Clinical Outcomes Following Implantation of Thin-Strut, Bioabsorbable Polymer-Coated, Everolimus-Eluting SYNERGY Stents
Abstract
Background:
The thin-strut SYNERGY stent has an abluminal everolimus-eluting bioabsorbable polymer coating designed to facilitate vascular healing and reduce risk of stent thrombosis. In the multicenter, randomized EVOLVE II trial (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]), SYNERGY was noninferior to the durable polymer PROMUS Element Plus everolimus-eluting stent for the primary end point of 1-year target lesion failure. Longer-term clinical follow-up will support the relative efficacy and safety of SYNERGY.
Methods:
Patients with ≤3 native coronary lesions (reference vessel diameter ≥2.25–≤4.00 mm; length ≤34 mm) in ≤2 major epicardial vessels were randomized 1:1 to SYNERGY (N=838) or PROMUS Element Plus (N=846). EVOLVE II included a Diabetes substudy which pooled patients with diabetes mellitus from the randomized controlled trial (n=263) and from a sequential, single-arm substudy (N=203).
Results:
The 5-year target lesion failure rate was 14.3% for SYNERGY and 14.2% for PROMUS Element Plus (P=0.91). Landmark analysis demonstrated similar rates of target lesion failure from discharge to 1-year (P=0.90) and from 1 to 5 years (P=0.94). Definite/probable stent thrombosis was infrequent in both arms (SYNERGY 0.7% versus PROMUS Element Plus 0.9%; P=0.75). There were no significant differences in the rates of cardiac death, myocardial infarction, or revascularization. Among patients with diabetes mellitus, the target lesion failure rate to 1-year was noninferior to a prespecified performance goal and to 5 years was 17.0%.
Conclusions:
SYNERGY demonstrated comparable outcomes to PROMUS Element Plus, with low rates of stent thrombosis and adverse events through 5 years of follow-up. Five-year clinical outcomes were favorable in patients with diabetes mellitus. These data support the long-term safety and effectiveness of SYNERGY in a broad range of patients.
Clinical Trial Registration:
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01665053.
WHAT IS KNOWN
Recent advances in bioabsorbable polymer stent technology have shown promising results in patients with coronary artery lesions.
The thin-strut platinum-chromium SYNERGY stent has an ultrathin abluminal bioabsorbable polymer coating that elutes everolimus in ≈3 months before complete resorption at ≈4 months. These design characteristics were intended to promote rapid healing and reduce stent thrombosis.
WHAT THE STUDY ADDS
EVOLVE II (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]) represents the largest population of patients with 5 years of follow-up after treatment with SYNERGY.
At 5 years, both stent platforms showed comparable safety and efficacy, with low adverse event rates. Five-year clinical outcomes were favorable in the EVOLVE II Diabetes substudy. Importantly, the incidence of stent thrombosis through 5 years was low in SYNERGY treated patients.
Introduction
Percutaneous coronary intervention with drug-eluting stents (DES) is the primary treatment for patients with coronary artery disease (CAD).1 However, the permanent presence of a polymer on DES may delay arterial healing, induce vascular inflammation and increase the risk of stent thrombosis (ST).2,3 There has been much discussion regarding the impact of polymer selection on DES performance. Some data have suggested worse outcomes in stents without a permanent polymer, and other studies have shown a protective effect of fluoropolymer-based everolimus-eluting stents (EES).4,5 Bioabsorbable polymer technology aims to reduce potential polymer related adverse events. Although clinical data from randomized trials and observational studies of bioabsorbable polymer DES have shown promising results, longer-term follow-up in larger patient cohorts has been lacking.6–8
The SYNERGY stent (Boston Scientific Corporation, Marlborough, MA) is a thin-strut platinum-chromium alloy stent coated abluminally with an ultrathin bioabsorbable everolimus-eluting polymer. The duration of everolimus release (≈90 days) is coincident with polymer resorption (≈120 days).9 The EVOLVE first human use10 trial demonstrated noninferiority of SYNERGY to the durable polymer PROMUS Element EES for 6-month late lumen loss as well as comparable rates of target lesion failure (TLF) at 30 days and 5 years.10,11 Importantly, no ST was observed in either treatment arm through 5 years.11
EVOLVE II (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]) is the pivotal randomized controlled trial (RCT) powered to evaluate the clinical efficacy and safety of SYNERGY for Food and Drug Administration approval.12 The prespecified and powered Diabetes substudy of EVOLVE II trial pooled patients with diabetes mellitus from the EVOLVE II RCT with those enrolled in a sequential, single-arm substudy.13 Both studies met their primary end points. This report characterizes the final 5-year clinical outcomes from the EVOLVE II RCT and Diabetes substudy.
Methods
Study Design and Patient Selection
EVOLVE II was a prospective, multinational, multicenter, randomized controlled, noninferiority trial. EVOLVE II included single-arm, nonrandomized (1) concurrent pharmacokinetic and (2) sequential diabetes mellitus substudies. Study design, methods, and primary outcomes have been previously described in detail.12,13 Briefly, patients with ≤3 native coronary lesions in ≤2 major epicardial vessels (reference vessel diameter ≥2.25 mm to ≤4.0 mm and lesion length ≤34 mm) were randomized 1:1 to SYNERGY or durable polymer PROMUS Element Plus stents. Patients with ST-segment–elevation myocardial infarction, left main or saphenous vein graft lesions, chronic total occlusion, in stent restenosis, and bifurcations requiring >1 stent were excluded. Following completion of RCT enrollment, patients with diabetes mellitus who met similar inclusion/exclusion criteria were enrolled into the Diabetes substudy.13 All patients were prescribed dual antiplatelet therapy with aspirin and a P2Y12 inhibitor for at least 6 months postprocedure (1-year in patients not at high bleeding risk).
This study was approved by Institutional Review Board at each site before enrollment and complied with the principles of the Declaration of Helsinki, the US Food and Drug Administration’s Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance and all applicable local and federal regulations. A written informed consent was obtained from all enrolled subjects. The data for this clinical trial may be made available to other researchers in accordance with the Boston Scientific Corporation Data Sharing Policy (http://www.bostonscientific.com/en-US/data-sharing-requests.html).
Study End Points
The study RCT primary end point was a noninferiority comparison of SYNERGY and PROMUS Element Plus for 1-year TLF (ischemia-driven target lesion revascularization, target vessel-related myocardial infarction [TV-MI], or cardiac death).12 For the Diabetes substudy, the primary end point of 1-year TLF was compared to a performance goal (14.5% based on event rates in patients with diabetes mellitus receiving EES and accounting for the more sensitive EVOLVE II MI definition).13 Additional prespecified clinical end points analyzed at 5 years included TLF, target vessel revascularization, target vessel failure (composite of ischemia-driven target vessel revascularization, TV-MI, or cardiac death related to target vessel), all-cause death, MI,11 and Academic Research Consortium defined ST.14 A clinical events committee reviewed and adjudicated all events of death, ST, target vessel revascularization, and MI through 5 years.
Statistical Analysis
Clinical time-to-event outcomes were evaluated by the Kaplan-Meier estimators. Hazard ratios were evaluated using the Cox proportional hazards regression model and P values using the Log-rank test. Discrete variables were reported as percentages (%), and continuous variables were estimated as mean±SD. Statistical analyses were conducted using SAS Version 9.0 or later (SAS Institute, Cary, NC).
Results
EVOLVE II Randomized Control Trial
EVOLVE II randomized 1684 patients to SYNERGY (N=846) or PROMUS Element Plus (N=838) stents. Figure 1 shows patient flow through 5 years. Twelve patients did not receive the assigned study stent and were not followed beyond 1-year per protocol. Rates of 5-year clinical follow-up were similar between SYNERGY and PROMUS Element Plus patients (Figure 1). As previously reported,12 clinical, lesion, and procedural characteristics were well-balanced between treatment groups (Table 1). Dual antiplatelet therapy and aspirin adherence were similar between treatment arms through 5 years (Table 2).
| EVOLVE II RCT PROMUS Element Plus | EVOLVE II RCT SYNERGY | |
|---|---|---|
| Patient characteristics | N=838 | N=846 |
| Male | 72.7% | 70.6% |
| Age (y)±SD | 63.9±10.5 | 63.5±10.4 |
| White | 79.2% | 77.4% |
| Smoking, ever | 62.8% | 61.7% |
| Current smoker | 22.4% | 21.8% |
| Diabetes mellitus* | 30.8% | 31.1% |
| Insulin treated | 10.9% | 12.3% |
| Hyperlipidemia* | 74.5% | 74.0% |
| Hypertension* | 75.1% | 77.3% |
| Unstable angina | 34.8% | 33.9% |
| Myocardial infarction | 29.2% | 25.9% |
| Target vessel treated† | ||
| LAD | 41.5% | 41.3% |
| LCx | 26.4% | 25.0% |
| RCA | 32.0% | 33.7% |
| Target lesions treated | 1.24±0.49 | 1.25±0.50 |
| 2 lesions | 19.3% | 18.6% |
| 3 lesions | 2.4% | 3.3% |
| Target lesion characteristics† | N=1043 | N=1059 lesions |
| RVD, mm | 2.63±0.50 | 2.62±0.49 |
| <2.25 mm | 23.3% | 23.9% |
| MLD, mm | 0.89±0.36 | 0.89±0.35 |
| Diameter stenosis, % | 66.26±11.75 | 66.02±12.03 |
| Lesion length, mm | 13.67±7.00 | 14.09±7.50 |
| Modified ACC/AHA B2/C | 74.3% | 76.8% |
| EVOLVE II RCT PROMUS Element Plus, N=838 Patients | EVOLVE II RCT SYNERGY, N=846 Patients | |
|---|---|---|
| Aspirin | ||
| Discharge | 99.8% | 100% |
| 1 y | 97.5% | 98.1% |
| 2 y | 96.0% | 96.6% |
| 3 y | 94.9% | 95.8% |
| 4 y | 94.3% | 96.0% |
| 5 y | 93.3% | 95.0% |
| Dual antiplatelet therapy | ||
| Discharge | 99.5% | 99.9% |
| 1 y | 84.2% | 85.9% |
| 2 y | 45.7% | 43.3% |
| 3 y | 39.3% | 39.9% |
| 4 y | 36.1% | 37.7% |
| 5 y | 34.3% | 36.0% |
Figure 1. EVOLVE II (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]) patient flow. *Includes investigator discretion. F/U indicates follow-up; PK, pharmacokinetic; and RCT, randomized control trial.
As previously reported,12 the RCT primary end point was met: SYNERGY was noninferior to PROMUS Element Plus for 1-year TLF (6.7% versus 6.5%, respectively; P[noninferiority] =0.0005). TLF rates through 5 years (Figure 2A) were similar between stents (SYNERGY 14.3% versus PROMUS Element Plus 14.2%; hazard ratio, 1.02; 95% CI, 0.79–1.31; P=0.91). Landmark analysis demonstrated comparable TLF rates at 1-year and between 1 and 5 years (Figure 2B). The individual components of TLF were not significantly different between treatment arms (Figure 3). Definite/probable ST occurred in 6 SYNERGY and 7 PROMUS Element Plus patients (Table 3). Additional clinical outcomes at 5 years poststent implantation were comparable between treatment arms (Table 3).
| EVOLVE II RCT PROMUS Element Plus, N=838 patients | EVOLVE II RCT SYNERGY, N=846 patients | |
|---|---|---|
| All death/myocardial infarction | 14.7% (118) | 15.2% (126) |
| Death | 7.4% (58) | 6.9% (56) |
| Cardiac death | 4.2% (33) | 3.5% (28) |
| Noncardiac death | 3.4% (25) | 3.5% (28) |
| Myocardial infarction | 8.9% (71) | 10.3% (84) |
| Q-wave | 0.5% (4) | 0.4% (3) |
| Non Q-wave | 8.4% (67) | 10.0% (82) |
| Target vessel revascularization | 11.2% (88) | 11.9% (96) |
| Target lesion revascularization | 5.2% (41) | 6.7% (54) |
| Target lesion failure | 14.2% (114) | 14.3% (118) |
| Target vessel failure | 18.1% (146) | 18.2% (150) |
| Definite/probable stent thrombosis | 0.9% (7) | 0.7% (6) |
| Definite | 0.5% (4) | 0.6% (5) |
| Probable | 0.4% (3) | 0.1% (1) |
Figure 2. Target lesion failure (TLF) in EVOLVE II (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]) randomized control trial (RCT).A, Kaplan-Meier curve for TLF through 5 y. B, Landmark analysis of TLF rates before and after 1-year follow-up. P value from log-rank test. HR indicates hazard ratio; and PE+, PROMUS Element Plus.
Figure 3. Time-to-event curves for individual components of target lesion failure (TLF).A, Cardiac death, (B) target vessel-related myocardial infarction (TV-MI), and (C) target lesion revascularization (TLR) through 5 y. P value from log-rank test. HR indicates hazard ratio; and PE+, PROMUS Element Plus.
EVOLVE II Diabetes Substudy
The Diabetes substudy pooled SYNERGY-treated patients with diabetes mellitus from the RCT (N=263) and the single-arm Diabetes substudy (N=203; Figure 1). Baseline characteristics have been reported previously.13 Three patients did not receive SYNERGY and were followed through 1-year. Five-year clinical follow-up was available in 86.4% of patients (Figure 1) and adherence to dual antiplatelet therapy and aspirin at 5 years was 36.4% and 93.1%, respectively (Table I in the Data Supplement). The primary end point of 1-year TLF was 7.5%, significantly less than the prespecified performance goal of 14.5% (P<0.0001)13; the 5-year rate of TLF was 17.0% (Figure 4). The components of TLF and additional prespecified outcomes through 5 years are shown in Figure 4 and Table II in the Data Supplement. Five patients experienced a definite ST (1.1%); no ST occurred after 30 days (Table II in the Data Supplement).
Figure 4. Target lesion failure (TLF) and components in the EVOLVE II (The EVOLVE II Clinical Trial to Assess the SYNERGY Stent System for the Treatment of Atherosclerotic Lesion[s]) Diabetes Substudy. Time-to-event curves through 5 y for (A) TLF, (B) target vessel-related myocardial infarction (TV-MI), (C) target lesion revascularization (TLR), and (D) cardiac death.
Discussion
EVOLVE II is the largest population of patients treated with SYNERGY to complete 5 years of follow-up. These results expand and extend our understanding of longer-term safety and efficacy of the bioabsorbable polymer EES in a broad patient population and provide valuable insights into the relative rates of clinical events observed with the permanent polymer PROMUS Element Plus stent. The principal findings through 5 years include (1) relatively low and similar TLF rates between cohorts; (2) no between-group differences in individual components of TLF (cardiac death, TV-MI, and target lesion revascularization); (3) rare occurrence of late/very late ST, with similar frequency between cohorts; and (4) low clinical event rates in patients with diabetes mellitus. Remarkably, no ST was observed in diabetic patients beyond 30 days after SYNERGY implantation. These observations must be viewed in context of recent data involving longer-term follow-up of patients treated with either bioabsorbable or permanent polymer DES.
Although permanent polymers with improved biocompatibility are associated with favorable clinical outcomes, they may still contribute to delayed/incomplete endothelialization and neoatherosclerosis.15,16 Recent DES design iterations involving antiproliferative drug-elution from bioabsorbable polymers may improve arterial healing and reduce late/very late thrombogenicity. Although both RCT and pooled analyses have shown promising clinical outcomes following bioabsorbable polymer versus permanent polymer second-generation DES, the relative contributions of polymer resorption versus stent strut thickness toward clinical events are difficult to discern.17,18 SYNERGY’s design includes thin platinum-chromium metal alloy struts (74 μm) with an ultrathin (4 μm) abluminal bioabsorbable everolimus-eluting polymer predicated on preclinical data suggesting facilitated endothelial coverage and healing as well as reduced thrombogenicity.19
Pooled analyses20 suggesting that ultrathin (<70 or 80 μm) stent strut thickness is associated with reduced clinical events (particularly TV-MI and ST) are supported by recent large-scale RCTs demonstrating low and comparable event rates in second-generation permanent polymer and newer bioabsorbable polymer DES.8,21 Despite marked differences in stent design, both SYNERGY and Orsiro (60 μm strut thickness, sirolimus-eluting) bioabsorbable polymer DES were noninferior to the thicker strut, permanent polymer, resolute integrity zotarolimus-eluting stent for 1-year target vessel failure in the all-comers BIO-RESORT (Comparison of Biodegradable Polymer and Durable Polymer Drug-Eluting Stents in an All Comers Population) RCT (N=3540).8 No between-group differences in target vessel failure or ST were observed at 3 years.21 Similarly, no difference in 1-year target vessel failure was observed in the all-comers BIONYX (Bioresorbable Polymer ORSIRO Versus Durable Polymer Resolute Onyx Stents) RCT (N=2488) despite differences in stent design between Orsiro and the thicker strut Resolute Onyx zotarolimus-eluting permanent polymer DES (4.7% Orsiro versus 4.5% Resolute Onyx); however, ST was lower following Resolute Onyx (0.1% versus 0.7% Orsiro; P=0.01).22 In the BIOFLOW V RCT (BIOFLOW Randomized Clinical Trial Comparing Orsiro Drug-Eluting Stent with Xience DES)23 (N=1334) for regulatory approval of Orsiro, TLF was significantly lower at both 1 and 2 years with Orsiro, driven largely by reduced TV-MI, compared to permanent polymer Xience EES. ST was also lower with Orsiro at 2 years (0.5% versus 1.2% Xience; P=0.17).23,24 Longer-term follow-up is necessary in these trials to evaluate the durability of these observations.
Five-year follow-up from large-scale all-comers RCT comparing permanent polymer second-generation DES exhibit TLF rates comparable to EVOLVE II. In the DUTCH PEERS (TWENTE II) trial (Durable Polymer-Based Stent Challenge of Promus Element Versus Resolute Integrity: TWENTE II; N=1811),25 5-year TLF rates for RESOLUTE Integrity versus PROMUS element stents were 12.0% versus 12.5%, and ST rates were 1.5% versus 1.3%. Five-year TLF rates in the COMPARE II trial (Comparison of the Everolimus Eluting With the Biolimus A9 Eluting Stent; N=2707 patients)26 for Xience versus Nobori (thick strut [120 μm] biolimus-eluting stent) were 11.5% versus 13.4% (P=0.17) and ST rates were 1.6% versus 1.7%. Acknowledging the pitfalls comparing trials, the 5-year rates of TLF in these all-comer trials are not dissimilar to those observed in EVOLVE II. Although 5-year rates of ST appear lower in EVOLVE II, particularly with SYNERGY (0.7%), EVOLVE II was not an all-comers trial and excluded ST-segment–elevation MI within 72 hours of enrollment. Longer clinical follow-up could provide important data to inform late-term outcomes and detect differences between stents. Recent longer-term follow-up (5–10 years) after DES implantation suggests that differences between devices may become more marked.27 ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents) demonstrated a divergence in clinical outcomes at 10 years favoring new versus early generation DES; no differences were observed between new-generation DES based on polymer resorption characteristics (permanent versus bioabsorbable).27
The diabetic substudy of EVOLVE II demonstrates exemplary clinical outcomes following SYNERGY stent treatment in patients with diabetes mellitus and provided basis for an indication for use in this population. The 1-year TLF rate was 7.5%, well below the prespecified performance goal, and the 5-year TLF rate was close to that in the overall study population. Annualized TLF rates beyond 1-year post SYNERGY implantation in the Diabetes substudy and RCT (2.4% and 1.9%, respectively) are consistent with other large-scale trials.28 Notably, the 5-year cumulative definite/probable ST rate in the Diabetic substudy was 1.1%, with no thrombotic events observed beyond 30 days. Although play of chance cannot be excluded, this observation supports durable safety of SYNERGY in a high-risk population. Multiple prior analyses have demonstrated diabetes to be a significant independent predictor of both TLF and ST following coronary stent deployment.29
Limitations
Several limitations should be noted. First, although the study population included patients with diabetes mellitus, MI, small target vessels, and complex target lesion morphology, it does not represent an all-comers population. Thus, observations made may not be extrapolated to all-comer populations. Alternatively, it might be argued that enrolling a more complex patient cohort could augment differences between stents. Such an observation was made in the BIOSCIENCE RCT (Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent for Percutaneous Coronary Revascularisation)30 in which the ultrathin-strut bioabsorbable polymer Orsiro performed better than the thicker strut, permanent polymer Xience when compared in the most complex patient subset. Second, EVOLVE II represents a large scale, pivotal trial for regulatory approval that was designed to test noninferiority of SYNERGY to PROMUS Element Plus for 1-year TLF. While a 5-year analysis was prespecified, it was neither designed nor powered to detect differences in clinical events or make definitive observations regarding the relative occurrences of low frequency events (ST). Finally, the Diabetes substudy includes a nonrandomized consecutive patient cohort and uses a performance goal. Although some have criticized this approach,31 this pragmatic substudy design has evolved in collaboration with the Food and Drug Administration because of the expense and difficulty to perform adequately-powered, randomized trials in individual patient subgroups. That said, a majority of patients in the Diabetes substudy came from the RCT, and outcomes in patients with diabetes mellitus from both sources were similar. Furthermore, clinical and angiographic inclusion/exclusion criteria for nonrandomized patients with diabetes mellitus were similar to the RCT.
Conclusions
The 5-year outcomes of EVOLVE II demonstrate long-term safety and efficacy of SYNERGY. Event rates were low and comparable between treatment groups. Furthermore, event rates in the Diabetes substudy were low through 5 years, with no incidence of ST beyond 30 days after implantation of SYNERGY. These observations support the favorable late/very late safety profile of the bioabsorbable polymer SYNERGY EES.
Acknowledgments
We thank Pooja Bhatt, PhD and Songtao Jiang, MSc (Boston Scientific Corporation) for assistance in article preparation and statistical analysis.
Sources of Funding
EVOLVE II was funded by Boston Scientific Corporation.
Disclosures
Dr Kereiakes received consultant fees (Boston Scientific Corporation [BSC], Abbott Vascular). Dr Windecker received research and educational grants (Abbott, Amgen, BSC, Biotronik, Bayer, BMS, CLS Behring, Edwards Lifesciences, Medtronic, Polares, and Sinomed). Dr Jobe received consultant fees from BSC. Dr Mehta received research grant support (Abbott Vascular, AstraZeneca, BSC, and Sanofi). Dr Feldman received research grants (BSC, Abbott Vascular, Medtronic, Svelte Medical Systems, Surmodics, Inc). Dr Stein received speaker’s bureau fees (AstraZeneca and Amgen). Dr Dubois received consultant fees (Medtronic and Xeltis). Dr Saito received consultant fees/honoraria (Terumo, Abbott Vascular, BSC, and Medtronic). Drs Underwood, Allocco, and Meredith are full-time employees with an equity interest in BSC. The other authors report no conflicts.
Footnotes
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