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Coronary artery disease
Original research
Clinical outcomes with thin versus thick strut polymer-free biolimus-coated stents at 3 years
  1. Franz R Eberli1,
  2. Keith G Oldroyd2,
  3. Philip Urban3,
  4. Mitchell W Krucoff4,
  5. Marie-Claude Morice5,
  6. Jean-François Tanguay6,
  7. Martin B Leon7,
  8. Philippe Brunel8,
  9. Luc Maillard9,
  10. Janus Lipiecki10,
  11. Stéphane Cook11,
  12. Jacques Berland12,
  13. Thomas Hovasse13,
  14. Didier Carrié14,
  15. Diana Schütte2,
  16. Sara Sadozai Slama2 and
  17. Philippe Garot13
  1. 1Municipal Hospital Triemli, Zurich, Switzerland
  2. 2Biosensors Europe SA, Morges, Switzerland
  3. 3Cardiovascular Department, Cardiovascular European Research Centre, Massy, France
  4. 4Duke Clinical Research Institute, Durham, North Carolina, USA
  5. 5Cardiovascular European Research Centre, Massy, France
  6. 6Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada
  7. 7Center for Interventional Vascular Therapy, Columbia University Medical Center, New York, New York, USA
  8. 8Clinique de Fontaine, Dijon, France
  9. 9GCS ES Axium-Rambot, Aix-en-Provence, France
  10. 10Pole Sante Republique, Clermont-Ferrand, France
  11. 11Cardiology, Université de Fribourg, Fribourg, Switzerland
  12. 12Clinique Saint Hilaire, Rouen, France
  13. 13Institut Cardiovasculaire Paris Sud, Massy, France
  14. 14Cardiology, Centre Hospitalier Universitaire Rangueil, Toulouse, France
  1. Correspondence to Sara Sadozai Slama; s.sadozai{at}biosensors.com

Abstract

Background For high bleeding-risk patients (HBR) undergoing percutaneous coronary intervention (PCI), the LEADERS FREE (LF) and LEADERS FREE II (LF II) trials established the safety and efficacy of a stainless steel polymer-free biolimus-coated stent (SS-BCS) with 30 days of dual antiplatelet treatment (DAPT). The LEADERS FREE III (LF III) trial investigated clinical outcomes after PCI with the next-generation cobalt-chromium thin-strut polymer-free biolimus-coated stent (CoCr-BCS) in HBR patients.

Aims To report the final 3-year results of the LF III trial and compare them to LF II.

Methods LF III was a prospective, multicentre, open-label single-arm study to evaluate the safety and efficacy of the CoCr-BCS stent. The primary safety endpoint was the composite of cardiac death (CD), myocardial infarction(MI) or definite/probable stent thrombosis (ST). The primary efficacy endpoint was clinically driven target lesion revascularisation (cd-TLR). We performed a propensity-matched comparison to the 3-year outcomes of LF II.

Results After 3 years, CD/MI/ST had occurred in 57 patients (15%, 95% CI 11.8% to 19%) and cd-TLR in 23 (6.2%, 95% CI 4.1% to 9.2%) patients. In a propensity-matched comparison of patients treated with the CoCr-BCS versus the SS-BCS, there were similar rates of CD (6.6% vs 7.8%, p=0.50), MI (7.1% vs 8.3%, p=0.47) and definite/probable ST (1.1% vs 2%, HR 0.56, 95% CI 0.16 to 1.93, p=0.35). The rates of cd-TLR were 5.3% with CoCr-BCS versus 9.8% with SS-BCS (HR 0.54, 95% CI 0.31 to 0.96, p=0.03).

Conclusion LF III confirms the long-term safety and efficacy of the CoCr-BCS in HBR patients treated with 1 month of DAPT.

Trial registration number NCT02843633, NCT03118895.

  • Percutaneous Coronary Intervention
  • Computer Simulation
  • Coronary Artery Disease

Data availability statement

Data are available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/openhrt-2024-002679

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • The LEADERS FREE III trial established the safety and efficacy of a polymer-free BA9-coated thin-strut cobalt-chromium stent in patients at high bleeding risk treated with only 1 month of dual antiplatelet treatment (DAPT) after 1 year follow-up.

    WHAT THIS STUDY ADDS

    • This study reports the final 3-year follow-up of LEADERS FREE III, including a propensity-matched comparison to patients treated with the predicate stainless steel version of the stent from the LEADERS FREE II study.

    • LEADERS FREE III confirms the sustained safety and efficacy of the thin-strut cobalt-chromium polymer-free BA9 coated in high bleeding-risk patients treated with only 1 month of DAPT.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • High bleeding risk patients undergoing percutaneous coronary intervention now have the option of treatment with a modern thin-strut polymer-free biolimus-coated stent and only 1 month of DAPT. This study strongly suggests that the use of this device will be associated with improved clinical outcomes compared with the predicate thick-strut stainless steel version.

    Introduction

    Up to 45% of patients undergoing percutaneous coronary intervention (PCI) have a high bleeding risk (HBR).1 2 Prior to 2015, guidelines recommended that these patients receive bare metal stents (BMS) to allow a short (30-day) duration of dual antiplatelet therapy (DAPT), reducing the risk of bleeding and the associated increase in mortality.3–5 In HBR patients treated with 30 days of DAPT, the double-blind randomised controlled LEADERS FREE (LF) study showed that a stainless steel polymer-free biolimus-coated stent (SS-BCS) was superior to a stainless steel BMS (both strut thickness 114–119 µm) for both safety and efficacy.6 7 These findings were confirmed in the LEADERS FREE II (LF II) trial.8 Subsequently, a thin-strut (84–88 μm) cobalt-chromium version of the stent was designed (CoCr-BCS) with the expectation that thinner struts would improve stent deliverability, reduce restenosis and confer a lower degree of thrombogenicity.9 In the LEADERS FREE III (LF III) study, 404 HBR patients were treated with this novel stent and only 30 days of DAPT. After 1 year of follow-up, the CoCr-BCS was associated with excellent safety and similar repeat revascularisation rates to other modern thin-strut permanent polymer or biodegradable polymer limus-eluting stents.10 Now, we report the final 3-year outcomes of LF III and compare them to the final 3-year outcomes of the LF II trial.

    Methods

    Study devices and procedures

    The 1-year results of LF III have already been published.10 Briefly, patients were eligible for inclusion if they were scheduled for PCI and were defined as being at HBR using the same selection criteria employed in the LF trial.7 (online supplemental table 1). All patients received at least one Co-Cr BCS. Patients were to be treated only with study stents during the index procedure but could be treated with non-study stents during the staged procedure. Staged procedures were to occur within 7 days of the index procedure.

    View this table:
    Table 1

    Baseline characteristics

    All patients were formally enrolled when the guidewire had crossed the target lesion and the intervention, including stent placement, was performed according to guidelines and local clinical practice. The choice of vascular access and periprocedural drug regimen was left to the operator’s discretion. The protocol-driven antiplatelet regimen included aspirin (75–250 mg/day) and a P2Y12 inhibitor (preferably clopidogrel 75–150 mg/day) for 30 days. After 30 days, one drug had to be discontinued (preferably the P2Y12 inhibitor) and single antiplatelet therapy was continued until the end of the study. Follow-up was at 1 month, 6 months and 1 year in person and at 4 months, 24 and 36 months via telephone.

    An independent data safety monitoring board reviewed the data periodically and a clinical event committee adjudicated all clinical events from the day of the index procedure to the end of study follow-up. Source document monitoring was performed on 100% of the patients and the study complied with the Declaration of Helsinki. Local ethics committees approved the study and all patients signed informed consent before being treated.

    Primary and secondary endpoints

    The primary safety endpoint was a composite of cardiac death (CD), myocardial infarction (MI) and definite/probable stent thrombosis (ST). The primary efficacy endpoint was clinically indicated target lesion revascularisation (cd-TLR). The current analysis presents rates of the primary and secondary endpoints at 3 years. ST was defined according to the Academic Research Consortium.11 Bleeding events were reported according to the Bleeding Academic Research Consortium (BARC) criteria.12 cd-TLR was defined as stenosis >70% (by QCA), stenosis >50% ischaemic symptoms or stenosis >50%+positive fractional flow reserve.

    Statistical analysis

    Means and SD are reported for continuous variables and counts, and percentages are reported for categorical variables. Baseline characteristics were compared using a two-sample t-test for continuous variables and the χ2 test or Fisher’s exact test, as appropriate, for categorical variables. Time-to-first-event curves were generated using Kaplan-Meier estimates. A Cox proportional hazards model was used to calculate the HRs and corresponding 95% CIs. All statistical analyses were performed using SAS V.9.4 or higher (SAS Institute).

    The LF II and LF III trials both had a 3-year follow-up and used identical inclusion and exclusion criteria and endpoint definitions (figure 1), facilitating a post hoc analysis to compare outcomes. We performed a propensity score analysis using 40 baseline variables to adjust for baseline imbalances (online supplemental table 2). The variables chosen were selected because they were collected prospectively in both trials before the procedures and could potentially impact clinical outcomes. We used multiple imputations from a logistic regression to obtain the propensity scores for each patient. The propensity-matched analysis was performed as follows: one LF III patient was matched with three LF II patients. This ratio was chosen to retain as many patients as possible from the LF II cohort. We used a calliper of 0.25 SD of the mean propensity score.

    Figure 1
    Figure 1

    Inclusion criteria HBR. CoCr-BCS, cobalt-chromium thin-strut polymer-free biolimus-coated stent; HBR, high bleeding risk; LF, LEADER FREE; SS-BCS, stainless steel polymer-free biolimus-coated stent.

    View this table:
    Table 2

    Procedural characteristics

    Results

    Baseline characteristics

    There were 404 patients in LF III and 1203 patients in LF II. After propensity matching, there were 276 patients treated with a CoCr-BCS and 828 patients treated with an SS-BCS. The baseline characteristics of both the unmatched and matched study populations are shown in table 1. For the unmatched populations, patients in LF III had a lower incidence of previous PCI, previous coronary artery bypass grafting, congestive heart failure, hypertension and hypercholesterolaemia, but a higher incidence of peripheral vascular disease. Those differences were resolved in the propensity-matched populations. Regarding procedural characteristics, the two populations were well matched in terms of lesion length and reference vessel diameter. There were some imbalances observed in the unmatched populations for bifurcations, chronic total occlusions and de novo lesions, but these were also resolved after matching (table 2).

    Clinical outcomes

    The 3-year clinical event rates for the unmatched and matched populations are displayed in table 3. In the unmatched populations, patients treated with CoCr-BCS had lower rates of both cd-TLR (6.2% vs 11.3%, p=0.005) and cd-TVR (8.7% vs 13.8%, p=0.011). CD, MI and ST were similar in the two groups. In the propensity-matched analysis, results were similar, although the decrease in sample size increased the level of uncertainty. However, the reduction in cd-TLR was still significant (5.3% vs 9.9%, p=0.03) with a numerically lower definite/probable ST. The Kaplan-Meier curves for the primary safety and efficacy endpoints are displayed in figure 2A,B.

    Figure 2
    Figure 2

    Clinical events at 3 years. MI, myocardial infarction; ST, stent thrombosis.

    View this table:
    Table 3

    Clinical events

    Within the acute coronary syndrome subgroups, we chose to match only for ST-segment elevation myocardial infarction (STEMI), as the use of high-sensitivity troponin was markedly different between the study populations (80% in LFIII vs 40% in LF II) and may have resulted in a different threshold for the diagnoses of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) in patients presenting acutely. If matching is performed using all acute coronary syndromes (STEMI, NSTEMI and unstable angina), the HR for cd-TLR is 0.61 (95% CI 0.36 to 1.04, p=0.07), in favour of the CoCr-BCS.

    Although the HBR criteria for inclusion were identical in both studies, there was significantly less BARC 3–5 bleeding in LF III compared with LF II (unmatched 7.3% vs 13%, p=0.006; matched 5.7% vs 11.1%, p=0.017; figure 3). The patterns of DAPT/single antiplatelet therapy usage were similar between the two studies (figure 4). There were non-significant trends towards more overall use of anticoagulants in LF III compared with LF II and more of these were novel oral anticoagulants (NOACs). This may be related to the time difference between the recruitment periods of the two studies (table 4).

    Figure 3
    Figure 3

    BARC 3–5 bleedings at 3 years. BARC, Bleeding Academic Research Consortium.

    Figure 4
    Figure 4

    Compliance DAPT over time. CoCr-BCS, cobalt-chromium thin-strut polymer-free biolimus-coated stent; DAPT, dual antiplatelet therapy; SS-BCS, stainless steel polymer-free biolimus-coated stent.

    View this table:
    Table 4

    Medication over time

    Discussion

    This is the first time that 3-year follow-up data has been reported for either the original stainless steel version of the polymer-free BCS (BioFreedom) or the newer thinner strut CoCr version (BioFreedom Ultra). At 3 years, LF III confirmed the sustained safety and efficacy of the thin-strut CoCr stent in HBR patients treated with only 1 month of DAPT. In an unmatched, non-randomised comparison to patients from LF II treated with the stainless steel version of the stent, patients treated with the CoCr-BCS had numerically lower rates of CD, MI and definite/probable ST and significantly lower rates of cd-TLR and cd-TVR. Similar differences were observed in a propensity-matched analysis. It is remarkable to note the extremely low rate of cd-TLR in the LF III population during the second and third years of follow-up. The open-label ONYX ONE study randomised 1996 HBR patients undergoing PCI to receive either the SS-BCS or a thin-strut durable polymer zotarolimus-coated cobalt-platinum-iridium stent with 1 month of DAPT. ONYX ONE showed non-inferiority for both the composite primary outcome of CD, MI and ST and the main composite secondary outcome of target lesion failure consisting of CD, target vessel MI or clinically indicated TLR (ci-TLR) after 1 year of follow-up. The 2-year results also showed no significant differences between the groups for these endpoints.13 14 There was a significant reduction in ci-TLR in the zotarolimus-eluting stent group, most likely due to the lower strut thickness, but this has now been addressed by the new version of the polymer-free BCS. Interestingly, there was also a 22% reduction in both all-cause and cardiac mortality in favour of the polymer-free BCS (p=0.025 for all-cause mortality). This could be statistical noise, but an alternative hypothesis is that the absence of chronic polymer-induced vascular inflammation coupled with the long tissue half-life of biolimus provides enhanced vascular healing and plaque stabilisation, which offsets the negative effects of a thicker strut stent causing more vascular injury at the time of implantation.

    LF II and III used identical HBR inclusion criteria and exactly the same event ascertainment strategies with comprehensive site monitoring. Paradoxically, despite overall higher anticoagulant usage in LF III, we found less BARC 3–5 bleeding in the more recent study in both the unadjusted and adjusted comparisons. The proportion of patients treated with warfarin was similar in the two studies but the use of NOACs was higher in LF III, and the lower bleeding perhaps reflects the increased safety of NOACs compared with warfarin. After 3 years, there were numerically lower rates of both single antiplatelet therapy and DAPT use in LF III, possibly because more patients were on monotherapy with oral anticoagulation. In addition, the lower need for repeat revascularisation with the thin strut stent may have led to a reduced need to restart DAPT. It should be acknowledged that we only have data for the drug regimens at the follow-up time points during the study and only have limited data on how these drug regimens were modified in response to a bleeding event. The difference between the studies may simply reflect improved awareness of bleeding risk and improved management of bleeding events over time.

    Limitations

    The key limitations of the LF III trial are the comparatively small sample size and the single-arm design. The major limitation of the comparison with the results of the LF II trial is that this is non-randomised and even with propensity matching using 40 variables, it was still not possible to resolve all the population baseline differences. Specifically, there continues to be an imbalance in the proportion of patients with chronic coronary syndromes in LF III compared with LF II. Although this could bias the results in favour of the CoCr-BCS group, there are in fact no statistically significant between-group differences in any of the clinical outcomes at 3 years in either the unadjusted or adjusted populations, except for cd-TLR, which favours the CoCr-BCS. We think it unlikely that the difference in this fully adjudicated lesion-level outcome is solely related to the differences in clinical presentation and speculate that it may also be at least partially related to the thinner struts of the CoCr stent platform.

    Conclusions

    This is the first report of longer-term follow-up data in HBR patients undergoing PCI with the first-generation polymer-free SS-BCS and the second-generation polymer-free CoCr-BCS. At 3 years, in patients treated with only 1 month of DAPT, the thin-strut CoCr device showed equivalent safety and significantly improved efficacy compared with the stainless steel predecessor. In HBR populations selected using the same criteria, BARC 3–5 bleeding rates have declined over time, possibly due to changes in antiplatelet and antithrombotic drug regimens.

    Impact on daily practice

    HBR patients undergoing PCI now have the option of treatment with a modern thin-strut polymer-free BCS and only 1 month of DAPT. This study strongly suggests that the use of this device will be associated with improved clinical outcomes compared with the predicate thick-strut stainless steel version.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and LF II and LF III studies have been performed in many countries (Switzerland, France, Germany, the UK, the USA, Canada, Italy and South Korea). Each hospital (over 50 sites) has its own CE and gives its approval. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We would like to thank Ute Windhövel (Centre Européen de Recherche Cardiovasculaire, Massy, France) for her expert contributions to the preparation of this article.

    References

    1. ↵
      1. Frigoli E,
      2. Smits P,
      3. Vranckx P, et al
      . Design and rationale of the management of high bleeding risk patients post Bioresorbable polymer. Am Heart J 2019;209:97–105.
      OpenUrlPubMed
    2. ↵
      1. Urban P,
      2. Mehran R,
      3. Colleran R, et al
      . Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019;140:240–61. doi:10.1161/CIRCULATIONAHA.119.040167
      OpenUrlCrossRefPubMed
    3. ↵
      1. Morice M-C,
      2. Urban P,
      3. Greene S, et al
      . Why are we still using coronary bare metal stents. J Am Coll Cardiol 2013;61:1122–3. doi:10.1016/j.jacc.2012.11.049
      OpenUrlFREE Full Text
    4. ↵
      1. Rymer JA,
      2. Harrison RW,
      3. Dai D, et al
      . Trends in bare metal stent use in the United States in patients aged ≥65 years (from the Cathpci Registry). Am J Cardiol 2016;118:959–66. doi:10.1016/j.amjcard.2016.06.061
      OpenUrl
    5. ↵
      1. Piccolo R,
      2. Bonaa KH,
      3. Efthimiou O, et al
      . Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet 2019;393:2503–10. doi:10.1016/S0140-6736(19)30474-X
      OpenUrl
    6. ↵
      1. Urban P,
      2. Abizaid A,
      3. Chevalier B, et al
      . Rationale and design of the leaders free trial: a randomized double-blind comparison of the Biofreedom drug-coated Stent vs the gazelle bare metal Stent in patients at high bleeding risk using a short (1 month) course of dual antiplatelet therapy. Am Heart J 2013;165:704–9. doi:10.1016/j.ahj.2013.01.008
      OpenUrlCrossRefPubMed
    7. ↵
      1. Urban P,
      2. Meredith IT,
      3. Abizaid A, et al
      . Polymer-free drug-coated coronary stents in patients at high bleeding risk. N Engl J Med 2015;373:2038–47. doi:10.1056/NEJMoa1503943
      OpenUrlCrossRefPubMed
    8. ↵
      1. Krucoff MW,
      2. Urban P,
      3. Tanguay J-F, et al
      . Global approach to high bleeding risk patients with polymer-free drug-coated coronary stents: the LF II study. Circ: Cardiovascular Interventions 2020;13. doi:10.1161/CIRCINTERVENTIONS.119.008603
    9. ↵
      1. Stefanini G,
      2. Byrne R,
      3. Windecker S, et al
      . State of the art: coronary artery Stents – past, present and future. EuroIntervention 2017;13:706–16. doi:10.4244/EIJ-D-17-00557
      OpenUrlCrossRef
    10. ↵
      1. Eberli FR,
      2. Stoll HP,
      3. Urban P, et al
      . Polymer-free Biolimus-A9 coated thin strut stents for patients at high bleeding risk 1-year results from the LEADERS FREE III study. Catheter Cardiovasc Interv 2022;99:593–600.
      OpenUrl
    11. ↵
      1. Garcia-Garcia HM,
      2. McFadden EP,
      3. Farb A, et al
      . Standardized end point definitions for coronary intervention trials: the academic research Consortium-2 consensus document. Circulation 2018;137:2635–50. doi:10.1161/CIRCULATIONAHA.117.029289
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Mehran R,
      2. Rao SV,
      3. Bhatt DL, et al
      . Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation 2011;123:2736–47. doi:10.1161/CIRCULATIONAHA.110.009449
      OpenUrlFREE Full Text
    13. ↵
      1. Windecker S,
      2. Latib A,
      3. Kedhi E, et al
      . Polymer-based or polymer-free stents in patients at high bleeding risk. N Engl J Med 2020;382:1208–18. doi:10.1056/NEJMoa1910021
      OpenUrlPubMed
    14. ↵
      1. Windecker S,
      2. Latib A,
      3. Kedhi E, et al
      . Onyx ONE investigators polymer-based versus polymer-free stents in high bleeding risk patients: final 2-year results from onyx ONE. JACC Cardiovascular Intervention 2022;15:1153–63. doi:10.1016/j.jcin.2022.04.010
      OpenUrl

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    Footnotes

    • X @BiosensorsLtd

    • Contributors All authors take full responsibility for planning, data collection, analysis and interpretation, research conduct and manuscript submission. FRE and SSS performed statistical analysis and drafted the manuscript. FRE and SSS accept full responsibility for the work as guarantors.

    • Funding This study was funded by Biosensors International SA, Morges, Switzerland.

    • Competing interests KGO, and SSS are employees of the sponsor. DS has a consultant relationship with Biosensors. MWK reports grants and personal fees from Biosensors during the conduct of the study and grants and personal fees from Abbott Vascular, Medtronic, OrbusNeich, Terumo, and Cordis/Johnson & Johnson outside the submitted work. PU reports personal fees from Biosensors and others from Centre Européen de Recherche Cardiovasculaire (CERC), Massy, France, during the conduct of the study. J-FT reports grants from the Duke Clinical Research Institute during the conduct of the study; grants from Abbott Vascular, Bayer and Biosensors; other from BMS-Pfizer Alliance; and grants from Novartis outside the submitted work. M-CM reports being the CEO of CERC, Massy, France. MBL reports grants from Edwards Lifesciences, Medtronic and Boston Scientific outside the submitted work. The other authors report no conflicts.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.