Exploring alternatives to drug-eluting stents: the potential of combining drug coated balloon with bare-metal stents

Despite the establishment of optimal pharmacologic therapies for atherosclerotic cardiovascular disease, ST-segment elevation myocardial infarction (STEMI) remains a leading cause of death in developed countries (1). For STEMI cases, coronary stenting with new-generation drug-eluting stents (DES) has demonstrated superior safety and efficacy compared with the use of bare-metal stents (BMS) and first-generation DES, and has gained global consensus as the first-line treatment option (2-4). However, even in the era of new-generation DES, there are the remaining problems of late in-stent restenosis and very late stent thrombosis caused by neoatherosclerosis, which is histologically characterized by accumulation of lipid-laden foamy macrophages within the neointima with or without necrotic core formation and/or calcification (5,6). One potential mechanism of accelerated neoatherosclerosis is the promotion of chronic inflammation derived from the polymers that coat the DES. Dedicated studies are warranted to explore new revascularization methods that reduce events in the chronic phase.

Drug-coated balloons (DCB), first introduced for the treatment of in-stent restenosis, have been gaining attention as an alternative to new-generation DES for de novo coronary artery lesions (7). To date, several randomized controlled trials (RCTs) have investigated efficacy of the DCB-only strategy in STEMI (Table 1) (8-15). These studies demonstrated that the incidence of adverse cardiovascular events in the early post-revascularization period was similar in the DCB-only group and the DES group (8,10,11). Furthermore, the values of fractional flow reserve and the degree of late lumen loss at 9 months were also comparable between the group (9,12). These results suggested the applicability of DCB-only strategy in STEMI, however, these RCTs had the limitation of small sample sizes and short observation periods. In addition, the DCB-only strategy required bailout stenting in a certain number of cases due to the inability to obtain sufficient luminal gain or the occurrence of coronary artery dissection, a causative factor for late restenosis. Since the majority of coronary dissections are not apparent on angiography, potential vascular injury in the DCB-only strategy may compromise their clinical efficacy (16).

In a recent study published on Cardiovascular Diagnosis and Therapy, the authors have explored the potential of the DCB-combined strategy; DCB dilatation following BMS implantation (14). The possible benefits of this strategy are that BMS may provide acute gains, DCB may inhibit endometrial proliferation in the early posttreatment period, and the absence of polymers may also inhibit neoatherosclerosis formation in the chronic period due to the lack of inflammation. In PEBSI (paclitaxel-eluting balloon after bare metal stent implantation)-1 trial, they have already reported smaller late lumen loss at 9 months and better clinical outcomes at 1 year in the DCB-combined group compared to the BMS group (13). Furthermore, their optical coherence tomography study has also demonstrated that the DCB-combined group exhibited more optimal strut coverage at 3 months compared to the treatment with new-generation sirolimus-eluting stents (17). In the present issue, García-Touchard et al. evaluated 8-year clinical follow-up of patients enrolled in the PEBSI-1 trial (14). The main findings of their study are (I) the DCB-combined group showed lower rate of target vessel revascularization (TVR) [3.7% vs. 14.3%; hazard ratio: 0.24, 95% confidence interval (CI): 0.08–0.73; P=0.006] and trends towards lower rate of target lesion revascularization (TLR) (2.8% vs. 8.9%; hazard ratio: 0.3, 95% CI: 0.083–1.090; P=0.052) compared to the BMS group; (II) there was no significant differences in the occurrence of all-cause death, cardiac death, reinfarction, or stent thrombosis between the groups; (III) there were no cardiac death, no TVR, no TLR in the DCB-combined group beyond the 5-year follow-up; (IV) in contrast, the BMS group experienced an additional cardiac death, one case of TVR, one case of TLR, and one case of stent thrombosis during the period from year 5 to 8.

Although this study provides additional clinical data to support the favorable anti-atherosclerotic effect of DCB-combined strategy, several limitations should be considered when interpreting the findings. First, the control group in this study was BMS, not new-generation DES, which is the first-line treatment for STEMI in the modern era. Therefore, it is not possible to assess whether the DCB-combined strategy is worth changing the current treatment strategy. Belkacemi et al. reported conflicting results with the present study, in which the BMS implantation after DCB dilatation strategy failed to demonstrate angiographic superiority over BMS alone; furthermore, in that study first-generation DES demonstrated angiographic superiority over both BMS and the BMS after DCB strategy, as well as a reduction in future in-stent restenosis and adverse cardiac events (15). Second, this study included only cases with successful BMS implantation, which may introduce the selection bias. Since this study included only cases of successful procedures, it is not surprising that the number of subsequent events in long-term follow-up was suppressed. Third, because the DCB-combined strategy significantly suppressed TVR rather than TLR, it may not have been able to demonstrate a significant effect on the suppression of neoatherosclerosis formation at the treated lesions, which is important in contrast to the conventional DES strategy. The Kaplan-Meier curve of TLR suggests that the early neointimal proliferation inhibition by DCB suppressed the restenosis better than the BMS group, but the nearly parallel curves in the chronic phase do not indicate a conferred effect of DCB for suppressing neoatherosclerosis formation. Fourth, the authors emphasized that TVR, TLR, and stent thrombosis did not occur after 5 years in the DCB-combined group, but only one case occurred in the BMS group during the same period. Given the small sample size of this study, which was set up to compare late lumen loss rather than clinical outcomes, it is unclear whether the difference in this small number of events makes sense. Fifth, the DCB-combined strategy uses both BMS and DCB, which may make revascularization procedure more expensive and time-consuming.

The novel and interesting concept of the DCB-combined strategy has proven to be effective in BMS-controlled studies, but caution is needed in interpreting the results. Further dedicated studies with new-generation DES-controlled, with large sample, and perhaps requiring long-term follow-up are needed to determine whether the DCB-combined strategy can be alternative to the current new-generation DES strategy.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-23-297/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. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation 2022;145:e153-639. [Crossref] [PubMed]
2. Brugaletta S, Gomez-Lara J, Ortega-Paz L, et al. 10-Year Follow-Up of Patients With Everolimus-Eluting Versus Bare-Metal Stents After ST-Segment Elevation Myocardial Infarction. J Am Coll Cardiol 2021;77:1165-78. [Crossref] [PubMed]
3. Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39:119-77. [Crossref] [PubMed]
4. Lawton JS, Tamis-Holland JE, Bangalore S, 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. Circulation 2022;145:e18-114. [Crossref] [PubMed]
5. Otsuka F, Byrne RA, Yahagi K, et al. Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment. Eur Heart J 2015;36:2147-59. [Crossref] [PubMed]
6. Otsuka F, Vorpahl M, Nakano M, et al. Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans. Circulation 2014;129:211-23. [Crossref] [PubMed]
7. Rissanen TT, Uskela S, Eränen 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;394:230-9. [Crossref] [PubMed]
8. Gobić D, Tomulić V, Lulić D, et al. Drug-Coated Balloon Versus Drug-Eluting Stent in Primary Percutaneous Coronary Intervention: A Feasibility Study. Am J Med Sci 2017;354:553-60. [Crossref] [PubMed]
9. Vos NS, Fagel ND, Amoroso G, et al. Paclitaxel-Coated Balloon Angioplasty Versus Drug-Eluting Stent in Acute Myocardial Infarction: The REVELATION Randomized Trial. JACC Cardiovasc Interv 2019;12:1691-9. [Crossref] [PubMed]
10. Hao X, Huang D, Wang Z, et al. Study on the safety and effectiveness of drug-coated balloons in patients with acute myocardial infarction. J Cardiothorac Surg 2021;16:178. [Crossref] [PubMed]
11. Niehe SR, Vos NS, Van Der Schaaf RJ, et al. Two-Year Clinical Outcomes of the REVELATION Study: Sustained Safety and Feasibility of Paclitaxel-Coated Balloon Angioplasty Versus Drug-Eluting Stent in Acute Myocardial Infarction. J Invasive Cardiol 2022;34:E39-42. [PubMed]
12. Wang Z, Yin Y, Li J, et al. New Ultrasound-Controlled Paclitaxel Releasing Balloon vs. Asymmetric Drug-Eluting Stent in Primary ST-Segment Elevation Myocardial Infarction - A Prospective Randomized Trial. Circ J 2022;86:642-50. [Crossref] [PubMed]
13. García-Touchard A, Goicolea J, Sabaté M, et al. A randomised trial of paclitaxel-eluting balloon after bare metal stent implantation vs. bare metal stent in ST-elevation myocardial infarction (the PEBSI study). EuroIntervention 2017;12:1587-94. [Crossref] [PubMed]
14. García-Touchard A, Sabaté M, Gonzalo N, et al. Very long-term efficacy and safety of paclitaxel-eluting balloon after a bare-metal stent for the treatment of ST elevation myocardial infarction: 8-year results of a randomized clinical trial (PEBSI Study). Cardiovasc Diagn Ther 2023;13:792-804.
15. Belkacemi A, Agostoni P, Nathoe HM, et al. First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial: a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes. J Am Coll Cardiol 2012;59:2327-37. [Crossref] [PubMed]
16. Chamié D, Bezerra HG, Attizzani GF, et al. Incidence, predictors, morphological characteristics, and clinical outcomes of stent edge dissections detected by optical coherence tomography. JACC Cardiovasc Interv 2013;6:800-13. [Crossref] [PubMed]
17. García-Touchard A, Gonzalo N, Goicolea J, et al. Early coronary healing in ST segment elevation myocardial infarction: sirolimus-eluting stents vs. drug-coated balloons after bare-metal stents. The PEBSI-2 optical coherence tomography randomized study. Coron Artery Dis 2021;32:673-80. [Crossref] [PubMed]