Geographic Variations on the Safety and Efficacy of the Supreme Biodegradable Polymer DES: Results From PIONEER III

Background The PIONEER III trial showed the 12-month safety and efficacy of the Supreme drug-eluting stent (DES) vs the durable polymer everolimus-eluting stent. We sought to assess whether the characteristics and clinical outcomes of the Supreme DES in PIONEER III were consistent among patients by enrollment location. Methods This subgroup analysis of the PIONEER III trial compared the characteristics and outcomes of patients recruited from North America, Europe, and Japan and the relative differences in patient outcomes according to the site recruitment volume. Results From October 2017 to July 2019, 1629 patients were recruited in North America (816, 50.1%), Europe (650, 39.9%), and Japan (163, 10%). Procedural success was achieved in 1556 of 1611 procedures (96.6%), with no difference by the geographic location. Target lesion failure at 12 months for combined groups was observed in 84 of 1629 patients (5.2%), with no significant geographic differences (4.7%, 6.5%, and 2.5%, respectively; P =.08), with similar results in the Supreme DES group alone (4.4%, 6.8%, and 3.7%, respectively, P =.20). Cardiac death at 12 months occurred in 0.4%, 0.2%, and 0.0% (P =.79), target vessel–related myocardial infarction occurred in 2.2%, 4.7%, and 3.7%, (P =.10), and clinically driven target lesion revascularization was required in 2.1%, 3.1%, and 0%, respectively (P =.15). Compared with those from high-recruiting sites, results from low-recruiting sites were similar for target lesion failure, major adverse cardiac events, stent thrombosis, and mortality, with a nonsignificant trend for higher rates of myocardial infarction. Conclusions Despite regional differences in patient characteristics, the clinical outcomes between Supreme DES and durable polymer everolimus-eluting stent in the PIONEER III trial were not different, supporting the generalizability and robustness of the findings from this multicenter controlled trial.


Introduction
Percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is the most frequently used method for coronary revascularization.Second-generation DES are now available that have more biocompatible polymer coatings, thinner struts, and a better safety profile than first-generation DES. 1 Biodegradable polymer DES were developed to reduce polymer-related adverse effects known to be associated with delayed vessel healing and higher rates of stent thrombosis. 2 The Supreme sirolimus-eluting stent (SES; SINOMED) consists of a thin-strut (80 μm) cobalt-chromium platform with a submicrometer thin electrografted base layer, interdigitated to a uniform biodegradable top-coat that releases sirolimus within 28 days. 3The PIONEER II OCT trial demonstrated that at 1 month, the Supreme DES had more complete strut coverage than the durable polymer everolimus-eluting stent (DP-EES) (XIENCE; Abbott Vascular), 4 which elutes its antiproliferative drug over a longer timeframe.The pivotal PIONEER III IDE trial demonstrated that in patients with both acute coronary syndrome (ACS) and chronic coronary syndrome (CCS), the Supreme DES performance was noninferior to that of the standard DP-EES (target lesion failure [TLF] 5.4% with Supreme DES and 5.1% with DP-EES; absolute risk difference, 0.32% [95% CI, À1.87 to 2.5]; P noninferiority ¼.002). 5egional differences in patient demographics, operator expertise and technique, use of adjunctive pharmacotherapy, and other factors may affect clinical outcomes.We sought to evaluate regional differences in risk factors, procedural performance, and the overall and relative outcomes after Supreme DES or DP-EES implantation among patients recruited from North America, Europe, and Japan in the International PIONEER trial.Our aim was to determine whether outcomes remained consistent despite known geographic variations in patient characteristics and clinical practice and site recruitment volumes.

Study design
This is a subgroup analysis of the PIONEER III trial (NCT03168776) based on geographic regions, comparing North America, Europe, and Japan and the volume of recruitment at clinical sites.The PIONEER III trial design and rationale along with the principal 1-year results have been reported previously. 5In brief, PIONEER III was a prospective, international, 2:1 randomized, single-blind trial that compared the safety and effectiveness of PCI using the Supreme cobalt-chromium SES vs DP cobalt-chromium EES platform in patients with coronary artery disease presenting with ACS or CCS.Patients were recruited from 74 sites in the United States, Canada, Europe, and Japan.Inclusion criteria were presence of symptomatic ischemic heart disease with evidence of ischemia, unstable angina, or non-ST-segment elevation myocardial infarction (NSTEMI) requiring elective or urgent PCI, along with a de novo target vessel with a reference diameter of !2.25 mm and 4.0 mm and a visual diameter stenosis of !50% and <100%.Unprotected left main coronary artery disease, STEMI, and cardiogenic shock represented the main criteria for exclusion.Complete details of the inclusion and exclusion criteria have been reported. 5The trial was conducted according to the Declaration of Helsinki and Good Clinical Practice and was approved by the investigational review board or research ethics committee at each participating site.All participants gave their informed consent.Randomization was stratified according to recruiting site, clinical presentation (ACS vs CCS), and diabetes mellitus.Procedural recommendations were per standard of care.Daily aspirin was mandatory in all patients.An adenosine diphosphate platelet receptor antagonist was initiated prior to PCI and was continued for at least 6 months in patients with CCS and at least 12 months in patients with ACS in accordance with guidelines. 6,7Clinical follow-up was performed at 1 month, 6 months, 1 year, and is planned annually up to 5 years.

End points
The primary end point was TLF, a composite of cardiac death, target vessel-related myocardial infarction (MI), or clinically driven target lesion revascularization (TLR) at 12 months.Major powered secondary end points included components of the primary end point.All patients were followed up to 1 year.The definitions of all end points have been reported previously. 5An independent clinical event committee (Cardiovascular Research Foundation, New York, NY) adjudicated all events after a review of original source documents.An independent angiographic core laboratory reviewed all angiograms (Yale Cardiovascular Research Center, New Haven, CT).

Statistical analysis
Patient and procedural characteristics and outcomes were compared by region (North America, Europe, and Japan) and between high-volume sites (defined as sites recruiting !20 patients) and lowvolume sites (recruiting <20 patients).
Discrete variables, expressed as percentages with frequencies, were compared using the χ

Baseline patient characteristics and procedures by regions
The North American cohort comprised more women, patients with higher body mass index, and more patients with hypertension, previous coronary artery bypass grafting, multivessel and left anterior descending disease, and more unstable angina on presentation compared with those in the European and Japanese cohorts (Table 1).The baseline demographic and angiographic characteristics in patients randomized to the Supreme DES and DP-EES groups within each region were well balanced (Supplemental Tables S1-S3).
In Japan, patients underwent less multivessel interventions, fewer lesions were treated with fewer stents, and lesions were more likely to have predilation and postdilation performed compared with PCI procedures performed in Europe and North America (Table 2).In the North American cohort, there were fewer PCIs using a radial access but more intravascular ultrasound (IVUS) than fractional flow reserve (FFR) evaluations.Japan had the highest IVUS use compared with North America and Europe.
Medication use varied by region.North American sites used more potent antiplatelet agents with more frequent P2Y12 loading before PCI and more frequent use of IIb/IIIa inhibitors compared with that in the other regions (Tables 1 and 2).Lesion, device, and procedural success rates were not different between the regions (Table 2).

Baseline patient characteristics and procedures by site recruitment volume
Patients recruited from low-recruiting sites had higher rates of diabetes, hypertension, dyslipidemia, and previous PCI (Supplemental Table S4).Compared with those in high-recruiting sites, PCI procedures in low-recruiting sites comprised more predilation and postdilation, with more FFR and IVUS use (Supplemental Table S5).Lesion, device, and procedural success was not significantly different between lowrecruiting and high-recruiting sites (Supplemental Table S5).

Outcomes by region
In the entire cohort, there was a trend (nonsignificant) for higher rates of in-hospital and 1-month TLF among patients recruited from European sites (Table 3).This was predominantly driven by increased rates of periprocedural MI, most of which were NSTEMI.In patients treated using Supreme DES, the in-hospital and 1-month TLF and its individual components did not vary substantially with respect to the region of recruitment.
At 1 year, mortality rates were similar by region, but MI was more common among patients recruited in Europe than among patients recruited in North America and Japan, resulting in a trend for TLF (P ¼.08) and major adverse cardiac events (MACE; composite of all-cause death, MI, or target vessel revascularization; P ¼.10) (Table 3 and Figure 1).Among patients treated with Supreme DES, 1-year TLF and its components were similar in the North American, European, and Japanese cohorts.The relative risks for 1-year TLF after Supreme DES vs DP-EES implantation were consistent irrespective of geography (Figure 2).There was no interaction between groups for major outcome measures by geographic location (Central Illustration).Low-and high-recruiting sites had similar rates of TLF, MACE, and mortality, but low-recruiting sites had a trend for higher rates of MI; stent thrombosis rates were similar among regions (Table 4 and Figure 3).

Discussion
The main findings of this analysis are as follows.(1) The relative risk of the 1-year device-oriented composite TLF end point was consistent irrespective of geography both in the entire cohort and when comparing the Supreme DES with DP-EES cohort.(2) Individuals recruited from Europe had fewer comorbidities but more frequently presented with NSTEMI compared with patients recruited from North America and Japan.In addition, patients in Europe had higher rates of MI at 30 days (typically target vessel-related NSTEMI), which persisted at 1-year follow-up.(3) The relative risk for 1-year TLF was consistent in low-and high-recruiting sites.(4) Patients recruited in Japan had very few events at the 1-year follow-up (only 1 noncardiovascular death and 4 target vessel-related NSTEMI of the 163 patients).
This analysis of the PIONEER III trial illustrates the substantial variability in baseline characteristics, procedural techniques, and clinical outcomes among patients undergoing PCI in North America, Europe, and Japan.][10][11] A recent review of 701 PCI trials between 1990 and 2014 indicated that North American trials recruited the lowest proportion of male participants but the highest proportion of individuals with hypertension and dyslipidemia, whereas Asia recruited the highest proportion of patients with diabetes. 11The population breakdown of PIONEER III was consistent with these previous observations.Because differences in patient characteristics by geography may also affect outcomes, Liu et al 11 indicated that clinical trial results may not be applicable to patient populations from different regions.The present analysis demonstrated that the findings of the PIONEER III trial and the excellent safety and efficacy of the Supreme DES are relevant in North America, Europe, and Japan despite substantial different patient characteristics and procedural approaches.
At 1 year, the primary end point of TLF occurred in similar proportions of patients regardless of region.Importantly, patients from Europe experienced higher rates of NSTEMI at 30-day, 6-month, and 1-year follow-ups without differences in mortality, clinically driven TLR, or stent thrombosis.These findings are likely to be a function of the higher prevalence of NSTEMI on presentation and the more frequent multilesion and multivessel PCIs among the European cohort. 12The sensitivity of cardiac enzyme testing methods was consistent irrespective of geography.Furthermore, lower use of potent antiplatelet therapy (both preprocedural P2Y12 loading dose and per-procedure glycoprotein IIb/IIIa inhibitors), IVUS, and postdilation could be important factors associated with the higher incidence of target vessel-related MI in the European cohort. 13,14These factors cannot wholly account for the disparity in NSTEMI rates because the rates of lesion/device/procedure success did not differ significantly in North America, Europe, and Japan.Importantly, this higher rate of NSTEMI among Europeans was observed in the entire cohort of the PIONEER III trial but not in patients treated with the Supreme DES, indicating that a Attainment of final in-stent residual diameter stenosis of <30% by quantitative coronary angiography (QCA) using any percutaneous method.b Attainment of final in-stent residual diameter stenosis of <30% of the target lesion (by QCA) using the assigned device.The analysis included all target lesions in the denominator, whether an attempt to implant the assigned device was made.Lesions treated with multiple stents in which 1 stent is an assigned device and >1 is not the assigned device are considered as device failures.c Lesion success without the occurrence of in-hospital major adverse cardiac events, defined as a composite of all-cause death, myocardial infarction, or target vessel revascularization during the hospital stay.
this was not related to the investigated device but more likely to be associated with different patient presentation or procedure details.Findings related to low-versus high-recruiting sites provide interesting additional information.Despite having fewer comorbidities and a higher prevalence of acute presentation compared with those from sites with lower volume recruitment, individuals recruited in high-recruiting sites had similar rates of TLF and MACE but a trend toward higher rates of MI at 1 year; these events were mainly STEMI and were not associated with higher rates of stent thrombosis.Notably, the extremely low event rates reported among Japanese patients is remarkable with only 4 target-vessel NSTEMI and 1 noncardiac death among 163 patients.No stent thrombosis and no TLR were reported from the Japanese cohort.The reasons for this are probably multifactorial.This cannot be attributed to favorable patient risk profile because Japanese sites recruited older patients with higher rates of comorbidities including diabetes mellitus (44.2%), previous PCI (48.5%), a history of congestive heart failure (10.4%), and a history of carotid disease and stroke (8.6% for both) at the time of randomization.However, Japanese patients had less acute presentations (83.4% of them had stable angina or silent ischemia), and most of them had single-vessel disease (97.5%), indicating a highly selected "ideal" population for the purpose of a .64 .26Major adverse cardiac events b 31 ( .72 .33All-cause death 3 ( .03 STEMI 3 (0.5) 3 (0.4) 4 (0.9) 6 (0.9) 0 (0.0) 0 (0.0 evaluation, which is typically protocolized in Japan.Furthermore, racial and genetic differences in bioavailability of adjunctive pharmacology and increased sensitivity to antiplatelet agents among Japanese patients may contribute to observed differences.

Limitations
Recruiting site region was not a stratification variable in the PIONEER III trial.Although the baseline characteristics of patients randomized to the Supreme DES versus DP-EES cohorts within each geographic region were well balanced, differences in unmeasured confounders cannot be excluded.The regions of recruitment were subgroups and, hence, were individually underpowered for hypothesis testing.We relied on tests for interaction to examine whether relative outcomes for Supreme DES versus DP-EES use varied across the geographies; however, interaction testing was also underpowered.Therefore, we cannot exclude small differences in outcomes between regions.This is particularly true for the components of the primary end point.Of note, however, early MI (typically, periprocedural NSTEMI, ie, cardiac enzymes elevation) tended to be greater in European sites compared with that at North American and Japanese sites.It is unknown whether the trend for greater rate of clinically driven TLR contributed to this difference or was a consequence of it.The use of stress testing during follow-up and the exact indications for reintervention depended on the operators' routine practice and geographical differences in clinical criteria that might account for regional differences in revascularization were not collected in detail in the PIONEER III trial.Further study is warranted to understand the greater rates of early NSTEMI in Europe, which were sustained at the 1-year follow-up.This cannot be entirely explained by European sites recruiting individuals with more complex coronary anatomy because patients recruited at North American and Japanese sites had greater rates of comorbidities (especially diabetes mellitus), previous PCI, and unstable angina on presentation.Additional studies are required to determine whether the numerous patient and procedural differences between Europe and North America translate into differences in early MI after complex or multivessel interventions.Only 163 patients were recruited from Japan (approximately 10% of the patients recruited in the trial), precluding meaningful comparisons of outcomes from this region.Moreover, the results do not apply to patients with complex PCI (total occlusions, unprotected left main lesion, a lesion located in an arterial or vein graft, in-stent restenosis, and 2-stent bifurcation lesions), who were excluded from the PIONEER III trial.Finally, this analysis reports the 1-year outcomes after Supreme DES versus DP-EES implantation, which precludes identifying any potential interaction between geography and Supreme DES technology in terms of late healing.An additional geographic analysis is warranted at the 5-year follow-up.
The high-/low-volume analysis has substantial limitations.First, the cutoff value of 20 patients recruited in the trial is arbitrary, and a different cutoff may yield different results.Second, a low recruitment volume in the trial does not necessarily imply a low-volume PCI center.Third, the recruitment volume in the trial may be different from a learning curve because multiple operators may have treated few  patients in a single high-recruitment site, whereas a single operator may have treated more patients in a low-recruitment site.

Conclusions
Geographic variability did not affect treatment effects at 1 year in the PIONEER III trial, supporting the generalizability and robustness of the findings from this multicenter randomized controlled trial.

Figure 1 .
Figure 1.Rates of target lesion failure at 12 months by the region of recruitment.(A) Target lesion failure by site of recruitment (y-axis).(B) Target lesion failure by the site of recruitment in the Supreme DES cohort (y-axis).Target lesion failure is a composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target lesion revascularization.DES, drug-eluting stents.

Figure 2 .
Figure 2. Rates of target lesion failure at 12 months by region of recruitment and stent used.Target lesion failure in Supreme DES vs DP-EES (y-axis) at sites in (A) North America, (B) Europe, and (C) Japan.Target lesion failure is a composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target lesion revascularization.DES, drugeluting stents; DP-EES, durable polymer everolimus-eluting stents; HR, hazard ratio.

Figure 3 .
Figure 3.Rates of target lesion failure at 12 months in high-vs low-recruiting sites.(A) Target lesion failure at high-vs low-recruiting sites (y-axis).(B) Target lesion failure at high-vs lowrecruiting sites in the Supreme DES cohort (y-axis).High-recruiting sites recruited !20 patients.Low-recruiting sites recruited <20 patients.Target lesion failure is a composite of cardiac death, target vessel-related myocardial infarction, or clinically driven target lesion revascularization.DES, drug-eluting stents; HR, hazard ratio.

Table 1 .
Baseline demographic and angiographic characteristics according to the region of recruitment.

Table 2 .
Procedural characteristics according to the region of recruitment Values are n/N (%) or mean AE standard deviation.LAD, left anterior descending; LCX, left circumflex; OM, obtuse marginal; RCA, right coronary artery; RPDA, right posterior descending artery; RPL, right posterolateral.

Table 3 .
Outcomes by region of recruitment Composite of cardiac death, target vessel-related MI, or clinically driven TLR.b Composite of all-cause death, MI, or target vessel revascularization.c 1 day after stent implantation.d 0 to 30 days after stent implantation.e >30 days to 1 year after stent implantation.P. Garot et al. / Journal of the Society for Cardiovascular Angiography & Interventions 2 (2023) 100515 randomized comparison.Moreover, procedural characteristics were significantly different from North American and European sites with the highest use of predilation and postdilation (97.8% and 84.3%, respectively) and PCI guidance with FFR (25%) and IVUS (75%) a

Table 4 .
Outcomes at 1 year by recruitment volume NSTEMI, non-ST-segment elevation MI; STEMI, ST-segment elevation MI; TLR, target lesion revascularization.a Hazard ratio and 95% Wald CI are from Cox proportional hazards model, including treatment as a covariate.b P values for treatment comparison are from the log-rank test.c Composite of cardiac death, target vessel-related MI, or clinically driven target lesion revascularization.d Composite of all-cause death, MI, or target vessel revascularization.