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BMC Cardiovascular Disorders
Published in: BMC Cardiovascular Disorders 1/2024

Open Access 01-12-2024 | Acute Coronary Syndrome | Study Protocol

Randomized evaluation of 5-month Ticagrelor monotherapy after 1-month dual-antiplatelet therapy in patients with acute coronary syndrome treated with drug-coated balloons: REC-CAGEFREE II trial rationale and design

Authors: Chao Gao, Bin Zhu, Jianzheng Liu, Zhiwei Jiang, Tao Hu, Qiong Wang, Yi Liu, Ming Yuan, Fei Li, Ruining Zhang, Jielai Xia, Yoshinobu Onuma, Duolao Wang, Patrick Serruys, Ling Tao, on behalf of the REC-CAGEFREE II Study Group

Published in: BMC Cardiovascular Disorders | Issue 1/2024

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Abstract

Background

Patients treated with drug-coated balloons (DCB) have the theoretical advantage of adopting a low-intensity antiplatelet regimen due to the absence of struts and polymers. Nevertheless, the optimal antiplatelet strategy for patients undergoing DCB-only treatment remains a topic of debate and has not been investigated in randomized trials.

Methods

The REC-CAGEFREE II is an investigator-initiated, prospective, open-label, multi-center, randomized, non-inferiority trial aimed to enroll 1908 patients from ≥ 40 interventional cardiology centers in China to evaluate the non-inferiority of an antiplatelet regimen consisting of Aspirin plus Ticagrelor for one month, followed by five months Ticagrelor monotherapy, and then Aspirin monotherapy for six months (Experimental group) compared to the conventional treatment of Aspirin plus Ticagrelor for 12 months (Reference group) in patients with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention (PCI) using paclitaxel-coated balloons (DCB) exclusively. Participants will be randomly assigned to the Experimental or Reference group in a 1:1 ratio. The randomization will be stratified based on the center and the type of lesion being treated (De novo or in-stent restenosis). The primary endpoint is net adverse clinical events (NACE) within 12 months of PCI, which includes the composite of all-cause death, any stroke, any myocardial infarction, any revascularization and Bleeding Academic Research Consortium (BARC) defined type 3 or 5 bleeding. The secondary endpoint, any ischemic and bleeding event, which includes all-cause death, any stroke, MI, BARC-defined type 3 bleeding, any revascularization, and BARC-defined type 2 bleeding events, will be treated as having hierarchical clinical importance in the above order and analyzed using the win ratio method.

Discussion

The ongoing REC-CAGEFREE II trial aims to assess the efficacy and safety of a low-intensity antiplatelet approach among ACS patients with DCB. If non-inferiority is shown, the novel antiplatelet approach could provide an alternative treatment for ACS patients with DCB.

Trial registration

ClinicalTrials.gov identifier: NCT04971356.
Appendix
Available only for authorised users
Literature
1.
Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet JP, Falk V, Head SJ, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87–165.PubMedCrossRef
2.
Jeger RV, Farah A, Ohlow MA, Mangner N, Mobius-Winkler S, Weilenmann D, Wohrle J, Stachel G, Markovic S, Leibundgut G, et al. Long-term efficacy and safety of drug-coated balloons versus drug-eluting stents for small coronary artery disease (BASKET-SMALL 2): 3-year follow-up of a randomised, non-inferiority trial. Lancet. 2020;396(10261):1504–10.PubMedCrossRef
3.
Merinopoulos I, Gunawardena T, Corballis N, Bhalraam U, Reinhold J, Wickramarachchi U, Maart C, Gilbert T, Richardson P, Sulfi S, et al. Assessment of paclitaxel drug-coated balloon only angioplasty in STEMI. JACC Cardiovasc Interv. 2023;16(7):771–9.PubMedCrossRef
4.
Vos NS, Fagel ND, Amoroso G, Herrman JR, Patterson MS, Piers LH, van der Schaaf RJ, Slagboom T, Vink MA. Paclitaxel-coated balloon angioplasty versus drug-eluting stent in acute myocardial infarction: the REVELATION randomized trial. JACC Cardiovasc Interv. 2019;12(17):1691–9.PubMedCrossRef
5.
Rissanen TT, Uskela S, Eranen J, Mantyla P, Olli A, Romppanen H, Siljander A, Pietila M, Minkkinen MJ, Tervo J, et al. Drug-coated balloon for treatment of de-novo coronary artery lesions in patients with high bleeding risk (DEBUT): a single-blind, randomised, non-inferiority trial. Lancet. 2019;394(10194):230–9.PubMedCrossRef
6.
Ali RM, Degenhardt R, Zambahari R, Tresukosol D, Ahmad WA, Kamar H, Kui-Hian S, Ong TK, bin Ismail O, bin Elis S, et al. Paclitaxel-eluting balloon angioplasty and cobalt-chromium stents versus conventional angioplasty and paclitaxel-eluting stents in the treatment of native coronary artery stenoses in patients with diabetes mellitus. EuroIntervention. 2011;7 Suppl K:K83-92.PubMedCrossRef
7.
Jeger RV, Farah A, Ohlow MA, Mangner N, Möbius-Winkler S, Leibundgut G, Weilenmann D, Wöhrle J, Richter S, Schreiber M, et al. Drug-coated balloons for small coronary artery disease (BASKET-SMALL 2): an open-label randomised non-inferiority trial. Lancet. 2018;392(10150):849–56.PubMedCrossRef
8.
Valgimigli M, Costa F, Lokhnygina Y, Clare RM, Wallentin L, Moliterno DJ, Armstrong PW, White HD, Held C, Aylward PE, et al. 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(11):804–10.PubMed
9.
Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, Claeys MJ, Dan GA, Dweck MR, Galbraith M, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720–826.PubMedCrossRef
10.
Capodanno D, Mehran R, Krucoff MW, Baber U, Bhatt DL, Capranzano P, Collet JP, Cuisset T, De Luca G, De Luca L, et al. Defining strategies of modulation of antiplatelet therapy in patients with coronary artery disease: a consensus document from the academic research consortium. Circulation. 2023;147(25):1933–44.PubMedCrossRef
11.
Gorog DA, Ferreiro JL, Ahrens I, Ako J, Geisler T, Halvorsen S, Huber K, Jeong YH, Navarese EP, Rubboli A, et al. De-escalation or abbreviation of dual antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention: a consensus statement from an international expert panel on coronary thrombosis. Nat Rev Cardiol. 2023;20:830.PubMedCrossRef
12.
Writing Committee M, Lawton JS, Tamis-Holland JE, Bangalore S, Bates ER, Beckie TM, Bischoff JM, Bittl JA, Cohen MG, DiMaio JM, et al. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79(2):e21–129.CrossRef
13.
14.
Chowdhury MM, Singh K, Albaghdadi MS, Khraishah H, Mauskapf A, Kessinger CW, Osborn EA, Kellnberger S, Piao Z, Lino Cardenas CL, et al. Paclitaxel drug-coated balloon angioplasty suppresses progression and inflammation of experimental atherosclerosis in rabbits. JACC Basic Transl Sci. 2020;5(7):685–95.PubMedPubMedCentralCrossRef
15.
Zhang Y, Zhang X, Dong Q, Chen D, Xu Y, Jiang J. Duration of dual antiplatelet therapy after implantation of drug-coated balloon. Front Cardiovasc Med. 2021;8:762391.PubMedPubMedCentralCrossRef
16.
Hahn JY, Song YB, Oh JH, Chun WJ, Park YH, Jang WJ, Im ES, Jeong JO, Cho BR, Oh SK, et al. 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):2428–37.PubMedPubMedCentralCrossRef
17.
Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T, Ohya M, Suwa S, Takagi K, Nanasato M, et al. 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):2414–27.PubMedPubMedCentralCrossRef
18.
Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha JY, Collier T, Dangas G, Dudek D, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med. 2019;381(21):2032–42.PubMedCrossRef
19.
Vranckx P, Valgimigli M, Jüni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, et al. 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):940–9.PubMedCrossRef
20.
Kim BK, Hong SJ, Cho YH, Yun KH, Kim YH, Suh Y, Cho JY, Her AY, Cho S, Jeon DW, et al. 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(23):2407–16.PubMedPubMedCentralCrossRef
21.
Valgimigli M, Frigoli E, Heg D, Tijssen J, Juni P, Vranckx P, Ozaki Y, Morice MC, Chevalier B, Onuma Y, et al. Dual antiplatelet therapy after pci in patients at high bleeding risk. N Engl J Med. 2021;385(18):1643–55.PubMedCrossRef
22.
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD. Fourth universal definition of myocardial infarction (2018). Eur Heart J. 2019;40(3):237–69.PubMedCrossRef
23.
Kleber FX, Rittger H, Bonaventura K, Zeymer U, Wöhrle J, Jeger R, Levenson B, Möbius-Winkler S, Bruch L, Fischer D, et al. Drug-coated balloons for treatment of coronary artery disease: updated recommendations from a consensus group. Clin Res Cardiol. 2013;102(11):785–97.PubMedCrossRef
24.
Jeger RV, Eccleshall S, Wan Ahmad WA, Ge J, Poerner TC, Shin ES, Alfonso F, Latib A, Ong PJ, Rissanen TT, et al. Drug-coated balloons for coronary artery disease: third report of the international DCB consensus group. JACC Cardiovasc Interv. 2020;13(12):1391–402.PubMedCrossRef
25.
Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, Juni P, Kastrati A, Kolh P, Mauri L, et al. 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):213–60.PubMedCrossRef
26.
Garcia-Garcia HM, McFadden EP, Farb A, Mehran R, Stone GW, Spertus J, Onuma Y, Morel MA, van Es GA, Zuckerman B, et al. Standardized end point definitions for coronary intervention trials: the academic research consortium-2 consensus document. Eur Heart J. 2018;39(23):2192–207.PubMedCrossRef
27.
Lansky AJ, Messé SR, Brickman AM, Dwyer M, van der Bart Worp H, Lazar RM, Pietras CG, Abrams KJ, McFadden E, Petersen NH, et al. Proposed standardized neurological endpoints for cardiovascular clinical trials: an academic research consortium initiative. Eur Heart J. 2018;39(19):1687–97.PubMedCrossRef
28.
Moussa ID, Klein LW, Shah B, Mehran R, Mack MJ, Brilakis ES, Reilly JP, Zoghbi G, Holper E, Stone GW. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013;62(17):1563–70.PubMedPubMedCentralCrossRef
29.
Bulluck H, Paradies V, Barbato E, Baumbach A, Botker HE, Capodanno D, De Caterina R, Cavallini C, Davidson SM, Feldman DN, et al. Prognostically relevant periprocedural myocardial injury and infarction associated with percutaneous coronary interventions: a Consensus Document of the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2021;42(27):2630–42.PubMedPubMedCentralCrossRef
30.
Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736–47.PubMedCrossRef
31.
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(4):256–65.PubMedCrossRef
32.
Investigators G. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993;329(10):673–82.CrossRef
33.
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization Committee of the International Society on T, Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3(4):692–4.PubMedCrossRef
34.
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.PubMedCrossRef
35.
Urban P, Mehran R, Colleran R, Angiolillo DJ, Byrne RA, Capodanno D, Cuisset T, Cutlip D, Eerdmans P, Eikelboom J, et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation. 2019;140(3):240–61.PubMedPubMedCentralCrossRef
36.
Valgimigli M, Garcia-Garcia HM, Vrijens B, Vranckx P, McFadden EP, Costa F, Pieper K, Vock DM, Zhang M, Van Es GA, et al. Standardized classification and framework for reporting, interpreting, and analysing medication non-adherence in cardiovascular clinical trials: a consensus report from the non-adherence academic research consortium (NARC). Eur Heart J. 2019;40(25):2070–85.PubMedCrossRef
37.
Vranckx P, Valgimigli M, Juni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, et al. 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):940–9.PubMedCrossRef
38.
Tomaniak M, Chichareon P, Onuma Y, Deliargyris EN, Takahashi K, Kogame N, Modolo R, Chang CC, Rademaker-Havinga T, Storey RF, et al. 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(11):1092–101.PubMedPubMedCentralCrossRef
39.
Kedhi E, Fabris E, van der Ent M, Buszman P, von Birgelen C, Roolvink V, Zurakowski A, Schotborgh CE, Hoorntje JCA, Eek CH, 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.PubMedPubMedCentralCrossRef
40.
Hahn JY, Song YB, Oh JH, Cho DK, Lee JB, Doh JH, Kim SH, Jeong JO, Bae JH, Kim BO, et al. 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):1274–84.PubMedCrossRef
41.
Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Stahle E, Feldman TE, van den Brand M, Bass EJ, et al. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961–72.PubMedCrossRef
42.
Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, et al. Cardiovascular risk reduction with Icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380(1):11–22.PubMedCrossRef
43.
Dmitrienko A, D’Agostino R Sr. Traditional multiplicity adjustment methods in clinical trials. Stat Med. 2013;32(29):5172–218.PubMedCrossRef
44.
Alosh M, Bretz F, Huque M. Advanced multiplicity adjustment methods in clinical trials. Stat Med. 2014;33(4):693–713.PubMedCrossRef
45.
Traby L, Kollars M, Kaider A, Eichinger S, Wolzt M, Kyrle PA. Effects of P2Y12 receptor inhibition with or without aspirin on hemostatic system activation: a randomized trial in healthy subjects. J Thromb Haemost. 2016;14(2):273–81.PubMedCrossRef
46.
Armstrong PC, Leadbeater PD, Chan MV, Kirkby NS, Jakubowski JA, Mitchell JA, Warner TD. In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation. J Thromb Haemost. 2011;9(3):552–61.PubMedPubMedCentralCrossRef
47.
De Luca G, Damen SA, Camaro C, Benit E, Verdoia M, Rasoul S, Liew HB, Polad J, Ahmad WA, Zambahari R, et al. 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):e990–8.PubMedCrossRef
48.
Han JK, Hwang D, Yang S, Park SH, Kang J, Yang HM. Comparison of 3- to 6-month versus 12-month dual antiplatelet therapy after coronary intervention using the contemporary drug-eluting stents with ultrathin struts: the HOST-IDEA randomized clinical trial. Circulation. 2023;147(18):1358–68.PubMedCrossRef
49.
Baber U, Dangas G, Angiolillo DJ, Cohen DJ, Sharma SK, Nicolas J, Briguori C, Cha JY, Collier T, Dudek D, et al. Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS. Eur Heart J. 2020;41(37):3533–45.PubMedCrossRef
50.
Watanabe H, Morimoto T, Natsuaki M, Yamamoto K, Obayashi Y, Ogita M, Suwa S, Isawa T, Domei T, Yamaji K, et al. Comparison of Clopidogrel monotherapy after 1 to 2 months of dual antiplatelet therapy with 12 months of dual antiplatelet therapy in patients with acute coronary syndrome: the STOPDAPT-2 ACS randomized clinical trial. JAMA Cardiol. 2022;7(4):407–17.PubMedPubMedCentralCrossRef
Metadata
Title
Randomized evaluation of 5-month Ticagrelor monotherapy after 1-month dual-antiplatelet therapy in patients with acute coronary syndrome treated with drug-coated balloons: REC-CAGEFREE II trial rationale and design
Authors
Chao Gao
Bin Zhu
Jianzheng Liu
Zhiwei Jiang
Tao Hu
Qiong Wang
Yi Liu
Ming Yuan
Fei Li
Ruining Zhang
Jielai Xia
Yoshinobu Onuma
Duolao Wang
Patrick Serruys
Ling Tao
on behalf of the REC-CAGEFREE II Study Group
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cardiovascular Disorders / Issue 1/2024
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-024-03709-1

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