The trial protocol (Supplement 1) was approved by the institutional review board at each center, and all participants provided written informed consent. The rationale and design have been previously published.11 This study was an investigator-initiated, multicenter, randomized, unblinded trial conducted at 38 centers in South Korea. Study coordination, data management, and site management services were performed at the Cardiovascular Research Center, Seoul, South Korea. The designated trial monitors reviewed the investigational data at appropriate intervals for accuracy and completeness and ensured protocol compliance.11 This trial was performed in accordance with the principles of the Declaration of Helsinki.

Study Population

Quiz Ref IDPatients who underwent successful PCI with ultrathin bioresorbable polymer sirolimus-eluting stents (Orsiro; Biotronik AG) for ACS (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina) were eligible for enrollment. Key exclusion criteria included increased risk of bleeding due to prior hemorrhagic stroke, traumatic brain injury or brain surgery within the past 6 months, internal bleeding within the past 6 weeks, need of oral anticoagulation therapy, and anemia (hemoglobin ≤8 g/dL). The full inclusion and exclusion criteria are listed in eTable 1 in Supplement 2.

Randomization and Study Procedures

After PCI, patients were randomly assigned in a 1:1 ratio to receive ticagrelor monotherapy after 3-month DAPT or ticagrelor-based 12-month DAPT. A web-response permuted-block randomization (mixed blocks of 4 or 6), which was conducted at each participating site, stratified the random assignment according to the presence of diabetes and ST-elevation myocardial infarction. The allocation sequence was computer generated by an external programmer who was not involved in the trial.

If patients were not taking aspirin or ticagrelor at the time of PCI, loading doses of aspirin (300 mg) and ticagrelor (180 mg) were administered. A single aspirin dose (100 mg per day) and 2 ticagrelor doses (90 mg per day) were maintained. After 3 months of DAPT, aspirin was discontinued in the patients who were assigned to receive ticagrelor monotherapy after 3 months of DAPT, and aspirin use was continued in patients who were randomized to receive ticagrelor-based DAPT for 12 months. The concomitant use of other antiplatelet agents or anticoagulants was not allowed. Other medical treatments were left to physician discretion, but guideline-directed medical therapy was strongly recommended.

Outcomes

The primary outcome was a net adverse clinical event, defined as a composite of major bleeding and adverse cardiac and cerebrovascular events, within 12 months following PCI. Major bleeding was defined according to the Thrombolysis in Myocardial Infarction (TIMI) criteria: intracranial bleeding, hemorrhage with a hemoglobin decrease of at least 5 g/dL, or fatal bleeding that caused death within 7 days.12 Major adverse cardiac and cerebrovascular events were defined as death, myocardial infarction, stent thrombosis, stroke, and target-vessel revascularization.

Secondary outcomes were major bleeding and major adverse cardiac and cerebrovascular events.11 Other secondary outcomes were defined as major or minor bleeding, death, myocardial infarction, stent thrombosis, stroke, and target-vessel revascularization. The composite of cardiac death or myocardial infarction, and the composite of cardiac death, myocardial infarction, stent thrombosis, or target-vessel revascularization were also assessed as prespecified secondary outcomes.

Cardiac death was defined as death due to myocardial infarction, cardiac perforation or pericardial tamponade; arrhythmia or conduction abnormality; stroke within 30 days of the procedure or related to the procedure; death due to a procedural complication; or any case of death in which a cardiac cause was not excluded by a clinical event committee.11 Myocardial infarction after hospital discharge was defined as symptoms, electrocardiographic changes, or abnormal imaging findings, combined with a creatine kinase MB fraction above the upper normal limits or a troponin T or troponin I level greater than the 99th percentile of the upper normal limit.13 Stent thrombosis was defined as definite or probable stent thrombosis according to the Academic Research Consortium definition.14 Stroke was defined as an acute cerebrovascular event that caused death, a neurological deficit lasting more than 24 hours, or an acute infarction shown by imaging studies.15 Stroke was further classified as an ischemic or hemorrhagic event. Target-vessel revascularization was defined as a repeat PCI or bypass surgery of the target vessel with either: (1) symptoms of ischemia or a positive stress test and angiographic diameter stenosis of greater than 50%; or (2) angiographic diameter stenosis of greater than 70% without symptoms of ischemia or a positive stress test.11,16 In a post hoc analysis, the Bleeding Academic Research Consortium’s definition of bleeding events was also used (eTable 2 in Supplement 2).12

Suspected adverse events, including bleeding and ischemic events, were reported on the electronic case report form with source documents. Monitoring by the study coordination center and local institutional review board was conducted to search for potential adverse events that were not reported. Adverse events were centrally collected, and any document that could lead to unblinding of treatment assignment was obliterated before submission to the clinical event committee. Outcomes were categorized according to predefined criteria by an independent clinical event committee blinded to the treatment assignments and primary results of the trial.11

Statistical Analysis

Sample size and power calculations were based on a superiority assumption for the primary outcome. Assuming an 18% incidence of net adverse clinical events at 1 year in the patients with ticagrelor-based 12-month DAPT,4,11 a sample size of 3056 was chosen. This sample size provided 90% power to detect a 25% difference (4.5% absolute difference) with a type I error rate of .05 and 10% follow-up loss.11,17 A minimal clinically important difference of 25% was chosen based on previous meta-analyses showing the benefit regarding the major bleeding in the short-term DAPT vs 1-year DAPT (hazard ratio [HR], 0.58 [95% CI, 0.47 to 0.72]),18 but it was chosen as a more conservative difference because ticagrelor monotherapy rather than aspirin monotherapy was given in the experimental group in this study. In November 2017, when 1967 patients (64%) were enrolled and 795 patients (26%) had completed the 1-year follow-up, a discussion among the members of the data and safety monitoring board found that the event rate of the primary outcome was reported to be 6.5% for all patients, which was lower than expected. Recalculation of the sample size, with an expected primary outcome of 9% with a detection of 25% difference, revealed that 6688 patients were needed to provide the original study power. However, considering the rate of enrollment, the steering committee reached a consensus to not change the sample size. In September 2019, after the meeting of the data and safety monitoring board, a consensus was reached to not expand the study duration, despite the event rates being lower than expected, in order to report the results in a timely manner.

The primary analysis was performed to determine whether the patients receiving ticagrelor monotherapy after 3 months of DAPT would be superior to those receiving ticagrelor-based 12 months of DAPT, with respect to the primary outcome. All patients enrolled were analyzed according to their randomization group, and those with missing outcome data were censored at the time of loss to follow-up or withdrawal of consent. Kaplan-Meier estimates were used to determine the cumulative incidences of the primary and secondary outcomes. HRs and 95% CIs were generated using Cox proportional hazards models. To assess the validity of the proportional hazards assumption, the assumption was assessed by log-minus-log-survival function and found to hold. To confirm the assumption of proportionality, time-dependent covariate analysis was used. The time-dependent covariate was not statistically significant, suggesting the proportional hazard assumption was reasonable. Although patients could experience more than 1 component of the composite primary outcome, each patient was assessed until the occurrence of their first event and only once during the analysis.

Because the same treatment was given in both groups during the first 3 months, prespecified 3-month landmark analyses were performed after excluding the patients who experienced adverse events within this period. Post hoc analyses were performed for the patients in the per-protocol population who adhered to the allocated therapy after excluding patients who did not receive the allocated therapy and for the as-treated population considering the actual treatments received. A mixed-effects model was constructed with site as a random effect for the primary outcome in a post hoc analysis. Subgroup analyses, according to the prespecified subgroups (age, sex, diabetes, hypertension, chronic kidney disease, clinical presentation, presence of multivessel disease, total stent length), were performed. The heterogeneity of effects in subgroups was assessed using interaction terms in a Cox proportional hazard model. Because of the potential for type I error due to multiple comparisons, findings for analyses of secondary end points should be interpreted as exploratory. The findings of subgroup analyses should also be interpreted as exploratory because of lack of adjustment for multiple testing of subgroups.

Categorical variables are reported as numbers and percentages, and compared using a χ2 test or Fisher exact test. Continuous variables are reported as mean (SD) or median interquartile range (IQR) values (as appropriate) and compared using a t test or Mann-Whitney test. SAS version 9.2 (SAS Institute Inc) was used for all analyses. All tests were 2-sided, and a P value of less than .05 was considered statistically significant.

Results

Between August 2015 and October 2018, 3056 patients were enrolled; 1527 patients were randomized to receive ticagrelor monotherapy after 3-month DAPT, and 1529 patients were randomized to receive ticagrelor-based 12-month DAPT (Figure 1). Randomization was primarily done within 1 day after PCI (95% on day 0 and 3.7% on day 1 after PCI) (eTable 3 in Supplement 2). In the patients who received ticagrelor monotherapy after 3 months of DAPT, 1339 patients (88%) adhered to the treatment regimen compared with 1321 (86%) patients in the group receiving ticagrelor-based 12-month DAPT, with no significant difference between groups (Figure 1). Details regarding the antiplatelet therapy and reasons for nonadherence are provided in eTable 4 and eTable 5 in Supplement 2. Despite the disallowing of the concomitant use of other antiplatelet agents, clopidogrel or prasugrel was used in the 8.2% of the patients receiving ticagrelor monotherapy after 3-month DAPT and in 8.9% of patients receiving ticagrelor-based 12-month DAPT (P = .49). At the time of the database lock (November 2019), 39 patients died, and clinical follow-up was completed for all except 78 patients (2939/3017; 97.4%) of whom 48 (1.6%) were lost to follow-up and 30 (1.0%) withdrew consent.

Baseline characteristics are provided in Table 1; the mean age was 61 years, 80% of the patients were men, and 27% had diabetes. Most patients (2107 patients [69%]) were admitted via the emergency department. The distribution of ACS among patients was 926 (30%) for unstable angina, 1027 (34%) for non–ST-elevation myocardial infarction, and 1103 (36%) for ST-elevation myocardial infarction. Primary PCI was performed in 1052 patients (34%). Detailed angiographic and procedural characteristics for treated lesions and the uses of medications during the study period are presented in eTable 6 and eTable 7 in Supplement 2; there were no significant differences between the study groups.

The primary outcome of a net adverse clinical event occurred in 59 patients (3.9%) receiving ticagrelor monotherapy after 3-month DAPT and in 89 patients (5.9%) receiving ticagrelor-based 12-month DAPT (absolute difference, −1.98% [95% CI, −3.50% to −0.45%]; HR, 0.66 [95% CI, 0.48 to 0.92]; P = .01) (Figure 2A and Table 2). On prespecified 3-month landmark analyses between 3 and 12 months, a net adverse clinical event occurred in 21 patients (1.4%) receiving ticagrelor monotherapy after 3-month DAPT and in 51 patients (3.5%) receiving ticagrelor-based 12-month DAPT (HR, 0.41 [95% CI, 0.25 to 0.68]; P = .001) (Figure 2B; eTable 8 in Supplement 2).

The secondary outcome of major bleeding occurred in 25 patients (1.7%) receiving ticagrelor monotherapy after 3-month DAPT and in 45 patients (3.0%) receiving ticagrelor-based 12-month DAPT (HR, 0.56 [95% CI, 0.34 to 0.91]; P = .02) (Table 2). Between months 3 and 12, major bleeding occurred in 3 patients (0.2%) receiving ticagrelor monotherapy after 3-month DAPT and in 23 patients (1.6%) receiving ticagrelor-based 12-month DAPT (HR, 0.13 [95% CI, 0.04 to 0.44]; P = .001) (eTable 8 in Supplement 2). Incidences of bleeding events, according to the Bleeding Academic Research Consortium definition, are provided in eTable 9 in Supplement 2. Another secondary outcome of major adverse cardiac and cerebrovascular events occurred in 35 (2.3%) patients receiving ticagrelor monotherapy after 3-month DAPT and in 51 (3.4%) patients receiving ticagrelor-based 12-month DAPT, with no significant difference between the groups (HR, 0.69 [95% CI, 0.45 to 1.06]; P = .09) (Table 2). Between months 3 and 12, the incidence of major adverse cardiac and cerebrovascular events did not significantly differ between the groups (HR, 0.58 [95% CI, 0.33 to 1.04]; P = .07) (eTable 8 in Supplement 2).

There was no significant difference in the occurrence of death between the 2 groups (16 [1.1%] in the group receiving ticagrelor monotherapy after 3-month DAPT vs 23 [1.5%] in the group receiving ticagrelor-based 12-month DAPT; HR, 0.70 [95% CI, 0.37 to 1.32]; P = .27). There was no significant difference in the occurrence of stent thrombosis, which occurred in 6 (0.4%) patients receiving ticagrelor monotherapy after 3-month DAPT and in 4 (0.3%) patients receiving ticagrelor-based 12-month DAPT (HR, 1.51 [95% CI, 0.43 to 5.33]; P = .53). Comparisons between the group receiving ticagrelor monotherapy after 3-month DAPT vs the group receiving ticagrelor-based 12-month DAPT showed no significant differences in the incidence of acute myocardial infarction (6 [0.4%] vs 11 [0.7%]; HR, 0.55 [95% CI, 0.20 to 1.48]; P = .24), stroke (8 [0.5%] vs 11 [0.7%]; HR, 0.73 [95% CI, 0.29 to 1.81]; P = .50), or target-vessel revascularization (8 [0.5%] vs 10 [0.7%]; HR, 0.80 [95% CI, 0.32 to 2.03]; P = .64) (Table 2).

From the post hoc analysis model, with site as a random effect, the results for the primary outcome were consistent with the main prespecified analysis (3.9% in the group receiving ticagrelor monotherapy after 3-month DAPT vs 5.9% in the group receiving ticagrelor-based 12-month DAPT; HR, 0.66 [95% CI, 0.48 to 0.92]; P = .01). Baseline characteristics for the per-protocol population and the as-treated population are presented in eTable 10 and eTable 11 in Supplement 2. As for the primary outcomes, the results were consistent in the per-protocol population (3.6% in the group receiving ticagrelor monotherapy after 3-month DAPT vs 5.7% in the group receiving ticagrelor-based 12-month DAPT; HR, 0.63 [95% CI, 0.43 to 0.90]; P = .01) (eFigure 1A and eTable 12 in Supplement 2), and in the as-treated population (3.6% in the group receiving ticagrelor monotherapy after 3-month DAPT vs 6.1% in the group receiving ticagrelor-based 12-month DAPT; HR, 0.61 [95% CI, 0.43 to 0.86]; P = .005) (eFigure 1B and eTable 12 in Supplement 2). Post hoc analyses of secondary outcomes for the per-protocol population and the as-treated population are presented in eTable 12 in Supplement 2.

A prespecified subgroup analysis showed that ticagrelor monotherapy after 3-month DAPT had a consistent effect on the primary outcome across subgroups except in the subset of patients with multivessel disease (Figure 3). Ticagrelor monotherapy after 3-month DAPT was more favored over ticagrelor-based 12-month DAPT in the subset of the patients without multivessel disease than in those without (P value for interaction = .04). Subgroup analyses for the secondary outcome in post-hoc analyses showed a consistent effect across subgroups (eFigure 2 and eFigure 3 in Supplement).

Discussion

Quiz Ref IDIn this randomized clinical trial of patients with ACS treated with drug-eluting stents, ticagrelor monotherapy after 3-months of DAPT compared with ticagrelor-based DAPT for 12 months resulted in a significant 2% absolute reduction in the composite outcome of 1-year net adverse clinical events, with a significant association with reduced risk of major bleeding and no significant association with risk of major adverse cardiac and cardiovascular events. These findings suggest that ticagrelor monotherapy after short-term DAPT could be an optimal strategy that balances both ischemic and bleeding risks for patients with ACS treated with drug-eluting stents.

Current guidelines recommend 12-month DAPT with potent antiplatelet agents for patients with ACS.1,2 However, the risk of increased bleeding has raised concerns,5-7 and the timepoint to switch to single-antiplatelet therapy and which antiplatelet agent should be stopped are still uncertain. Although previous studies had evaluated short-term DAPT,19,20 these were limited because of the small number of enrolled patients with ACS who had implanted drug-eluting stents that were no longer commercially available. Although 3 recent randomized clinical trials have evaluated the efficacy of short-term DAPT targeting only for ACS,21-23 these studies included substantial proportions of patients (41% to 81%) receiving clopidogrel-based DAPT. Therefore, in the post-clopidogrel and new-generation drug-eluting stent era, the present trial investigated the effectiveness of short-term DAPT followed by ticagrelor monotherapy for patients with the whole spectrum of ACS.

Four randomized trials evaluated stopping aspirin instead of the P2Y12 inhibitor.9,10,24,25 Ticagrelor monotherapy was used in the GLOBAL LEADERS trial and the TWILIGHT trial.9,10 The GLOBAL LEADERS trial found that ticagrelor with aspirin for 1 month followed by ticagrelor alone for 23 months did not reduce the risk of mortality or myocardial infarction 2 years after PCI, compared with 12 months of DAPT followed by 12 months of aspirin alone.9 The TWILIGHT trial had the same experimental strategy as the present trial and found that ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin in high-risk patients who underwent PCI.10 Similar to the results of the present trial, type 3 or 5 bleeding, defined by the Bleeding Academic Research Consortium, was significantly lower in the ticagrelor monotherapy group in the TWILIGHT trial. A higher incidence of bleeding events in the present trial compared with the TWILIGHT trial may be attributed to the events between the index PCI and 3 months, racial differences, and enrollment of the patients with ST-elevation myocardial infarction.5,20 In line with the previous studies, this trial provides confirmatory findings and expands the existing knowledge on the safety and feasibility of an aspirin-free approach and the use of a P2Y12 inhibitor monotherapy strategy for patients with ACS. Quiz Ref IDHowever, this study differs from previous trials by including only patients presenting with ACS. More than two-thirds of the patients were admitted via emergency department, and one-third presented with ST-elevation myocardial infarction requiring primary PCI. Also, this trial differs from the TWILIGHT trial because this trial excluded the patients with a high bleeding risk, whereas the TWILIGHT trial enrolled the patients with a high bleeding risk. Thus, the differences in bleeding events between the groups may have been more easily achieved in the TWILIGHT trial.

There was a significant interaction between the antiplatelet therapy strategy and the presence of multivessel disease for the occurrence of the primary outcome. Although it is known that atherosclerotic burden and procedural complexities might affect the strategies of antiplatelet therapy,26 these relationships have not been well investigated in patients with ACS.

Considering the new-generation drug-eluting stents, thin-strut based bioresorbable polymer sirolimus-eluting stents are expected to reduce thrombogenicity and vascular injury, as well as accelerate endothelialization, leading to the superior clinical outcomes.27,28 The improved clinical performances of stents might have influenced the positive results of the ticagrelor monotherapy after short-term DAPT in the present trial. Quiz Ref IDBecause this study was performed exclusively in patients who received these ultrathin sirolimus-eluting stents, extrapolation of the results to other drug-eluting stents requires caution.

Limitations

This study has several limitations. First, study power was calculated by estimating the occurrence of net adverse clinical events, the composite outcome. Comparisons of the occurrence of each component, particularly major adverse cardiac and cerebrovascular events, could be underpowered. Second, this study was an open-label trial and not placebo-controlled, and drug adherence was not monitored. However, clinical outcomes were assessed by members of an independent clinical event committee, and statistical analyses were performed by independent statisticians. Third, although the primary outcome met the superiority assumption, the lower than anticipated event rate of the primary outcome led to a lower than expected power. Fourth, patients at high risk of bleeding, which generally account for approximately 40% of patients undergoing PCI in a real-world setting, were excluded. Fifth, randomization was performed after the index PCI, not at 3 months after PCI. However, the superiority comparison was initially designed with an estimated event rate including the first 3 months after PCI. Furthermore, prespecified 3-month landmark analyses showed results that were consistent with the main results. Sixth, this study was conducted only in South Korea. Caution is needed in extrapolating these results outside of South Korea.

Conclusions

Among patients with ACS treated with drug-eluting stents, ticagrelor monotherapy after 3-month DAPT, compared with ticagrelor-based 12-month DAPT, resulted in a modest but statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year. The study population and lower than expected event rates should be considered in interpreting the trial.

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Article Information

Corresponding Author: Yangsoo Jang, MD, PhD, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, South Korea (jangys1212@yuhs.ac).

Accepted for Publication: April 22, 2020.

Author Contributions: Dr Jang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs B.-K. Kim and S.-J. Hong contributed equally to this work.

Concept and design: B.-K. Kim, S.-J. Hong, Y.-H. Cho, S. Cho, Jeon, D.-K. Cho, B.-K. Hong, Ahn, Shin, Nam, J.-S. Kim, Choi, M.-K. Hong, Jang.

Acquisition, analysis, or interpretation of data: B.-K. Kim, S.-J. Hong, Y.-H. Cho, Yun, Y.-H. Kim, Suh, J.Y. Cho, Her, S. Cho, Jeon, Yoo, D.-K. Cho, B.-K. Hong, Kwon, Shin, Nam, J.-S. Kim, Ko, Choi, M.-K. Hong, Jang.

Drafting of the manuscript: B.-K. Kim, S.-J. Hong, Yun, Y.-H. Kim, Suh, J.Y. Cho, Jeon, D.-K. Cho, B.-K. Hong, Kwon, J.-S. Kim, M.-K. Hong, Jang.

Critical revision of the manuscript for important intellectual content: B.-K. Kim, S.-J. Hong, Y.-H. Cho, Suh, Her, S. Cho, Jeon, Yoo, Ahn, Shin, Nam, J.-S. Kim, Ko, Choi, M.-K. Hong, Jang.

Statistical analysis: B.-K. Kim, S.-J. Hong, Suh, Her, Jeon, Shin, Nam, J.-S. Kim, Jang.

Obtained funding: Jeon, Jang.

Administrative, technical, or material support: B.-K. Kim, S.-J. Hong, Yun, Y.-H. Kim, J.Y. Cho, Her, S. Cho, Jeon, D.-K. Cho, Kwon, Ahn, Shin, J.-S. Kim, Choi, M.-K. Hong, Jang.

Supervision: B.-K. Kim, S. Cho, Jeon, D.-K. Cho, B.-K. Hong, Kwon, J.-S. Kim, Choi, M.-K. Hong, Jang.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by the Cardiovascular Research Center, Seoul, South Korea and funded by Biotronik (Bülach, Switzerland).

Role of the Funder/Sponsor: Biotronik had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The TICO Investigators: Yangsoo Jang, MD, Yonsei University, Severance Hospital, Seoul; Bum-Kee Hong, MD, Yonsei University, Gangnam Severance Hospital, Seoul; Seung-Hwan Lee, Wonju Christian Hospital, Wonju; Myung-Ho Yoon, Ajou University Hospital, Suwon; Jin-Bae Lee, Daegu Catholic University Medical Center, Daegu; Jung-Hee Lee, Yeungnam University Medical Center, Daegu; Woong Cheol Kang, Gachon Gil University Hospital, Incheon; Sungsoo Cho, Dankook University Hospital, Cheonan; Kyeong Ho Yun, MD, PhD, Wonkwang University Hospital, Iksan; Ki-Hwan Kwon, Ewha Womans University Mokdong Hospital, Seoul; Sang-Yong Yoo, MD, PhD, GangNeung Asan Hospital, Gangneung; Sang-Ho Park, Soonchunhyang University Hospital Cheonan, Cheonan; Jang-Hwan Bae, Chungbuk National University Hospital, Chungbuk; Jong-Pil Park, Presbyterian Medical Center, Jeonju; Doo-Il Kim, Inje University Haeundae Paik Hospital, Busan; Jung-Ho Heo, Kosin University Gospel Hospital, Busan; Yon-Hyeong Cho, Myongji Hospital, Hanyang University, Goyang; Woong-Kil Choi, Konkuk University Chungju Hospital, Chungju; Jin-Man Cho, Kyung Hee University Gandong Hospital, Gangdong; Hyun-Hee Choi, Hallym University Chuncheon Scared Hospital, Chuncheon; Yong Hoon Kim, Kangwon National University School of Medicine, Chuncheon; Seung-Ki Yoo, Seoul Eulji Hospital, Seoul; Kee-Seok Kim, Jeju National University Hostpial, Jeju; Yoon-Kyoung Cho, Keimyung University Dongsan Hospital, Daegu; Kook-Jin Chun, Pusan National University Yangsan Hospital, Yangsan; Moo-Hyun Kim, Dong-A University Hospital, Busan; Dong Woon Jeon, National Health Insurance Service Ilsan Hospital, Goyang; Eui Im, Yonsei University Yongin Severance Hospital, Yongin; Jung-Rae Cho, Hallym University Kangnam Sacred Heart Hospital, Seoul; Gwang-Soo Cha, Pusan National University Hospital, Busan; Tae-Hyun Yang, Inje University Busan Paik Hospital, Busan; Seung-Yul Lee, Wonkwang University Sanbon Hospital, Gunpo; Won Kim, Kyung Hee University Hospital, Seoul; Woo-Jung Park, Hallym University Sacred Heart Hospital, Anyang; Sang-Wook Kim, Chung-Ang University Hospital, Seoul; Hee-Yul Kim, St Mary's Hospital, The Catholic University, Bucheon; Woo-Jung Cheon, Samgsung Changwon Hospital, Changwon; Sung-Woo Kwon, Inha University Hospital, Incheon.

Data Sharing Statement: See Supplement 3.

References
1.
Levine  GN, Bates  ER, Bittl  JA,  et al.  2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.   J Am Coll Cardiol. 2016;68(10):1082-1115. doi:10.1016/j.jacc.2016.03.513PubMedGoogle ScholarCrossref
2.
Valgimigli  M, Bueno  H, Byrne  RA,  et al; 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(3):213-260. doi:10.1093/eurheartj/ehx419PubMedGoogle ScholarCrossref
3.
Wiviott  SD, Braunwald  E, McCabe  CH,  et al; TRITON-TIMI 38 Investigators.  Prasugrel versus clopidogrel in patients with acute coronary syndromes.   N Engl J Med. 2007;357(20):2001-2015. doi:10.1056/NEJMoa0706482PubMedGoogle ScholarCrossref
4.
Wallentin  L, Becker  RC, Budaj  A,  et al; PLATO Investigators.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes.   N Engl J Med. 2009;361(11):1045-1057. doi:10.1056/NEJMoa0904327PubMedGoogle ScholarCrossref
5.
Park  DW, Kwon  O, Jang  JS,  et al; TICAKOREA Investigators.  Clinically significant bleeding with ticagrelor versus clopidogrel in Korean patients with acute coronary syndromes intended for invasive management: a randomized clinical trial.   Circulation. 2019;140(23):1865-1877. doi:10.1161/CIRCULATIONAHA.119.041766PubMedGoogle ScholarCrossref
6.
Antman  EM, Wiviott  SD, Murphy  SA,  et al.  Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis.   J Am Coll Cardiol. 2008;51(21):2028-2033. doi:10.1016/j.jacc.2008.04.002PubMedGoogle ScholarCrossref
7.
Becker  RC, Bassand  JP, Budaj  A,  et al.  Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial.   Eur Heart J. 2011;32(23):2933-2944. doi:10.1093/eurheartj/ehr422PubMedGoogle ScholarCrossref
8.
Capodanno  D, Mehran  R, Valgimigli  M,  et al.  Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention.   Nat Rev Cardiol. 2018;15(8):480-496. doi:10.1038/s41569-018-0049-1PubMedGoogle ScholarCrossref
9.
Vranckx  P, Valgimigli  M, Jüni  P,  et al; 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(10151):940-949. doi:10.1016/S0140-6736(18)31858-0PubMedGoogle ScholarCrossref
10.
Mehran  R, Baber  U, Sharma  SK,  et al.  Ticagrelor with or without aspirin in high-risk patients after PCI.   N Engl J Med. 2019;381(21):2032-2042. doi:10.1056/NEJMoa1908419PubMedGoogle ScholarCrossref
11.
Kim  C, Hong  SJ, Shin  DH,  et al.  Randomized evaluation of ticagrelor monotherapy after 3-month dual-antiplatelet therapy in patients with acute coronary syndrome treated with new-generation sirolimus-eluting stents: TICO trial rationale and design.   Am Heart J. 2019;212:45-52. doi:10.1016/j.ahj.2019.02.015PubMedGoogle ScholarCrossref
12.
Mehran  R, Rao  SV, Bhatt  DL,  et al.  Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.   Circulation. 2011;123(23):2736-2747. doi:10.1161/CIRCULATIONAHA.110.009449PubMedGoogle ScholarCrossref
13.
Thygesen  K, Alpert  JS, Jaffe  AS,  et al; Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction.  Third universal definition of myocardial infarction.   Circulation. 2012;126(16):2020-2035. doi:10.1161/CIR.0b013e31826e1058PubMedGoogle ScholarCrossref
14.
Cutlip  DE, Windecker  S, Mehran  R,  et al; Academic Research Consortium.  Clinical end points in coronary stent trials: a case for standardized definitions.   Circulation. 2007;115(17):2344-2351. doi:10.1161/CIRCULATIONAHA.106.685313PubMedGoogle ScholarCrossref
15.
Sacco  RL, Kasner  SE, Broderick  JP,  et al; American Heart Association Stroke Council, Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; Council on Peripheral Vascular Disease; Council on Nutrition, Physical Activity and Metabolism.  An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association.   Stroke. 2013;44(7):2064-2089. doi:10.1161/STR.0b013e318296aecaPubMedGoogle ScholarCrossref
16.
Kim  BK, Hong  MK, Shin  DH,  et al; RESET Investigators.  A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation).   J Am Coll Cardiol. 2012;60(15):1340-1348. doi:10.1016/j.jacc.2012.06.043PubMedGoogle ScholarCrossref
17.
Kaul  S, Diamond  GA.  Making sense of noninferiority: a clinical and statistical perspective on its application to cardiovascular clinical trials.   Prog Cardiovasc Dis. 2007;49(4):284-299. doi:10.1016/j.pcad.2006.10.001PubMedGoogle ScholarCrossref
18.
Palmerini  T, Benedetto  U, Bacchi-Reggiani  L,  et al.  Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials.   Lancet. 2015;385(9985):2371-2382. doi:10.1016/S0140-6736(15)60263-XPubMedGoogle ScholarCrossref
19.
Feres  F, Costa  RA, Abizaid  A,  et al; OPTIMIZE Trial Investigators.  Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial.   JAMA. 2013;310(23):2510-2522. doi:10.1001/jama.2013.282183PubMedGoogle Scholar
20.
Hong  SJ, Shin  DH, Kim  JS,  et al; IVUS-XPL Investigators.  6-Month versus 12-month dual-antiplatelet therapy following long everolimus-eluting stent implantation: the IVUS-XPL randomized clinical trial.   JACC Cardiovasc Interv. 2016;9(14):1438-1446. doi:10.1016/j.jcin.2016.04.036PubMedGoogle ScholarCrossref
21.
Hahn  JY, Song  YB, Oh  JH,  et al; SMART-DATE Investigators.  6-Month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial.   Lancet. 2018;391(10127):1274-1284. doi:10.1016/S0140-6736(18)30493-8PubMedGoogle ScholarCrossref
22.
De Luca  G, Damen  SA, Camaro  C,  et al; Collaborators.  Final results of the randomised evaluation of short-term dual antiplatelet therapy in patients with acute coronary syndrome treated with a new-generation stent (REDUCE trial).   EuroIntervention. 2019;15(11):e990-e998. doi:10.4244/EIJ-D-19-00539PubMedGoogle ScholarCrossref
23.
Kedhi  E, Fabris  E, van der Ent  M,  et al.  Six months versus 12 months dual antiplatelet therapy after drug-eluting stent implantation in ST-elevation myocardial infarction (DAPT-STEMI): randomised, multicentre, non-inferiority trial.   BMJ. 2018;363:k3793. doi:10.1136/bmj.k3793PubMedGoogle ScholarCrossref
24.
Watanabe  H, Domei  T, Morimoto  T,  et al; 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(24):2414-2427. doi:10.1001/jama.2019.8145PubMedGoogle ScholarCrossref
25.
Hahn  JY, Song  YB, Oh  JH,  et al; 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(24):2428-2437. doi:10.1001/jama.2019.8146PubMedGoogle ScholarCrossref
26.
Lee  SY, Hong  MK, Shin  DH,  et al.  Association between duration of dual antiplatelet therapy and angiographic multivessel disease on outcomes in patients treated with newer-generation drug-eluting stents.   Circ Cardiovasc Interv. 2016;9(11):e004256. doi:10.1161/CIRCINTERVENTIONS.116.004256PubMedGoogle Scholar
27.
Kandzari  DE, Mauri  L, Koolen  JJ,  et al; BIOFLOW V Investigators.  Ultrathin, bioresorbable polymer sirolimus-eluting stents versus thin, durable polymer everolimus-eluting stents in patients undergoing coronary revascularisation (BIOFLOW V): a randomised trial.   Lancet. 2017;390(10105):1843-1852. doi:10.1016/S0140-6736(17)32249-3PubMedGoogle ScholarCrossref
28.
Iglesias  JF, Muller  O, Heg  D,  et al.  Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial.   Lancet. 2019;394(10205):1243-1253. doi:10.1016/S0140-6736(19)31877-XPubMedGoogle ScholarCrossref
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