Durable versus biodegradable polymer drug-eluting stents in all-comers

Study population

The Cardio-FR registry at the University and Hospital Fribourg includes all patients aged 18+ admitted for PCI who provided written informed consent. It collects data on baseline characteristics, procedural details, in-hospital outcomes and annual clinical follow-ups via phone. The registry has been previously described.8 9 Briefly, stent allocation is randomised using a preset distribution key based on the annual calendar. We included all patients undergoing PCI with second-generation DP-DES or BP-DES from May 2015 to August 2021, with a completed 2-year follow-up. Exclusion criteria were lack of consent, loss to follow-up or hybrid procedures involving different DES types.

The registry complies with the Helsinki Declaration and was approved by the local ethics committee (003-REP-CER-FR) and registered in ClinicalTrials.gov (NCT04185285).

PCIs and medications

Procedures were performed via femoral or radial artery with a 6 French guiding catheter using standard techniques per guidelines. Intravascular imaging was at the operator’s discretion. Preprocedural antithrombotic therapy included aspirin (250–500 mg IV bolus if not pretreated, 100 mg/day thereafter) and unfractionated heparin (70 UI/kg); cangrelor and tirofiban were used at operator discretion. All patients received a loading dose of 600 mg clopidogrel, 180 mg ticagrelor or 60 mg prasugrel preprocedure or postprocedure. Long-term antiplatelet therapy included aspirin ≥100 mg/day plus either clopidogrel 75 mg, ticagrelor 90 mg two times per day or prasugrel 10 mg for at least 3 months. In patients on oral anticoagulation, aspirin 100 mg was given for at least a week and clopidogrel 75 mg daily for 6 months. Other medications followed standard care. Patients were monitored for 4–12 hours in intermediate care and underwent biomarker and ECG assessments preprocedure and postprocedure.

Study endpoints

The primary endpoint was device-oriented composite endpoint (DOCE), including cardiac death, non-fatal target vessel myocardial infarction (TVMI) and target lesion revascularisation (TLR). Secondary endpoints included patient-oriented composite endpoint (POCE), individual primary endpoints, all-cause mortality and ST incidence. Endpoints followed the Academic Research Consortium-2 (ARC-2) criteria.10 Death was cardiac if the cause was evident, unwitnessed or unknown. TLR was defined as repeat revascularisation within the stent or 5 mm proximal/distal. Target-vessel revascularisation was any revascularisation in the stented vessel, considered ischaemia-driven if associated with a positive functional study, stenosis ≥50% with ischaemic symptoms or stenosis ≥70% regardless of symptoms. Myocardial infarction (MI) was defined as new pathological Q waves (≥0.04 s in ≥2 contiguous leads) or creatine phosphokinase elevation >2× normal with specific elevation of myocardial enzymes, such as the CK-MB isoenzyme or troponin I.

ST was definite with angiographic thrombus confirmation and ischaemic signs or creatine kinase elevation >2× normal within 48 hours. Probable ST included unexplained death within 30 days or MI in the target vessel area without angiographic confirmation. Possible ST included unexplained death beyond 30 days. ST was classified as acute (<24 hours), subacute (24 hours–30 days), late (30 days–1 year) and very late (>1 year).

Statistical analysis

Categorical variables are reported as counts and percentages while continuous variables are reported as mean and SD. Normality was assessed by the computation of Q-Q plots and the Shapiro-Wilk test. Continuous variables were analysed using the Student’s t-test or the Wilcoxon rank-sum test per distribution. Categorical variables were compared using the χ² or Fisher exact test as appropriate. Survival data were analysed with the log-rank test. The proportional hazard condition was assessed with Kaplan Meier plots as well as ln/ln curves. Primary outcomes were also analysed using win ratio and Cox regression or binary logistic regression as appropriate. All statistical analyses except win ratios were performed using SPSS version 29 (SPSS, Chicago, Illinois, USA) at a 2-tailed significance level of alpha=0.05. Win ratios were performed with R V.4.4.1 (R Core Team, Vienna, Austria) using the WinRatio package11 at a 2-tailed significance level of alpha=0.05.

Population

During the inclusion period, 2824 patients were registered in the Cardio-FR registry. Of these, 2695 met the inclusion and exclusion criteria, but 616 patients were lost to follow-up. Consequently, the study population comprised 2079 patients, divided into two groups: 793 patients in the BP-DES group and 1286 patients in the DP-DES group. The flowchart is shown in figure 1. The presentation in terms of acute or chronic coronary syndromes is summarised in online supplemental table S1.

Baseline patient, lesion and procedural characteristics

The DP-DES group exhibited significantly higher rates of arterial hypertension (63.1% vs 57.5%, p=0.010), a greater average number of stents implanted per patient (1.72±0.92 vs 1.63±0.84, p=0.040), a higher proportion of patients with dual lesions (26.5% vs 22.1%, p=0.023) and more frequent use of postdilatation (42.2% vs 35.2%, p<0.001). Conversely, the BP-DES group demonstrated a significantly higher maximal inflation pressure (14.7±3.5 vs 14.3±3.2 ATM, p=0.003), higher rates of predilatation (80.1% vs 76.6%, p=0.026) and a numerical, though not statistically significant, difference in the number of patients who had undergone a previous PCI (29.9% vs 26.1%, p=0.062). The two groups also differed significantly in presentation, with more acute coronary syndrome (ACS) cases (55.1% vs 50.2%, p=0.031) in the DP-DES group and more chronic coronary syndrome cases (47.4% vs 42.7%, p=0.035) in the BP-DES group (table 1).

Studied stent characteristics

Table 2 presents the stents included in this study along with their key characteristics. The BP-DES group primarily comprised the Synergy II BP-DES (70.1%), whereas the DP-DES group mainly consisted of the Resolute Onyx DP-DES (66.2%).

Clinical outcomes

Table 3 and figure 2 illustrate clinical outcomes at 1-month, 1-year, and 2-year follow-up. At 1 month, treatment with BP-DES was associated with significantly higher rates of MI (7.6% vs 5.0%, p=0.015), a greater need for ischaemia-driven revascularisation (3.7% vs 2.0%, p=0.024) and a higher incidence of definite/probable ST (1.8% vs 0.8%, p=0.040). However, these differences were no longer observed at longer follow-up, and the occurrence of all events was similar between the two groups up to 2 years: the overall DOCE rate was comparable between the BP-DES and DP-DES groups (12.1% vs 14.5%, p=0.132), as was the incidence of TLR (6.3% vs 7.7%, p=0.238).

A subanalysis of the timing of ST revealed a notably higher incidence of acute ST in the BP-DES group (1.3% vs 0.3%, p=0.010) online supplemental table S2. The antiplatelet status, lesion and patient characteristics, as well as the use of intravascular imaging were similar between groups.

Multivariate analyses to adjust for potential confounders were also conducted. A Cox regression confirmed the significantly higher rate of acute ST (HR 0.240, 95% CI 0.075 to 0.766; p=0.016) in the BP-DES group but a similar rate of ST (HR 0.520, 95% CI 0.259 to 1.043; p=0.065) between the two groups at 2-year follow-up. Similarly, a binary logistic regression corroborated the comparable incidence of DOCE (OR 1.218, 95% CI 0.926 to 1.600; p=0.158) and POCE (OR 1.043, 95% CI 0.855 to 1.274; p=0.677) between the two groups at 2-year follow-up(online supplemental table S3).

Finally, an exploratory win ratio analysis was performed, further supporting the higher rate of acute ST (win ratio 4.09, 95% CI 1.28 to 13.09; p=0.018) in the BP-DES group, while showing a similar incidence of ST (win ratio 1.86, 95% CI 0.93 to 3.73; p=0.081) between the two groups at 2-year follow-up.

No net clinical benefit of BP-DES over DP-DES

This study found no significant difference in cumulative endpoints between the two groups. The BP-DES cohort consisted of 70% Synergy II, 20% Orsiro and 8% Biomatrix Alpha. This distribution may have influenced the results, as the most favourable studies supporting BP-DES over DP-DES were conducted with Orsiro.

Indeed, large-scale RCTs with 5-year follow-ups, such as BIOSCIENCE (A Randomized Comparison of a Sirolimus-eluting Stent With Biodegradable Polymer Versus an Everolimus-eluting Stent With a Durable Polymer for Percutaneous Coronary Revascularization),13 BIO-RESORT (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population),15 and COMPARE II (Abluminal biodegradable polymer biolimus-eluting stent versus durable polymer everolimus-eluting stent),16 have shown no significant differences between BP-DES and DP-DES. Similarly, the HOST REDUCE POLYTECH ACS RCT (Harmonizing Optimal Strategy for Treatment of coronary artery diseases--comparison of REDUCtion of prasugrEl dose or POLYmer TECHnology in ACS patients)17 reported comparable patient-oriented outcomes between DP-DES and BP-DES after 3 years in an ACS population. However, treatment with BP-DES was associated with a higher risk of device-oriented endpoints (HR 0.73, 95% CI 0.57 to 0.95; p=0.020), primarily due to an increased rate of TLR. This heightened risk was attributed to polymer degradation, as the higher incidence of device-oriented endpoints was only observed during the polymer degradation phase (8–16 months).

Conversely, BIOFLOW V (Ultrathin, bioresorbable polymer sirolimus-eluting stents versus thin, durable polymer everolimus-eluting stents in patients undergoing coronary revascularisation)¹⁸ reported significantly lower rates of TVMI (6.6% vs 10.3%, p=0.015) and late/very late ST (0.3% vs 1.6%, p=0.021) in the BP-DES group compared with the Xience DP-DES. Similarly, the BIOSTEMI (Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction)19 trial also noted a significant reduction in target lesion failure (TLF) in favour of BP-DES versus DP-DES (∆−3%; RR 0.70, 95% CI 0.51 to 0.95) in patients with acute ST-segment elevation myocardial infarction. Both studies were conducted with the Orsiro BP-DES.

A 2017 meta-analysis by El-Hayek et al,7 including 20 000 patients over 26 months, as well as longer 5-year follow-up meta-analyses by Kobayashi et al20 and Lou et al,21 found no significant differences between BP-DES and DP-DES. However, Zhu et al22 and Monjur et al23 reported a significant reduction in MI risk (RR 0.78, 95% CI 0.62 to 0.98) and TLF risk (OR 0.82, 95% CI 0.69 to 0.98; p=0.037) in the Orsiro BP-DES group. Furthermore, a network meta-analysis by Taglieri et al24 involving 99 039 patients identified the Orsiro BP-DES as potentially the DES with the lowest DOCE after 5 years, while reporting no significant differences between other BP-DES and DP-DES.

These findings suggest that the overall benefits of BP-DES may be primarily driven by Orsiro and that the predominance of Synergy II in the BP-DES cohort analysed in this study may have influenced the observed results. However, overall, the differences between the two DES classes remain marginal.

Increased early ST with BP-DES compared with DP-DES

Early ST is influenced by multiple factors, including patient characteristics (eg, diabetes mellitus), clinical setting (eg, ACS), procedural factors (eg, malapposition, malexpansion, stent length) and stent-related properties.25 The use of BP-DES has been theoretically associated with an increased prothrombotic risk during the polymer resorption phase, due to its proinflammatory properties. Indeed, experimental models have shown that conformal permanent polymer stents exhibit lower platelet accumulation under single antiplatelet therapy compared with abluminal bioabsorbable polymer-coated stents such as Synergy, which was the most commonly used BP-DES in this study.26 27

Consistently, despite the DP-DES group having a higher proportion of ACS cases and more stents per patient, the rate of acute ST was lower in the DP-DES group than in the BP-DES group in our study. The literature remains divided on this matter, with some studies reporting higher acute ST rates with BP-DES like the one by Zanchin et al12 (1.2% vs 0.3%; p=0.03) and others reporting higher unspecified ST rates with BP-DES like the MAUDE registry28 (10.0% vs 2.6%, p<0.001), while others, like the BIOFLOW V¹⁸ study reported lower late/very late ST rates (0.3% vs 1.6%, p=0.021) with BP-DES or the study from de Araujo and colleagues14 which reported equal unspecified ST rates between DP-DES and BP-DES (1.4% vs 1.4% p=1.000).

A possible explanation for this discrepancy is the specific stent used. In this registry, the most frequently implanted BP-DES was Synergy II, which may exhibit prothrombotic characteristics compared with other BP-DES, such as Orsiro18 or Inspiron.14 Supporting this hypothesis, an analysis of Synergy stent data from the POEM (Performance of Bioresorbable Polymer-Coated Everolimus-Eluting Synergy Stent in Patients at HBR Undergoing Percutaneous Coronary Revascularization Followed by 1-Month Dual Antiplatelet Therapy) trial,29 which evaluated 1-month dual antiplatelet therapy discontinuation, reported a higher ST rate (0.94%) (14) than comparable DP-DES cohorts (eg, 0.3% in Xience 28).30 This may be attributable to the proinflammatory degradation of Synergy’s polymer or from the more thrombogenic abluminal coating design.31

Finally, there is no reason to assume there was any difference in the implantation technique between the two groups in this study, and the statistical analysis revealed comparable antiaggregation status and lesion and patient characteristics in ST patients. It should be noted that STs are not systematically confirmed by intravascular imaging and that this significant difference in acute ST rates could be a chance finding resulting from the number of analyses from this current study. In any case, these findings should be interpreted with caution, as neither the other trials reporting ST rates12 14 18 28 nor this study were sufficiently powered to detect such rare events effectively.