Superiority of coronary paclitaxel DCBs to limus DCBs in the late angiographic outcomes: the first meta-analysis showing the differences of coronary DCBs

Sedhom et al. (1), conducted a systematic review and meta-analysis to compare the outcomes after coronary angioplasty by using limus coronary drug-coated balloons (DCBs) with those of paclitaxel DCBs. Recently, the potential of coronary DCBs with the matched outcomes of drug-eluting stents (DESs) without leaving a permanent metal implant in native coronaries was reported (2). There has been the clinical question whether the angiographic and/or clinical outcomes of limus DCBs angioplasty were the same with those of paclitaxel DCBs angioplasty or not. The systematic review using three databases identified 624 reports at January 2024 [Fig. 1 (1)]. Six terms were used for screening. Finally, six randomized controlled trials (RCTs) comparing the outcomes in patients after limus DCBs angioplasty for any lesions (n=446) with those after paclitaxel DCBs angioplasty (n=375) were included. The estimated primary outcome of the study was the incidence of clinically driven target lesion revascularization (TLR). The estimated secondary outcomes of angiographic outcomes were the four parameters of quantitative coronary angiogram (QCA), such as minimal lumen diameter (MLD), acute lumen gain, late lumen loss (LLL), and percent diameter stenosis (%DS), and the percentages of binary restenosis and late lumen enlargement (LLE) at follow-up. In addition, as clinical outcomes, the incidences of major adverse cardiovascular events (MACEs), cardiac mortality, and target vessel myocardial infarction (TVMI) were estimated. The conclusion was that there were no differences between limus DCBs (n=446) and paclitaxel DCBs (n=375) in the risk of clinical outcomes (TLR, TVMI, cardiac mortality, or MACEs) at a mean of 13.4 months (1). This was consistent in the subgroup analyses of de novo lesions group [limus-DCB (n=131) vs. paclitaxel-DCB (n=130)], and in-stent restenosis (ISR) groups [limus-DCB (n=298) vs. paclitaxel-DCB (n=244)]. However, paclitaxel DCBs were associated with lower rates of binary restenosis (1) [limus-DCB (n=189) vs. paclitaxel-DCB (n=181)], smaller LLL (1) [limus-DCB (n=459) vs. paclitaxel-DCB (n=376)], better MLD (1) [limus-DCB (n=459) vs. paclitaxel-DCB (n=376)], and the higher rate of LLE at late follow-up than those of limus DCBs (1) [limus-DCB (n=255) vs. paclitaxel-DCB (n=182)]. Thus, the present meta-analysis examined the outcomes in the major two types of coronary DCBs with a powered clinical endpoint, i.e., class effects, and firstly showed the statistical differences in the angiographic outcomes within one year.

The pivotal review concerning about the recent wide spread DCB use of the International DCB Consensus Group (3) stated that there was none of class effects among commercially available limus DCBs and paclitaxel DCBs by referring the ESC guideline at that time. However, the International DCB Consensus Group (3) added the comment that there remained the issues to be explored concerning about those DCB angioplasties, such as the overall impacts of drugs (sirolimus versus paclitaxel) on the lesion and vascular responses by taking into the drug doses, release kinetics, and diffusion and retention in the plaque. The major angiographic difference demonstrated in the present meta-analysis was the significantly larger, and approximately double percentage of LLE after paclitaxel DCBs angioplasty (approximately 50%) compared to limus DCBs angioplasty (27.5%) (1). This novel finding brought very important impacts on the coronary revascularization because the following LLE-related issues based on paclitaxel DCBs angioplasty might be also different after limus DCBs angioplasty:

• LLE has been the unique phenomenon after a single application of paclitaxel on the plaque induced the most advantageous late outcome of the stent-less PCI by using paclitaxel DCBs. LLE enables paclitaxel DCBs angioplasty to discriminate those angiographic outcomes (LLL, %DS, and binary ISR) from DES placement that LLE could not be developed after metallic stent placement.
• Approximately 50% of lesions developed LLE after paclitaxel DCBs angioplasty to de novo coronary lesions resulted in the very small magnitude of LLL (4). Thus, the rates of restenosis after paclitaxel DCBs angioplasty have been statistically equivalent with that of ISR after DES placement (4,5), although the lower ISR rate has been the most advantageous angiographic outcome of the recent advanced DES compared to the former generation DES. Therefore, in the selected lesions, the clinical and angiographic outcomes after paclitaxel DCBs angioplasty were statistically equivalent with those of after DESs placement (3,4).
• The predictor of LLE after paclitaxel DCBs angioplasty for de novo coronary stenosis was the insignificant (types A or B) dissection (5-7). Therefore, it is very important to ascertain the angiographic and intravascular findings from the initial step of pre-ballooning with small-sized balloon, highly used pre-treatment with scoring balloon angioplasty, and the final dilation step by a paclitaxel DCB. When, the significant dissection (types more C) reducing the coronary flow was occurred, it needs to bail out by DES placement. The frequencies of bailout DES placement were approximately 10% (4,5).
• The optimal angiographic outcome of paclitaxel DCBs angioplasty was defined as post-procedural %DS ≤30 without significant coronary flow (3). Therefore, the present differences in the late angiographic outcomes between the two types of coronary DCBs would be also affected the optimal angiographic endpoint of two types of DCBs.

The explanation for the first LLE-related issue was that LLE has been a representative angiographic outcome of a stent-less paclitaxel DCBs angioplasty. Recently, mean age of the first experience of coronary artery disease (CAD) has become lower. Therefore, patients with CAD need the long-term secondary prevention. The ten-year outcomes of the randomized NEXT (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial) showed that the cumulative incidence of TLR after biolimus- and everolimus-eluting second-generation DESs increased up to approximately 15%, although the median values of SYNTAX score was approximately 10 (8). Therefore, high prevalence of LLE after paclitaxel DCBs angioplasty would bring large advantages in the late clinical outcomes by comparing with not only limus DCB angioplasty, but also limus DESs placement. Therefore, it is required to show further long-term clinical and angiographic outcomes by examining the serial angiographic outcomes including the late percentages of LLE after paclitaxel DCBs angioplasty, to discriminate the late TLR incidence of stent-less paclitaxel DCB angioplasty from the cumulative increased late TLR of the limus DESs placement and limus DCBs angioplasty.

The second issue was about the developed percentage of LLE. It has been consistent that approximately a half of the entire angiographic followed-up cohorts after paclitaxel DCBs angioplasty showed LLE (4-7). Since LLE was defined as minus LLL, the percentage of binary restenosis and the mean magnitude of LLL became acceptable compared to those of after DES placement (4,5). Therefore, these midterm favorable angiographic outcomes made the recent prevalence of paclitaxel DCBs angioplasty for de novo coronary lesions (3,4). The authors stated the effects of both of sirolimus and paclitaxel in Introduction and in Discussion (1). Of them, they explained the reason for higher percentage of LLE after paclitaxel DCBs angioplasty was owing to the superior tissue absorption and retention ability of paclitaxel in the plaque (1). The currently available limus DCBs cannot compete with the superior lipophilicity, rapid tissue absorption, and retention of paclitaxel (1). Good retention of paclitaxel did not link to the increased mortality compared to limus DCBs (1). We have previously proposed 4 steps involved in establishing LLE after paclitaxel DCB angioplasty (5): (I) balloon angioplasty mechanically enlarges the lumen and vessel areas (mechanical vessel enlargement), (II) minor dissections formed during the procedure can facilitate the diffusion of paclitaxel into the plaques (diffusion of paclitaxel via minor dissection), (III) paclitaxel distribution suppresses plaque growth and reduces regression (induction of plaque regression by diffusion of paclitaxel), and (IV) almost all of the insignificant (types A or B) minor dissections heal in the chronic phase without significant LLL (lumen enlargement with seal of dissection). Although the differences in the types of dissection after two types of DCB angioplasty were not fully estimated (1), the insignificant residual dissections of types A and B are the consistent predictors of LLE after paclitaxel DCBs (5-7). Thus, by including these issues about the mechanism of establishing LLE, the characteristics of paclitaxel to the atherosclerotic plaque would be the major reasons for the present meta-analysis-based superiority in the late angiographic outcomes compared to limus DESs, as suggested by the International DCB Consensus Group (3).

The class effects between sirolimus and paclitaxel had been debated among the first-generation DES of silorimus-eluting stent (SES: Cypher; Cordis, Johnson & Johnson, Miami, FL, USA) and paclitaxel-eluting stent (PES: Taxus; Boston, USA). Sirolimus has the theoretical advantage over paclitaxel for its anti-inflammatory and anti-restenotic effects, as well as a broader therapeutic range. The magnitude of LLL after SES placement had been consistently smaller than that after PES placement in general. However, in the selected complex cohorts, such as the lesions in patients with diabetes and on chronic hemodialysis, lesions in severely calcification, ostiums of right coronary and left circumflex arteries, and the bifurcation 2-stent, SES showed the disadvantage with the large increase in the magnitudes of LLL, although that of PES remained not to increase even in those complex lesions (9). There were none of differences in the clinical and angiographic outcomes in a long-term observational interval between the first-generation SES and PES (10). However, the superiority of everolimus-eluting stent (EES), a representative second-generation DES, to PES was consistently reported (11). The outcomes of two DCBs in the peripheral artery disease (PAD) of femoral-popliteal lesions could be referred into debates. Thus, the class effects of the two types of DCBs angioplasty needed to be further explored in the advanced generation.

The last issue was about the relationship between the present result and the optimal angiographic endpoint of DCB angioplasty. The angiographic post-procedural residual percent diameter stenosis (% DS) ≤30 has been the optimal endpoint (3). This cutoff value originated from a retrospective assessment of the Belgian Netherlands Stent (BENESTENT) trial, where achieving a post-procedural %DS ≤30 using plain old balloon angioplasty (POBA), a “stent-like result”, yielded similar clinical and angiographic outcomes in patients with stable angina compared to Palmaz-Schatz stent implantation (12). However, three decades have passed since the BENESTENT trial (13), and percutaneous coronary intervention (PCI) has evolved significantly with new technologies. Therefore, according to these differences in late angiographic outcomes (1), the optimal angiographic endpoint for DCB angioplasty in relation to adverse cardiovascular outcomes needs a re-evaluation individually in the two types of DCBs.

In conclusion, the present first meta-analysis showing the better angiographic outcomes of paclitaxel DCBs with the higher probability of LLE compared to limus DCBs would bring a large impact on the recent wide utility of DCBs. Further investigations would be warranted to the optimal use of coronary DCBs angioplasty.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-391/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-391/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sedhom R, Hamed M, Elbadawi A, et al. Outcomes With Limus- vs Paclitaxel-Coated Balloons for Percutaneous Coronary Intervention: Meta-Analysis of Randomized Controlled Trials. JACC Cardiovasc Interv 2024;17:1533-43. [Crossref] [PubMed]
2. Korjian S, McCarthy KJ, Larnard EA, et al. Drug-Coated Balloons in the Management of Coronary Artery Disease. Circ Cardiovasc Interv 2024;17:e013302. [Crossref] [PubMed]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. Natsuaki M, Watanabe H, Morimoto T, et al. Biodegradable or durable polymer drug-eluting stents in patients with coronary artery disease: ten-year outcomes of the randomised NEXT Trial. EuroIntervention 2023;19:e402-13. [Crossref] [PubMed]
9. Ishikawa T, Nakano Y, Mutoh M. Retrospective comparison of midterm clinical and angiographic outcomes after the implantation of paclitaxel- and sirolimus-eluting stents for de novo coronary complex lesions in nonrandomized Japanese patients. Intern Med 2012;51:2695-701. [Crossref] [PubMed]
10. Nakano Y, Ishikawa T, Hino S, et al. Propensity score matched lesion-based comparison of long-term clinical and angiographic outcomes after placement of sirolimus (Cypher Bx Velocity) and paclitaxel (TAXUS Express)-eluting stents for de novo native coronary stenosis. Cardiovasc Interv Ther 2014;29:93-101. [Crossref] [PubMed]
11. Stone GW, Rizvi A, Newman W, et al. Everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease. N Engl J Med 2010;362:1663-74. [Crossref] [PubMed]
12. Foley DP, Serruys PW. Provisional stenting--stent-like balloon angioplasty: evidence to define the continuing role of balloon angioplasty for percutaneous coronary revascularization. Semin Interv Cardiol 1996;1:269-73. [PubMed]
13. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331:489-95. [Crossref] [PubMed]