Inferiority of coronary paclitaxel-coated balloon angioplasty to sirolimus-eluting stents for de novo non-complex lesions without a restriction of target vessel diameter: the REC-CAGEFREE I trial

Drug-coated balloon (DCB) angioplasty is a part of the “leave nothing behind” approach and could theoretically have many advantages in the present drug-eluting stent (DES) era (1-3). A brief contact of paclitaxel on the vessel wall makes paclitaxel diffuse into the plaque, and exerts the anti-restenotic effect without the scaffolding effect of a metal stent (1-3). The 2018 European Society of Cardiology guidelines for revascularization (4) gave paclitaxel-coated balloon (PCB) angioplasty as a class IA recommendation for the management of in-stent restenosis (ISR). The BASKET-SMALL 2 trial showed non-inferiority of PCB angioplasty to DES placement in de novo lesions in small vessels coronary arteries defined as reference vessel diameter (RVD) less than 2.75 mm (5). The safety and efficacy of PCB angioplasty for de novo lesions in small vessels compared to DES placement have been confirmed by a plenty of prospective studies (1-3). The most advantageous outcome of PCB angioplasty was the very small mean magnitude (within 0.1 mm) of late luminal loss (LLL) (1-3). The very small magnitude of LLL was brought by approximately half of late lumen enlargement (LLE) (6-9). Thus, on the basis of the angiographic efficacy of PCB angioplasty, de novo lesions in non-small or large vessels, at bifurcation, in patients with diabetes, and in patients with acute coronary syndrome (ACS), have been raised as candidates for PCB angioplasty (1-3). Of them, de novo lesions in large coronary vessels have the highest possibility of PCB angioplasty, because very small LLL after PCB angioplasty would exert the efficacy by reducing the frequency of angiographic restenosis (1-3). The safety and efficacy of PCB angioplasty for large vessels compared to DES placement have been reported in a retrospective, non-randomized cohort study (9) and meta-analyses by recruiting those retrospective studies (10-12). However, de novo lesions in large coronary vessels have not been defined as the guideline-directed approved target of PCB angioplasty (4). This is because there was none of randomized, large, prospective, and comparative studies of PCB angioplasty and DES placements.

For these backgrounds, the REC-CAGEFREE I trial (13) was designed as the first open-label, randomized controlled, non-inferiority trial in a large population in 43 sites of China. The primary outcome was the device-oriented composite endpoint (DoCE), including cardiovascular death, target vessel myocardial infarction, and clinically and physiologically indicated target lesion revascularization (TLR) assessed at 24 months in the intention-to-treat (ITT) population. Bailout stenting due to severe coronary dissections occurred in 9.4% of the patients in the PCB group. DoCE at 24 months occurred in 6.4% of the PCB group vs. 3.4% of the sirolimus-eluting stent (SES) group. Thus, PCB angioplasty did not reach pre-specified non-inferiority margins compared with the SES placement. In the non-small vessel disease subgroup (defined by balloon diameter ≥3.0 mm), the frequency of DoCE in the PCB group was highly significant compared to that in the SES group. On the other hand, in the small vessel disease subgroup, the frequency of DoCE in the PCB group was not significantly with that in the SES group. Therefore, the REC-CAGEFREE I trial concluded that the use of PCB for de novo non-complex coronary artery lesions did not reach non-inferiority compared with an intended SES strategy in the entire vessel diameter. Thus, DES implantation should remain the preferred treatment strategy, especially for non-small vessel disease.

In this article, the novelty and clinical implications of the REC-CAGEFREE I trial were briefly discussed in terms of (I) vessel size and lesion length (LL), (II) clinical presentation, and (III) optimal angiographic endpoint of preparation.

Vessel size and LL

In the comparative studies of PCB and DES, the definition of “large” vessel needed to be clarified. There were many definitions of “large” or “non-small” vessel, such as the RVD [2.5 mm, 2.75 mm (5,6,9), or 2.8 mm], vessel diameter by an intravascular assessment, or used balloon device size [3.0 mm (13) or else] (10-12). The REC-CAGEFREE I trial consistently showed the equivalent 2-year outcomes of PCB angioplasty with DES placement in de novo small coronary artery disease, as the BASKET-SMALL 2 trial (5). However, the REC-CAGEFREE I trial showed the inferiority of PCB angioplasty for large vessels compared to SES placement. Therefore, as mentioned above about the angiographic advantage of PCB angioplasty, a sub-analysis examined the mean magnitude of LLL with the percentage of LLE after PCB angioplasty would attribute to further explore the outcomes of the REC-CAGEFREE I trial.

The total LL was less than 28 mm in more than 90% of the whole (13). This was slightly longer than the former reports showing the efficacy of DCB angioplasty (5-9,14). However, the frequency of DoCE in total LL less than 28 mm in the PCB group was 6.5%, and was approximately 2-fold, significantly higher than that in the SES group (3.3%) (13). The pre-procedural LL has been one of the predictors of DoCE and recurrent ISR after DCB angioplasty for not only de novo lesions (6-9), but also ISR lesions (14). Related to the pre-procedural LL, mean PCB length of approximately 20 mm has consistently showed as the possible factor for non-inferior of PCB angioplasty to DES placement in cohorts of DES-ISR (14), and of small vessel (5,7,8), large vessel (9), and the entire vessel size without restriction (6). This issue about the mean PCB length of approximately 20 mm was also consistent in the studies estimating the benefits of PCB angioplasty with the intravascular parameters (8). Therefore, in contrast to the previous retrospective studies (6-9,14), the REC-CAGEFREE I trial showed the superiority of contemporary SES placement to the recent PCB angioplasty fashion (13). Since both vessel size and LL were the predictors of adverse clinical outcomes of DES (15), the subgroup analysis comparing 2-year cumulative DoCE by dividing into 4 cohorts according to vessel size (or balloon size) and LL would be warranted in the REC-CAGEFREE I trial.

Clinical presentation

The REC-CAGEFREE I trial included de novo lesions in patients with any clinical presentations [ACS or chronic coronary syndrome (CCS)] (13). All of ACS, comprised of ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina (UA) were included as approximately 55% of the whole. The feasibility of PCB angioplasty for patients with ACS was concurrently suggested in the pivotal narrative reviews (1-3) and in a meta-analysis (16). Therefore, cumulative meta-analyses by adding this large ACS population of PCB angioplasty of the REC-CAGEFREE I trial to the previous meta-analysis (16) would be significant to re-ascertain the feasibility of PCB angioplasty for patients with ACS in comparison to DES placement.

Optimal endpoint of lesion preparation prior to PCB angioplasty

The REC-CAGEFREE I trial enrolled the lesions with the successful pre-dilation prior to PCB angioplasty after the successful pre-dilatation with any use of non-compliant, cutting, or scoring balloons at a 0.8–1.0 balloon-to-vessel size ratio. This was the first attempt to apply in the comparative study of PCB angioplasty and DES placement. The definition of satisfactory preparation was referred from the optimal angiographic endpoint of DCB angioplasty (post-procedural %DS ≤30) (1-3). The significance of QCA in balloon angioplasty and DES placement was quite different (17). However, since the final post-procedural %DS closely relates to the clinical outcomes, final post-procedural %DS was proposed as a suitable surrogate marker to compare the following outcomes after PCB angioplasty and DES placement (18); post-procedural %DS ≤30 after PCB angioplasty (1-3), and ≤10 after DES placement (19). Therefore, it is necessary to clarify why PCB angioplasty could not show the non-inferiority compared to SES placement, even though the angiographic outcomes at pre-dilation accomplished the optimal endpoint of final PCB angioplasty. Since the post-procedural %DS of 30 was defined approximately three decades ago (20), it is necessary to confirm the optimal endpoint of angiographic outcomes after PCB angioplasty with the advances in percutaneous coronary intervention (PCI) technology.

In summary, the REC-CAGEFREE I trial did not show the non-inferiority of PCB angioplasty to SES placement for the de novo non-complex lesions irrespective of vessel size. The comparative studies of the DCB angioplasty and DES placement need to continue by updating contemporary devices and procedural strategies, and to renew the evidence with statistical power.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-249/coif). The authors have no conflicts of interest to declare.

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References

1. Yerasi C, Case BC, Forrestal BJ, et al. Drug-Coated Balloon for De Novo Coronary Artery Disease: JACC State-of-the-Art Review. J Am Coll Cardiol 2020;75:1061-73. [Crossref] [PubMed]
2. Jeger RV, Eccleshall S, Wan Ahmad WA, et al. Drug-Coated Balloons for Coronary Artery Disease: Third Report of the International DCB Consensus Group. JACC Cardiovasc Interv 2020;13:1391-402. [Crossref] [PubMed]
3. Muramatsu T, Kozuma K, Tanabe K, et al. Clinical expert consensus document on drug-coated balloon for coronary artery disease from the Japanese Association of Cardiovascular Intervention and Therapeutics. Cardiovasc Interv Ther 2023;38:166-76. [Crossref] [PubMed]
4. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019;40:87-165. [Crossref] [PubMed]
5. Jeger RV, Farah A, Ohlow MA, 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;396:1504-10. [Crossref] [PubMed]
6. Yamada K, Ishikawa T, Nakamura H, et al. Midterm safety and efficacy of elective drug-coated balloon angioplasty in comparison to drug-eluting stents for unrestrictive de novo coronary lesions: A single center retrospective study. J Cardiol 2023;81:537-43. [Crossref] [PubMed]
7. Onishi T, Onishi Y, Kobayashi I, et al. Late lumen enlargement after drug-coated balloon angioplasty for de novo coronary artery disease. Cardiovasc Interv Ther 2021;36:311-8. [Crossref] [PubMed]
8. Yamamoto T, Sawada T, Uzu K, et al. Possible mechanism of late lumen enlargement after treatment for de novo coronary lesions with drug-coated balloon. Int J Cardiol 2020;321:30-7. [Crossref] [PubMed]
9. Nakamura H, Ishikawa T, Mizutani Y, et al. Clinical and Angiographic Outcomes of Elective Paclitaxel-Coated Balloon Angioplasty in Comparison with Drug-Eluting Stents for De Novo Coronary Lesions in Large Vessels. Int Heart J 2023;64:145-53. [Crossref] [PubMed]
10. Sun B, Zhang XT, Chen RR. Comparison of Efficacy and Safety Between Drug-Coated Balloons Versus Drug-Eluting Stents in the Treatment of De Novo Coronary Lesions in Large Vessels: A Study-Level Meta-Analysis of Randomized Control Trials. Cardiovasc Drugs Ther 2024;38:1375-84. [Crossref] [PubMed]
11. Jiang JL, Huang QJ, Chen MH. Efficacy and safety of drug-coated balloon for de novo lesions of large coronary arteries: Systematic review and meta-analysis of randomized controlled trials. Heliyon 2024;10:e25264. [Crossref] [PubMed]
12. Caminiti R, Vizzari G, Ielasi A, et al. Drug-coated balloon versus drug-eluting stent for treating de novo large vessel coronary artery disease: a systematic review and meta-analysis of 13 studies involving 2888 patients. Clin Res Cardiol 2024; Epub ahead of print. [Crossref] [PubMed]
13. Gao C, He X, Ouyang F, et al. Drug-coated balloon angioplasty with rescue stenting versus intended stenting for the treatment of patients with de novo coronary artery lesions (REC-CAGEFREE I): an open-label, randomised, non-inferiority trial. Lancet 2024;404:1040-50. [Crossref] [PubMed]
14. Giacoppo D, Alfonso F, Xu B, et al. Paclitaxel-coated balloon angioplasty vs. drug-eluting stenting for the treatment of coronary in-stent restenosis: a comprehensive, collaborative, individual patient data meta-analysis of 10 randomized clinical trials (DAEDALUS study). Eur Heart J 2020;41:3715-28. [Crossref] [PubMed]
15. Claessen BE, Smits PC, Kereiakes DJ, et al. Impact of lesion length and vessel size on clinical outcomes after percutaneous coronary intervention with everolimus- versus paclitaxel-eluting stents pooled analysis from the SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) and COMPARE (Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice) Randomized Trials. JACC Cardiovasc Interv 2011;4:1209-15. [Crossref] [PubMed]
16. Kondo Y, Ishikawa T, Shimura M, et al. Cardiovascular Outcomes after Paclitaxel-Coated Balloon Angioplasty versus Drug-Eluting Stent Placement for Acute Coronary Syndrome: A Systematic Review and Meta-Analysis. J Clin Med 2024;13:1481. [Crossref] [PubMed]
17. White JM, Webster MW, Ormiston JA. Choice of appropriate endpoints for a balloon versus stent trial. J Am Coll Cardiol 2013;61:1831. [Crossref] [PubMed]
18. Lang X, Wang Y, Li W, et al. Appropriate Surrogate Endpoint in Drug-Coated Balloon Trials for Coronary Artery Diseases. Front Cardiovasc Med 2022;9:897365. [Crossref] [PubMed]
19. Watanabe H, Morimoto T, Shiomi H, et al. Impact of Angiographic Residual Stenosis on Clinical Outcomes After New-Generation Drug-Eluting Stents Implantation: Insights From a Pooled Analysis of the RESET and NEXT Trials. J Am Heart Assoc 2018;7:e008718. [Crossref] [PubMed]
20. Cox DA, Stone GW, Grines CL, et al. Outcomes of optimal or "stent-like"balloon angioplasty in acutemyocardial infarction: the CADILLAC trial. J Am Coll Cardiol 2003;42:971-7. [Crossref] [PubMed]