Drug coated balloons and bare metal stents in ST-elevation myocardial infarction: eternal life or return of the living dead?

During the dawn of interventional treatment of coronary artery disease, bare metal stents (BMS) were developed to treat acute vessel closure and restenosis after plain balloon angioplasty (1). Since their efficacy was limited due to high rates of restenosis (2), first- and later second-generation drug-eluting stents (DES) were used more and more frequently. However, despite their beneficial efficacy and safety profile, modern DES continue to exhibit a constant occurrence of stent-related events at a rate of 2% per year (3). Therefore, new approaches to overcome this limitation were sought, e.g., biodegradable scaffolds and drug-coated balloons (DCB). While the use of biodegradable scaffolds was limited by high rates of stent thrombosis (4), drug-coated balloons are a novel and promising tool in the armamentarium of interventional cardiologists (5).

Currently, most interventions in the coronary field are performed using either DES or DCB, limiting the use of BMS in the real world to only 3.5% (6). However, in ST-elevation myocardial infarction (STEMI) some interventional cardiologists still may prefer BMS over DES (6,7) despite worse outcomes (8) and the clear recommendation of the current STEMI guidelines (9). The main motive of this preference is the long-term unfavorable safety and efficiency profile of DES and the risk of late and very late stent thrombosis (10).

In this context, the 8-year follow-up of the PEBSI study opens up new vistas (11). PEBSI randomized 223 patients with STEMI to either an interventional treatment with BMS (PRO-Kinetic Energy, Biotronik, Berlin, Germany) alone or to a combined therapy with BMS followed by a post-dilatation with a DCB (Pantera Lux, Biotronik, Berlin, Germany) and showed a median late lumen loss of 0.80 mm [interquartile range (IQR) 0.36–1.26 mm] in the BMS group vs. 0.31 mm (IQR 0.00–0.58 mm) in the combined BMS/DCB group after nine months (P<0.0001) (12). The long-term follow-up shows the very interesting finding of a target vessel failure (TVF) rate of only 3.7% in the combined BMS/DCB treatment group (vs. 14.3% in the BMS comparator group, P=0.006), which is one of the lowest TVF rates in BMS or DES studies ever published. While the very long follow up duration of 8 years and the low TVF rate of less than 4% are very intriguing, the fact that the PEBSI investigators randomized the patients after a successful BMS-Implantation needs special attention.

The combination of BMS and DCB has been tested in other settings already. In 2009, the results of the PEPCAD III trial were presented at the AHA Scientific Sessions in Orlando FL, but have never been published in a scientific journal. In this trial, the combination of a paclitaxel DCB and a BMS mounted on the same device was compared with DES in 637 patients with stable de-novo coronary artery disease and showed a target vessel revascularization (TVR) rate of 13.8% for the combined DCB/BMS and 6.9% for DES group (P<0.1). The difference between the PEPCAD III and PEBSI trials was not only the selection of devices and the patient population, but also the strategy. In PEPCAD III, BMS and DCB were used concomitantly in a combined device, whereas in PEBSI, the BMS and the DCB were used sequentially with individual devices. It is possible that the assembly of the simultaneous-use device impaired the efficacy of the DCB, while the sequential use of the devices allowed for a proper transfer of the drug to the vessel wall.

Apart from these considerations, the results of the combined BMS/DCB group in PEBSI may be related to various characteristics of the devices used, such as the DCB itself, the drug used on the DCB, the absence of polymer on the stent, or the thin stent strut design.

Is it the strut design? In the observational BIOHELIX-I study (13), the Prokinetik Energy platform, that was used for the present study as well, is characterized by very thin struts of only 60 µm and showed target-vessel failure rate of 9%. In the BIO-STEMI trial, the same stent platform combined with a biodegradable polymer (Orsiro, Biotronik) showed a target-lesion failure rate of only 5.1%, while the comparator durable-polymer DES (Xience, Abbott) showed a target lesion failure rate of 8.1% (14). In another STEMI study, the HEROES investigators (15) reported a target failure rate of only 0.6% in 353 STEMI patients treated with the same stent (Orsiro, Biotronik). Therefore, the thin stent strut design might have contributed to the result.

Is it the absence of the polymer? Although long-term presence of a polymer can cause inflammation and thrombogenesis, previous studies demonstrated that current second-generation durable-polymer DES is non-inferior to biodegradable or even polymer-free DES (16). Specifically, polymer-free DES were investigated in many trials in acute coronary syndromes (ACS) and STEMI, such as the LEADERS-FREE ACS sub-study (17) showing polymer-free DES being superior to DES in the setting of ACS with a target lesion failure of 3.9% vs. 9.0%, and the ISAR-5 study (18) showing no difference between polymer-free DES und durable-polymer DES in STEMI patients up to 5 years follow up with a major adverse cardiovascular event (MACE) of 18% vs. 20%. The results of these studies support the theory that the success of the present DCB/BMS combination may be eased by the absence of a polymer.

Is it the DCB itself? The DEB-AMI trial failed to show an equipoise of DCB combined with BMS to BMS or DES (19). In this trial, DES was superior to the other two groups, while BMS alone was even better than the combined strategy with DCB and BMS. However, in this trial the STEMI patients were randomized to one of the 3 groups before dilatation. In two other studies, the use of DCB alone was compared to DES in STEMI patients (20,21). In these studies, DCB were non-inferior regarding the primary endpoint, but there was a high percentage of patients requiring stent implantations due to dissections. Just recently, Merinopoulos et al. (22) assessed the use of DCB alone versus DES in more than 1,000 STEMI patients. This observational study showed non-inferiority of DCB vs. DES for up to 3 years regarding mortality and target lesion revascularization. Therefore, the effect of DCB in the setting of STEMI may be favorable but its use may be limited by flow-limiting dissections after the first balloon dilatation leading to stent implantation.

Is it the drug on the DCB? Paclitaxel, which has been used as drug coating on the balloon in the current trial, has a potent antiproliferative effect by binding to the β subunit of tubulin, resulting in arrest of microtubule function, and thus preventing restenosis (23). The PEBSI authors evaluated 53 patients with optical coherence tomography after 9 months (24), which revealed a significantly lower rate of major coronary evaginations and development of a thin homogeneous neointimal layer in the DCB/BMS combined group, suggesting distinct superior healing at 3 months compared to BMS alone. Major coronary evaginations were mainly present with first-generation sirolimus stents, but not with later-generation DES (25). Therefore, the 9-month optical coherence tomography data of the current trial support the theory that the potent antiproliferative effect of paclitaxel delivered by the DCB prevented intimal hyperplasia and instent restenosis, but allowed for a thin neointimal layer, thus prevented instent thrombosis.

Therefore, all of these four device characteristics may have been contributed to the favorable long-term outcome of PEBSI. However, it is fair to say that the postdilatation of the BMS with DCB may have prevented the unfavorable consequences of the stent, i.e., restenosis, by adding an antiproliferative drug, while the stent may have prevented the unfavorable consequences of angioplasty, i.e., high-grade dissections or relevant residual stenosis.

Based on the presented data showing an excellent long-term outcome of a combined treatment strategy of BMS implantation followed by DCB postdilatation, the question remains whether PEBSI will change our daily practice. Based on the presented data, a combined BMS/DES-treatment strategy for STEMI may be a feasible approach. However, in the light of the conflicting PEPCAD data, a combined DCB/BMS strategy cannot be recommended to be pursued at the time being. However, these appealing results may encourage the interventional community to intensively evaluate of the role of DCB in a STEMI population, in order to overcome current limitations of DES in this indication. These investigations may answer the question if DCB are going to give BMS an eternal life or if it is just a return of the living dead.

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-2023-4/coif). AF received support from Euro-PCR to attend London valves and Euro-PCR. RVJ reports grants from Abbott Medical (Schweiz) AG, AstraZeneca, Bayer (Schweiz) AG, Boehringer Ingelheim (Schweiz) AG, Biotronik (Schweiz) AG, Boston Scientific AG, Cordis Medical GmbH, Edwards Lifesciences SA, Johnson Johnson AG, Medtronic (Schweiz) AG, and Terumo Deutschland AG. The authors have no other 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. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987;316:701-6. [Crossref] [PubMed]
2. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis. Lancet 2007;370:937-48. [Crossref] [PubMed]
3. Madhavan MV, Kirtane AJ, Redfors B, et al. Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention. J Am Coll Cardiol 2020;75:590-604. [Crossref] [PubMed]
4. Brugaletta S, Gori T, Low AF, et al. Absorb bioresorbable vascular scaffold versus everolimus-eluting metallic stent in ST-segment elevation myocardial infarction: 1-year results of a propensity score matching comparison: the BVS-EXAMINATION Study (bioresorbable vascular scaffold-a clinical evaluation of everolimus eluting coronary stents in the treatment of patients with ST-segment elevation myocardial infarction). JACC Cardiovasc Interv 2015;8:189-97. [Crossref] [PubMed]
5. 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]
6. Giannini F, Pagnesi M, Campo G, et al. Italian Multicenter Registry of Bare Metal Stent Use in Modern Percutaneous Coronary Intervention Era (AMARCORD): A multicenter observational study. Catheter Cardiovasc Interv 2021;97:411-20. [Crossref] [PubMed]
7. Hensey M, Sathananthan J, Teguh WP, et al. Is There a Role for Bare-Metal Stents in Current STEMI Care?. In: Watson TJ, Ong PJL, Tcheng JE, eds. Primary Angioplasty: A Practical Guide. Singapore: Springer; July 14, 2018.137-150.
8. Wang CH, Fang Q, Zhang SY, et al. Long-term effects of drug-eluting stents versus bare metal stents on patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: outcomes of 3-year clinical follow-up. Chin Med J (Engl) 2012;125:2803-6. [PubMed]
9. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289-367. [Crossref] [PubMed]
10. Dangas GD, Caixeta A, Mehran R, et al. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation 2011;123:1745-56. [Crossref] [PubMed]
11. Touchard AG, Sabaté M, Alfonso F, 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 Randomized Clinical Trial (PEBSI). Cardiovasc Diagn Ther 2023;13:792-804.
12. 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]
13. Michael TT, Richardt G, Lansky A, et al. Nine-month results of the BIOHELIX-I clinical trial study: Evaluation of the PRO-Kinetic Energy cobalt chromium bare-metal stent system. Catheter Cardiovasc Interv 2018;92:1030-9. [Crossref] [PubMed]
14. Pilgrim T, Muller O, Heg D, et al. Biodegradable- Versus Durable-Polymer Drug-Eluting Stents for STEMI: Final 2-Year Outcomes of the BIOSTEMI Trial. JACC Cardiovasc Interv 2021;14:639-48. [Crossref] [PubMed]
15. De Marzo V, Parisi R, Caruso M, et al. Hard Events AfteR Orsiro Sirolimus-Eluting Stent (HEROES) in STEMI: A Multicenter Registry. J Invasive Cardiol 2020;32:E331-7. [PubMed]
16. Srdanovic I. Factors Influencing 1st and 2nd Generation Drug-Eluting Stent Performance: Understanding the Basic Pharmaceutical Drug-in-Polymer Formulation Factors Contributing to Stent Thrombosis Do We Really Need to Eliminate the Polymer? J Pharm Pharm Sci 2021;24:435-61. [Crossref] [PubMed]
17. Naber CK, Urban P, Ong PJ, et al. Biolimus-A9 polymer-free coated stent in high bleeding risk patients with acute coronary syndrome: a Leaders Free ACS sub-study. Eur Heart J 2017;38:961-9. [PubMed]
18. Colleran R, Kufner S, Harada Y, et al. Five-year follow-up of polymer-free sirolimus- and probucol-eluting stents versus new generation zotarolimus-eluting stents in patients presenting with ST-elevation myocardial infarction. Catheter Cardiovasc Interv 2017;89:367-74. [Crossref] [PubMed]
19. Nijhoff F, Agostoni P, Belkacemi A, et al. Primary percutaneous coronary intervention by drug-eluting balloon angioplasty: the nonrandomized fourth arm of the DEB-AMI (drug-eluting balloon in ST-segment elevation myocardial infarction) trial. Catheter Cardiovasc Interv 2015;86:S34-44. [Crossref] [PubMed]
20. 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]
21. 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]
22. Merinopoulos I, Gunawardena T, Corballis N, et al. Assessment of Paclitaxel Drug-Coated Balloon Only Angioplasty in STEMI. JACC Cardiovasc Interv 2023;16:771-9. [Crossref] [PubMed]
23. Gray WA, Granada JF. Drug-coated balloons for the prevention of vascular restenosis. Circulation 2010;121:2672-80. [Crossref] [PubMed]
24. 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]
25. Radu MD, Räber L, Kalesan B, et al. Coronary evaginations are associated with positive vessel remodelling and are nearly absent following implantation of newer-generation drug-eluting stents: an optical coherence tomography and intravascular ultrasound study. Eur Heart J 2014;35:795-807. [Crossref] [PubMed]