Safety and Efficacy of 1-Month Dual Antiplatelet Therapy (Ticagrelor + Aspirin) Followed by 23-Month Ticagrelor Monotherapy in Patients Undergoing Staged Percutaneous Coronary Intervention (A Sub-Study from GLOBAL LEADERS)

Hideyuki Kawashima, MDa,b, Mariusz Tomaniak, MDc, Masafumi Ono, MDa,b, Rutao Wang, MDb,d, Hironori Hara, MDa, Chao Gao, MDb,d, Kuniaki Takahashi, MDa, Faisal Sharif, MD, PhDb, Attila Thury, MD, PhDe, Harry Suryapranata, MD, PhDd, Simon Walsh, MDf, James Cotton, MDg, Didier Carrie, MD, Phh, Manel Sabate, MDi, Clemens Steinwender, MD, PhDj, Gregor Leibundgut, MDk, Joanna Wykrzykowska, MD, PhDa, Robbert J. de Winter, MD, PhDa, Scot Garg, MD, PhDl, Christian Hamm, MDm, Philippe Gabriel Steg, MDn,o, Peter J€uni, MDp, Pascal Vranckx, MD, PhDq, Marco Valgimigli, MD, PhDr, Stephan Windecker, MDr, Yoshinobu Onuma, MD, PhDb, and Patrick W. Serruys, MD, PhDb,s,*

Abstract

Patients undergoing staged percutaneous coronary intervention (SPCI) are exposed to extended duration of antiplatelet therapy, and a novel aspirin-free antiplatelet regimen after SPCI should be specifically evaluated among these patients. This is a prespecified substudy of the GLOBAL LEADERS which is a randomized, open-label trial, comparing an experimental regimen of 1-month dual antiplatelet therapy (DAPT; ticagrelor and aspirin) followed by 23-month ticagrelor monotherapy to a reference regimen of 12-month DAPT followed by 12month aspirin monotherapy. Patients were stratified according to whether or not SPCI was performed. The impact of the timing of SPCI on clinical outcomes was also investigated. Of 15,968 randomized patients, 1,651 patients underwent SPCI within 3 months. These patients with SPCI had a significantly higher risk of bleeding and ischemic endpoints than those without SPCI. In patients undergoing SPCI, the primary endpoint (composite of all-cause death or new Q-wave myocardial infarction at 2 years) and secondary safety endpoint (Bleeding Academic Research Consortium [BARC]-defined bleeding 3 or 5) were similar in the 2 regimens. However, in patients presenting with acute coronary syndrome (ACS), the experimental regimen reduced a risk of BARC 3 or 5 bleeding (1.8% vs 4.5%; HR 0.387; 95% CI 0.179 to 0.836; p = 0.016). In patients undergoing SPCI later than 10 days after index procedure, this risk reduction was still prominent (0.8% vs 2.3%; HR 0.321; 95% CI 0.116 to 0.891; p = 0.029). In conclusion, patients undergoing SPCI are at high risk and may need special attention from clinicians. In ACS patients undergoing SPCI, a novel aspirin-free antiplatelet regimen appears to be associated with a lower bleeding risk than with standard DAPT.

Introduction

Dual antiplatelet therapy (DAPT) reduces the risk of stent-related and spontaneous recurrent ischemic events in patients undergoing percutaneous coronary intervention (PCI).1 Currently, the potency and duration of DAPT after PCI are primarily based on clinical presentation and the estimated bleeding risk.2,3 An abbreviated DAPT regimen followed by P2Y12-receptor-antagonist monotherapy could favorably affect the balance between bleeding risks and ischemic benefits.4 Ticagrelor is a reversible and direct-acting oral antagonist of the P2Y12 receptor providing faster, greater, and more consistent platelet inhibition than clopidogrel.5 Up to one tenth of patients enrolled in PCI trials require more than one procedure to complete an intended percutaneous revascularization strategy due to multivessel coronary disease.6,7 It would be ideal, both from patient and societal (health care economic) perspectives, to treat all lesions requiring intervention in a single session. However, there are legitimate clinical and nonclinical reasons that may justify a staged procedure, the timing of which could range from 1 to 12 weeks.8,9 Extension of the time delay between the index and staged procedure would prolong the period of DAPT if a prespecified duration was imposed by a trial protocol or guidelines following the final staged procedure. The latest European and American guidelines on DAPT regimen post PCI made no specific recommendation on staged procedures, and therefore optimal antiplatelet regimens after staged procedures have not yet been specifically evaluated.2,3 Moreover, optimal timing of staged procedure especially in patients with acute coronary syndrome (ACS) has not yet been determined. The aims of the current substudy of the GLOBAL LEADERS trial are (1) to compare the clinical outcomes of patients with staged percutaneous coronary intervention (SPCI) and those without SPCI, (2) to compare a novel aspirin-free antiplatelet regimen to standard DAPT regimen in patients undergoing staged procedures, and (3) to investigate the impact of the timing of staged procedure on clinical outcomes in ACS patients.

Methods

This study is a prespecified substudy of the GLOBAL LEADERS trial, a multicenter, prospective, open-label, allcomers randomized controlled trial (NCT01813435).10 Details of the study design and protocol have been reported elsewhere.10 In brief, the trial randomly assigned patients before their index PCI to either (1) the experimental regimen with 1-month DAPT (aspirin and ticagrelor) followed by 23-month ticagrelor monotherapy, or (2) the reference regimen with 12-month DAPT (clopidogrel for chronic coronary syndrome [CCS] or ticagrelor for ACS) followed by 12-month aspirin monotherapy. Patients prescribed oral anticoagulation were excluded. All types of anatomic lesions (e.g., saphenous vein grafts, chronic total occlusions, and in-stent restenosis) were included and treated by default with Biolimus A9-eluting stents, (BioMatrix, Biosensors, Europe) the use of which was unrestricted in number, length, and diameter. The trial was approved by the institutional review board at each center and followed the ethical principles of the Declaration of Helsinki. All the patients gave written informed consent prior to participation in the trial.
SPCI was defined as an intervention planned at the time of the index study procedure, according to the protocol of the GLOBAL LEADERS trial (Figure 1). Execution of SPCI was determined at the discretion of each operator. When SPCI were inevitable for medical or logistic reasons, the reason was documented in the electronic case report form (eCRF) and patient file. In the “index procedure” form of the eCRF, the investigator indicated which lesion would be treated during the SPCI. The investigator also completed an “SPCI” form. SPCI had to be performed within 3 months of the start of the index procedure, and the patient had to receive the same type of study stent (Biolimus A9-eluting stents) and bivalirudin. Timing of SPCI after index procedure was recorded in the eCRF. When an SPCI occurred outside the time window of 3 months after the index procedure, the procedure was considered to be a reintervention and reported as a revascularization event. SPCI performed in the experimental regimen arm required that the 1-month treatment period with aspirin (and thus DAPT) was restarted after the staged procedure. SPCI in the reference regimen arm required that the 12-month DAPT time clock re-started at the time of the final staged procedure (Figure 1). Patients were followed-up after hospital discharge for up to 2 years after the index procedure. This included 6 clinic visits (at 1 month, 3 months, 6 months, 1 year, 1.5 years, and 2 years after the index PCI) to obtain information regarding cardiovascular drug use, hospitalizations and serious adverse events (SAE). An assessment of the cardiovascular drug use and any SAE were recorded during clinical follow-up visits.
The primary endpoint was the composite of all-cause death or new Q-wave myocardial infarction (MI) at 2 years. Details of the primary endpoints were reported elsewhere.10 The key secondary safety endpoint was bleeding according to Bleeding Academic Research Consortium (BARC) criteria 3 or 5 up to 2 years. Other secondary endpoints included individual components of the primary endpoint (all-cause death and non-fatal new Q-wave MI), any stroke (ischemic, hemorrhagic, or undetermined), any MI (periprocedural or spontaneous MI), any revascularization (repeated PCI or coronary artery bypass graft [CABG] surgery in target or nontarget vessel), and definite stent thrombosis. In addition, patient-oriented composite endpoint (POCE) and net adverse clinical endpoint (NACE) were evaluated at 2 years according to the Academic Research Consortium (ARC)-2 definition.11,12 POCE is defined as the composite of allcause death, any stroke, any MI, and any revascularization. NACE is defined as the composite of POCE and BARC 3 or 5 bleeding. Composite endpoints were analyzed hierarchically. Individual components of the composite endpoints as well as definite stent thrombosis according to ARC definition,13 were reported nonhierarchically.
Continuous variables were reported as mean § standard deviations and were compared using Student’s t tests or Mann-Whitney U test, respectively. Categorical variables were reported as percentages and numbers and are compared using Chi-square or Fisher’s exact test as appropriate. All analyses were performed according to intention-to-treat principle. The cumulative incidence of clinical events up to 2 years was calculated using the Kaplan-Meier method and compared using the log-rank test. Hazard ratio (HR) with 95% confidence interval (CI) is estimated using a Cox proportional regression model. The treatment effect of the experimental regimen versus the reference regimen between the 2 arms was estimated using a Cox regression model. In addition, a prespecified subgroup analysis according to clinical presentation (CCS or ACS) was performed, since P2Y12 inhibitors in the reference regimen were different according to clinical presentation.10 All tests were 2sided and a p value of <0.05 was considered to be statistically significant. No adjustment for multiple testing was performed in view of the post-hoc nature of the analysis.14 All data were processed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA) and R version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

The GLOBAL LEADERS trial randomized 15,968 patients from 130 hospitals in 18 countries between July 2013 and November 2015.15 The flow chart of the present study is shown in Online Figure 1. After randomization, 1,651 patients received SPCI according to the trial protocol. Of these, 847 patients were assigned to the experimental regimen, and 804 patients were assigned in the reference regimen.
Baseline patient and procedural characteristics in patients with SPCI and non-SPCI are shown in Table 1.
Multivessel treatment and bifurcation or trifurcation treatment were more frequently observed in the SPCI group compared with in the non-SPCI group (84.9% vs 15.3%; p < 0.001 and 27.6% vs 14.4%; p < 0.001, respectively). The Kaplan-Meier curves of clinical outcomes at 2 years in patients with SPCI and non-SPCI are shown in Figure 2. After adjusting the confounding factors, the risks of allcause death (HR 1.437; 95% CI 1.020 to 2.025; p = 0.038), POCE (HR 1.388; 95% CI 1.186 to 1.625; p < 0.001), any revascularization (HR 1.515; 95% CI 1.263 to 1.817; p < 0.001), BARC 2, 3, or 5 bleeding (HR 1.261; 95% CI 1.006 to 1.581; p = 0.044), and NACE (HR 1.365; 95% CI 1.174 to 1.588; p < 0.001) were significantly higher in patients with SPCI than in those without SPCI (Online Table 1). Baseline patient and procedural characteristics at index procedure in patients undergoing SPCI according to the allocated antiplatelet regimen are shown in Table 2. There was no significant difference between the 2 groups. In patients undergoing SPCI, the Kaplan-Meier curves of 2-year clinical outcomes according to the randomized antiplatelet regimen are presented in Figure 3. At 2 years, the risks of the primary endpoint and key secondary safety endpoint were similar between the 2 arms (4.7% vs 4.7%; HR 0.922; 95% CI 0.586 to 1.450; p = 0.725 and 2.4% vs 3.4%; HR 0.700; 95% CI 0.392 to 1.247; p = 0.226, respectively), as were the risk of all other bleeding and ischemic endpoints.
In patients undergoing SPCI, irrespective of clinical presentation (ACS: Figure 4A or CCS: Figure 4B), there was no significant difference in the primary endpoint at 2 years between the 2 arms. Baseline patient characteristics in ACS patients undergoing SPCI are shown in Online Table 2, and there was no significant difference between the 2 arms. The risk of NACE was significantly lower in patients allocated to the experimental regimen than the reference regimen (15.0% vs 20.4%; HR 0.707; 95% CI 0.526 to 0.951; p = 0.022), which was mainly driven by a lower frequency of BARC 3 or 5 bleeding in the experimental regimen (1.8% vs 4.5%; HR 0.387; 95% CI 0.179 to 0.836; p = 0.016). The risk of BARC 2, 3, or 5 bleeding was also lower in the experimental regimen compared with the reference regimen (5.7% vs 11.2%; HR 0.496; 95% CI 0.317 to 0.776; p = 0.002; Figure 4A).

Discussions

The main findings of this study can be summarized as follows:
1. The risks of all-cause death, POCE, any revascularization, BARC 2, 3, or 5 bleeding, and NACE were higher in patients with SPCI than in those without SPCI.
2. Overall, the risks of the composite of all-cause death ornew Q-wave MI and BARC 3 or 5 bleeding in patients undergoing SPCI were similar between the experimental regimen and reference regimen, as were the risks of all other bleeding and ischemic events. When stratified according to clinical presentation, in ACS patients undergoing SPCI, the experimental regimen was significantly associated with lower risks of BARC 3 or 5 and BARC 2, 3, or 5 bleedings compared with the reference regimen.
3. In ACS patients undergoing late SPCI (>10 days) after index procedure, the experimental regimen was associated with reduced risks of BARC 3 or 5 and BARC 2, 3, or 5 bleedings and POCE, whereas in patients undergoing early SPCI (≤10 days), there was no significant difference in bleeding and ischemic events between the 2 regimens.
Our analysis demonstrated that patients with SPCI has a higher risk of 2-year bleeding and ischemic events than those without SPCI. In patients with SPCI, ACS and multivessel treatment and bifurcation or trifurcation treatment during index procedure were more common compared with in those without SPCI, and this high frequency of PCI in more complex situation could result in a higher risk of ischemic events. In the latest European and American guidelines, there is no specific recommendation on antiplatelet regimen of SPCI.2,3 Given the association between the extent and complexity of coronary artery disease and subsequent high rates of adverse events,6 the need to identify and provide patients at high risk of bleeding and ischemic events with optimal treatment is of paramount importance.
At variance with our results, in the randomized EXCEL trial which enrolled patients with unprotected left main coronary artery disease, SPCI (77 patients), compared with single procedure, was associated with a comparable rate of 3year all-cause death, stroke, or MI (10.5% vs 15.4%; logrank p = 0.28) and a lower rate of all-cause death (1.3% vs 8.4%; log-rank p = 0.03), despite the higher anatomic and procedural complexity (anatomical SYNTAS score: SPCI 32.9 § 9.3 vs single procedure 26.3 § 8.5; p < 0.001).7 In the GLOBAL LEADERS trial, only 0.4% (62 patients) underwent left main intervention. Our results could therefore be applied to the general all-comer PCI population, but not to the population undergoing complex left main PCI.
In the high-risk population who underwent SPCI, the risks of bleeding events were overall not significantly different between the experimental regimen and reference regimen. However, in ACS patients undergoing SPCI, the frequency of bleeding events was significantly lower with the experimental regimen than with the reference regimen. According to the protocol of the GLOBAL LEADERS trial, the duration of randomly assigned DAPT was reset at the final staged procedure.10 Therefore, irrespective of its timing, SPCI extended the duration of DAPT in the both arms (Figure 1). Several studies reported that long-term DAPT after placement of a drug-eluting stent was associated with an increased risk of bleeding events compared with short-term DAPT.1,16 Tomaniak et al17 have demonstrated that in ACS patients between 1 and 12 months after index procedure, aspirin was associated with an increased bleeding risk and appeared not to add to the benefit of ticagrelor in ischemic events. Recently, the randomized TICO trial also showed that exclusively in ACS patients, ticagrelor monotherapy after 3 months of dual antiplatelet therapy, compared with ticagrelor-based 12-month DAPT, resulted in a statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year.18
The present study suggested that in ACS patients undergoing SPCI, ticagrelor monotherapy after 1-month DAPT, compared with 12-month DAPT regimen followed by 12-month aspirin monotherapy, might provide a clinical benefit up to 2 years through a risk reduction of bleeding events, and importantly, this antibleeding safety was achieved without a trade-off in an increased risk of ischemic events.
To date, there is a lack of evidence regarding the optimal timing of the staged procedures and the optimal antiplatelet regimen. In ACS patients, SPCI was scheduled most frequently within 10 days after index procedure (Figure 1). In ACS patients undergoing late SPCI (>10 days) after index procedure, the experimental regimen demonstrated reduced risks of 2-year bleeding and ischemic events.
The present study has several limitations. Although planned in the design paper of the GLOBAL LEADERS trial, the study is a post hoc analysis of a neutral randomized controlled study. Inherent subgroup analysis limitations, including the risk of multiple testing, cannot be excluded. Therefore, our findings should be considered as strictly hypothesis generating. Further, deaths from any cause were ascertained without adjudication,19 and all secondary clinical endpoints were site-reported; the trial did not have a central clinical adjudication committee for SAEs due to limited financial resources. However, 7 onsite monitoring visits were performed in each participating center, and 20% of the reported events were checked according to the source documents. In addition, the rate of site reported BARC 3 bleeding in the GLOBAL LEADERS trial and the rate of adjudicated BARC 3 bleeding in the GLOBAL LEADERS adjudication substudy were similar.20,21 This indicates that any serious issue of reclassification is unlikely.
In conclusion, patients undergoing SPCI are at high risk and may need special attention from clinicians. In ACS patients undergoing SPCI, 1-month DAPT followed by 23month ticagrelor monotherapy might be associated with a reduced bleeding rate without an increased risk of ischemic events.

References

1. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, Normand SL, Braunwald E, Wiviott SD, Cohen DJ, Holmes DR Jr., Krucoff MW, Hermiller J, Dauerman HL, Simon DI, Kandzari DE, Garratt KN, Lee DP, Pow TK, Ver Lee P, Rinaldi MJ, Massaro JM, Investigators DS. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155–2166.
2. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, Montalescot G, Neumann FJ, Petricevic M, Roffi M, Steg PG, Windecker S, Zamorano JL, Levine GN. Group ESCSD. Guidelines ESCCfP. Societies ESCNC. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213–260.
3. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O’Gara PT, Sabatine MS, Smith PK, Smith SC Jr.. 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;68:1082–1115.
4. Gargiulo G, Windecker S, Vranckx P, Gibson CM, Mehran R, Valgimigli M. A critical appraisal of aspirin in secondary prevention: Is less more? Circulation 2016;134:1881–1906.
5. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Investigators P, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057.
6. Stefanini GG, Serruys PW, Silber S, Khattab AA, van Geuns RJ, Richardt G, Buszman PE, Kelbaek H, van Boven AJ, Hofma SH, Linke A, Klauss V, Wijns W, Macaya C, Garot P, Di Mario C, Manoharan G, Kornowski R, Ischinger T, Bartorelli AL, Gobbens P, Windecker S. The impact of patient and lesion complexity on clinical and angiographic outcomes after revascularization with zotarolimus- and everolimus-eluting stents: a substudy of the RESOLUTE All Comers Trial (a randomized comparison of a zotarolimus-eluting stent with an everolimus-eluting stent for percutaneous coronary intervention). J Am Coll Cardiol 2011;57:2221–2232.
7. Collet C, Modolo R, Banning A, Kandzari DE, Stables R, Dressler O, Sabik JF, Kappetein AP, Stone GW, Serruys PW. Impact of staging percutaneous coronary intervention in left main artery disease: insights from the EXCEL trial. JACC Cardiovasc Interv 2019;12:411–412.
8. Blankenship JC, Moussa ID, Chambers CC, Brilakis ES, Haldis TA, Morrison DA, Dehmer GJ, Society for Cardiovascular A, Interventions. Staging of multivessel percutaneous coronary interventions: an expert consensus statement from the Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv 2012;79:1138–1152.
9. Spitzer E, McFadden E, Vranckx P, de Vries T, Ren B, Collet C, Onuma Y, Garcia-Garcia HM, Lopes RD, Stone GW, Cutlip DE, Serruys PW. Defining staged procedures for percutaneous coronary intervention trials: a guidance document. JACC Cardiovasc Interv 2018;11:823–832.
10. Vranckx P, Valgimigli M, Windecker S, Steg PG, Hamm C, Juni P, Garcia-Garcia HM, van Es GA, Serruys PW. Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial. EuroIntervention 2016;12:1239–1245.
11. Garcia-Garcia HM, McFadden EP, Farb A, Mehran R, Stone GW, Spertus J, Onuma Y, Morel MA, van Es GA, Zuckerman B, Fearon WF, Taggart D, Kappetein AP, Krucoff MW, Vranckx P, Windecker S, Cutlip D, Serruys PW, Academic Research C. Standardized end point definitions for coronary intervention trials: the Academic Research Consortium-2 consensus document. Eur Heart J 2018; 39:2192–2207.
12. Serruys PW, Tomaniak M, Chichareon P, Modolo R, Kogame N, Takahashi K, Chang CC, Spitzer E, Walsh SJ, Adlam D, HildickSmith D, Edes I, van de Harst P, Krackhardt F, Tijssen JGP, Rademaker-Havinga T, Garg S, Steg PG, Hamm C, Juni P, Vranckx P, Onuma Y, Verheugt FWA. Patient-oriented composite endpoints and net adverse clinical events with ticagrelor monotherapy following percutaneous coronary intervention: insights from the randomized GLOBAL LEADERS trial. EuroIntervention 2019;15:e1090–e1098.
13. Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW, Academic Research C. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344–2351.
14. Li G, Taljaard M, Van den Heuvel ER, Levine MA, Cook DJ, Wells GA, Devereaux PJ, Thabane L. An introduction to multiplicity issues in clinical trials: the what, why, when and how. Int J Epidemiol 2017;46:746–755.
15. Vranckx P, Valgimigli M, Juni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E, Mollmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns RJ, Huber K, Slagboom T, Serruys PW, Windecker S, Investigators GL. 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;392:940–949.
16. Lee SY, Hong MK, Palmerini T, Kim HS, Valgimigli M, Feres F, Colombo A, Gilard M, Shin DH, Kim JS, Kim BK, Ko YG, Choi D, Jang Y, Stone GW. Short-term versus long-term dual antiplatelet therapy after drug-eluting stent implantation in elderly patients: a metaanalysis of individual participant data from 6 randomized trials. JACC Cardiovasc Interv 2018;11:435–443.
17. Tomaniak M, Chichareon P, Onuma Y, Deliargyris EN, Takahashi K, Kogame N, Modolo R, Chang CC, Rademaker-Havinga T, Storey RF, Dangas GD, Bhatt DL, Angiolillo DJ, Hamm C, Valgimigli M, Windecker S, Steg PG, Vranckx P, Serruys PW. Investigators GLT. Benefit and Risks of Aspirin in Addition to Ticagrelor in Acute Coronary Syndromes: A Post Hoc Analysis of the Randomized GLOBAL LEADERS Trial. JAMA Cardiol 2019;4:1092–1101.
18. Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, Cho JY, Her AY, Cho S, Jeon DW, Yoo SY, Cho DK, Hong BK, Kwon H, Ahn CM, Shin DH, Nam CM, Kim JS, Ko YG, Choi D, Hong MK, Jang Y, Investigators T. Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: the TICO randomized clinical trial. JAMA 2020;323:2407–2416.
19. Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler JR, Teerlink JR, Farb A, Morrow DA, Targum SL, Sila CA, Hai MTT, Jaff MR, Joffe HV, Cutlip DE, Desai AS, Lewis EF, Gibson CM, Landray MJ, Lincoff AM, White CJ, Brooks SS, Rosenfield K, Domanski MJ, Lansky AJ, McMurray JJV, Tcheng JE, Steinhubl SR, Burton P, Mauri L, O’Connor CM, Pfeffer MA, Hung HMJ, Stockbridge NL, Chaitman BR, Temple RJ. Standardized data collection for cardiovascular trials I. 2017 cardiovascular and stroke endpoint DAPT inhibitor definitions for clinical trials. Circulation 2018;137:961–972.
20. Leonardi S, Franzone A, Piccolo R, McFadden E, Vranckx P, Serruys P, Benit E, Liebetrau C, Janssens L, Ferrario M, Zurakowski A, van Geuns RJ, Dominici M, Huber K, Slagboom T, Buszman P, Bolognese L, Tumscitz C, Bryniarski K, Aminian A, Vrolix M, Petrov I, Garg S, Naber C, Prokopczuk J, Hamm C, Steg G, Heg D, Juni P, Windecker S, Valgimigli M. Rationale and design of a prospective substudy of clinical endpoint adjudication processes within an investigator-reported randomised controlled trial in patients with coronary artery disease: the GLOBAL LEADERS Adjudication Sub-StudY (GLASSY). BMJ Open2019;9:e026053.
21. Franzone A, McFadden E, Leonardi S, Piccolo R, Vranckx P, Serruys PW, Benit E, Liebetrau C, Janssens L, Ferrario M, Zurakowski A, Diletti R, Dominici M, Huber K, Slagboom T, Buszman P, Bolognese L, Tumscitz C, Bryniarski K, Aminian A, Vrolix M, Petrov I, Garg S, Naber C, Prokopczuk J, Hamm C, Steg PG, Heg D, Juni P, Windecker S, Valgimigli M, Investigators G. Ticagrelor alone versus dual antiplatelet therapy from 1 month after drug-eluting coronary stenting. J Am Coll Cardiol 2019;74:2223–2234.