Abstract
Background
Contemporary large-scale trials have demonstrated enhanced safety and efficacy for ultrathin strut coronary drug-eluting stents. A postmarket US study evaluating ultrathin strut drug-eluting stents committed to long-term follow-up was performed to evaluate the long-term clinical results following percutaneous coronary intervention with ultrathin strut (60 μm) bioresorbable polymer sirolimus-eluting stents (BP SES) in real-world clinical practice.
Methods
BIOFLOW VII is a prospective, multicenter, single-arm registry examining the clinical effectiveness of an ultrathin strut (60 μm) BP SES with dedicated follow-up through 5 years. The primary end point of 12-month target lesion failure (TLF) was previously reported. A prespecified analysis of 2-year clinical outcomes was performed.
Results
BIOFLOW VII enrolled 556 patients at 31 sites in the United States. The average stent length (mean ± SD) was 20.2 ± 11.8 mm, and the mean number of stents per patient was 1.3 ± 0.6. The 2-year TLF rate was 5.2% (27/522). TLF component rates included cardiac death, 1.7% (9/522); target vessel-related myocardial infarction, 1.7% (9/515); and ischemia-driven target lesion revascularization, 2.7% (14/515). Definite stent thrombosis was observed in 3 cases (0.5%): 1 acute (≤24 hours), 1 late (>30 days and ≤1 year), and 1 very late (>1 year) event.
Conclusions
The 2-year BIOFLOW VII results demonstrate the durability of efficacy and safety of ultrathin BP SES. Favorably low rates of ischemia-driven target lesion revascularization and definite late/very late stent thrombosis were concordant with prior trials with ultrathin BP SES.
Keywords: bioresorbable polymer, myocardial infarction, percutaneous coronary intervention, sirolimus, ultrathin strut drug-eluting stent
Introduction
Percutaneous coronary intervention (PCI) with ultrathin strut drug-eluting stents (DES) has demonstrated both early and late-term reductions in thrombotic events and clinical restenosis compared with alternative contemporary DES designs in both randomized trials and meta-analyses.1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Among these trials, treatment with an ultrathin strut (60 μm) bioresorbable polymer sirolimus-eluting stent (BP SES; Orsiro, Biotronik AG) has demonstrated superior clinical outcomes compared with alternative stent designs both at the time of primary end point ascertainment1,5, 6, 7 and during extended follow-up.2, 3, 4
As a postapproval study with regulatory oversight, the BIOFLOW VII study (BIOTRONIK - A Prospective Multicenter Study to Confirm the SaFety and Effectiveness of the Orsiro SiroLimus Eluting Coronary Stent System in the Treatment Of Subjects With up to Three De Novo or Restenotic Coronary Artery Lesions - VII)11 was performed to characterize the safety and effectiveness among patients treated with BP SES in routine clinical practice and compare these clinical outcomes with a prespecified performance goal derived from the BIOFLOW V and other contemporary DES trials that included 2 investigational device exemption studies and involving a total of >2000 subjects.1,12 At 1 year, the study met its primary end point of target lesion failure (TLF) (TLF 1.7%, P < .0001 compared with the 1-year performance goal of 6.9%; 95% CI, 0.69%-3.43%).11 As a prespecified analysis, the present report examines the 2-year clinical performance of the Orsiro DES in a broad clinical setting among US centers and reflects current standards of care. No formal hypothesis testing was planned beyond descriptive outcomes of the 2-year analysis.
The BIOFLOW VII 2-year study differs from prior international registries by evaluating ultrathin BP SES exclusively in a broad US real-world population, incorporating contemporary procedural practices and patient characteristics; these outcomes do not materially differ from those reported internationally, thus providing incremental validation of the stent’s safety and effectiveness and supporting its generalizability to routine US clinical practice.
Methods
Study design and study population
The study design, methods, and primary 1-year outcomes from the BIOFLOW VII study (ClinicalTrials.gov identifier NCT04175626) have been previously reported.11 In brief, BIOFLOW VII is a multicenter, single-arm postmarket approval study designed to evaluate the safety and performance of PCI using BP SES in a diverse US patient population. The study protocol was approved by local and central institutional review boards, and all eligible patients provided written informed consent within 24 hours of the index procedure.
The Orsiro (BP SES) stent consists of a cobalt-chromium alloy platform with a strut thickness of 60 μm for stent diameters ≤3.0 mm and 80 μm for diameters ≥3.5 mm. The stent surface is coated with amorphous silicon carbide, and the polymer excipient is poly-L-lactic acid, applied asymmetrically with a maximal thickness of 7.5 μm on the abluminal surface and 3.5 μm on the luminal side. Preclinical data indicate that >80% of the sirolimus dose is released within 90 days, with polymer scission initiating immediately postimplant and complete degradation occurring by approximately 24 months.1 BP SES devices are available in diameters ranging from 2.25 to 4.0 mm and lengths from 9 to 40 mm.
Enrollment criteria matched those of the BIOFLOW V trial1 to allow for performance goal comparison. Patients with coronary artery disease undergoing clinically indicated PCI of no more than 3 de novo native coronary artery lesions in a maximum of 2 native target vessels were screened for enrollment. All treated lesions were required to be ≤36 mm in length with a reference vessel diameter of 2.25 to 4.0 mm. Hemodynamically stable non-ST elevation myocardial infarction (MI) and acute coronary syndrome patients were eligible for enrollment. Major angiographic exclusions included chronic total occlusions, bifurcations involving a side branch with diameter >2.0 mm, bypass graft stenoses, and in-stent restenosis. Calcified lesions requiring atherectomy were permitted following instances of inadequate angioplasty balloon predilation. Patients with acute or recent (<72 hours) ST-segment elevation MI, left ventricular ejection fraction <30%, active stent thrombosis, impaired renal function, any prior nontarget vessel PCI within 30 days or within 9 months involving the target vessel, and those unlikely to adhere to dual antiplatelet therapy (DAPT) were also excluded. Patients who received an Orsiro stent as part of the second phase of a staged procedure were eligible for enrollment provided there was no prior nontarget vessel PCI within 30 days or target vessel intervention within 9 months. Any PCI planned within the next 1 year represented an exclusion.
All procedures adhered to the approved labeling for the Orsiro stent system, and angiographic assessments followed local institutional protocols. Antiplatelet therapy was administered in alignment with current professional society recommendations for PCI. Follow-up was performed through in-person clinic visits or telephone interviews. Assessment of clinical events occurred during the index hospitalization, 30 days, 1 year, and annually for up to 5 years after the index procedure.
Study end points and data management
The BIOFLOW VII study met the study primary end point regarding TLF, defined as the composite of cardiac death, target vessel-related MI, and ischemia-driven target lesion revascularization (TLR) among enrolled patients receiving BP SES. As a prespecified analysis, the primary and secondary end points were evaluated at 2 years. Secondary end points included the individual outcomes of all-cause and cardiac death, MI (including Q-wave and non–Q-wave MI) and ischemia-driven TLR in addition to the composite end point of major adverse cardiovascular events (all-cause death, any MI, and ischemia-driven TLR). Stent thrombosis was assessed using Academic Research Consortium-2 criteria.13
End point events were assessed utilizing the definitions previously reported.1 Per the Society for Cardiovascular Angiography & Interventions (SCAI) definition, periprocedural MI occurring within 48 hours of PCI is identified by significant elevations in cardiac biomarkers, specifically creatinine kinase myocardial band or troponin, above defined thresholds, with additional electrocardiographic or clinical criteria applied depending on baseline biomarker status and stability.14 In accordance to the protocol, peri-procedural cardiac biomarker assessments were performed per institutional standard of care. Spontaneous MI was defined as any creatine kinase myocardial band or troponin elevation above the upper normal limit with associated ischemic symptoms, new electrocardiographic abnormalities suggestive of ischemia, and/or new development of imaging evidence of infarction or regional wall motion abnormalities occurring greater than 48 hours of PCI. Ischemia-driven revascularization was identified as any repeat revascularization of the target lesion or target vessel associated with either: (1) ischemic symptoms and/or an abnormal functional study and ≥50% coronary stenosis by quantitative angiography; or (2) any revascularization ≥70% diameter stenosis. An independent clinical events committee and angiographic core laboratory (Angiographic Core Laboratory, MedStar Cardiovascular Research Network, Washington, DC) adjudicated all primary and secondary clinical end points and performed all related angiographic assessments for repeat and/or unscheduled angiograms.
Statistical analyses
A Kaplan-Meier survival analysis (time-to-event) for the secondary end point outcome of TLF at 2 years was performed for the intention-to-treat population. Patients who had sufficient follow-up data (≥660 days or had experienced an end point event prior) were included in the 2-year TLF end point analysis. Patients lost to follow-up were censored at the time of last contact in time-to-event analyses. Prespecified subgroups assessed for 2-year outcomes were exploratory and not powered for statistical inference.
Results
Patient characteristics
A total of 556 patients were enrolled at 31 US centers between January and November 2020. Completeness of follow-up at 2 years was 95.4% (521/546). Figure 1 reports patient visit accountability through the 2-year follow-up. Baseline clinical and angiographic characteristics were previously reported.11 In summary, mean patient age (mean ± SD) was 65.2 ± 10.5 years, and 34.7% of patients were women. Additional baseline clinical characteristics included: diabetes mellitus, 35.6%; prior MI, 37.3%; and unstable angina, 52.4%. The mean stent length was 20.2 ± 11.8 mm, and the mean number of stents per patient was 1.3 ± 0.6. Adherence to DAPT at 2 years was 42.9% (221/515).
Figure 1.
Patient visit accountability.
2-year clinical outcomes
At 2 years, among 522 patients included in the secondary end point analysis, the TLF rate increased from 1.7% (9/531) at 1 year to 5.2% (27/522) at 2 years. Rates of individual component end points at 2 years included: target vessel-related MI, 1.8% (9/515); ischemia-driven TLR, 2.7% (14/515); and cardiac death, 1.7% (9/522) (Table 1). The Kaplan-Meier cumulative incidence TLF rate was 4.9% (95% CI, 3.22-6.99) (Central Illustration). Through 2 years, definite stent thrombosis occurred in 3 cases (0.5%; 3/556) with 1 acute event (≤24 hours), 1 late event (>30 days and ≤1 year) and 1 very late event (>1 year). There were no probable stent thrombosis events.
Table 1.
Clinical events through 2 years.
| Enrolled patients (N = 556) | |
|---|---|
| Death | 3.21% (17/529) |
| Cardiac death | 1.72% (9/522) |
| Vascular death | 0.19% (1/516) |
| Noncardiovascular death | 1.34% (7/521) |
| MI | 2.33% (12/515) |
| Target vessel | 1.75% (9/515) |
| Nontarget vessel | 0.78% (4/515) |
| Q-wave | 0.19% (1/515) |
| Target vessel | 0.19% (1/515) |
| Nontarget vessel | 0.00% (0/515) |
| Non–Q-wave | 2.33% (12/515) |
| Target vessel | 1.55% (8/515) |
| Nontarget vessel | 0.78% (4/515) |
| Timing | |
| Periprocedural PCI | 0.58% (3/515) |
| Periprocedural CABG | 0.19% (1/515) |
| Spontaneous | 1.75% (9/515) |
| TLR | 3.29% (17/516) |
| Ischemia-driven TLR | 2.72% (14/515) |
| Non–ischemia-driven TLR | 0.78% (4/516) |
| TVR | 4.84% (25/516) |
| Ischemia-driven TVR | 4.08% (21/515) |
| Non–ischemia-driven TVR | 1.16% (6/516) |
| Cardiac death or MI | 3.83% (20/522) |
| TLF (cardiac death, target vessel MI, ischemia-driven TLR) | 5.17% (27/522) |
| TVF (cardiac death, target vessel MI, ischemia-driven TVR) | 6.13% (32/522) |
| MACE (death, Q-wave or non–Q-wave MI, ischemia-driven TLR) | 6.99% (37/529) |
Data are presented as percentage (n/N).
MACE, major adverse cardiovascular event; MI, myocardial infarction; PCI, percutaneous coronary intervention; TLF, target lesion failure; TLR, target lesion revascularization; TVF, target vessel failure; TVR, target vessel revascularization.
Central Illustration.
BIOFLOW VII 2-year results. CD-TLR, clinically driven target lesion revascularization; TLF, target lesion failure; TV-MI, target vessel myocardial infarction.
Subgroup analyses
Subgroup analyses were performed among intention-to-treat patients defined according to prespecified factors: reference vessel diameter (≤2.75 vs >2.75 mm), age (>75 vs ≤75 years), sex, presence or absence of diabetes, lesion length (>26 vs ≤26 mm), overlapping stents versus single stent in lesions >26 mm in length, stent diameter (≤3.0 vs >3.0mm) and acute coronary syndrome status. Results were consistent across all subgroups except age and sex. Observed TLF rates for patients aged >75 years was 10.3% compared with 4.0% for those ≤75 years (P = .02). Women experienced higher TLF than men, with rates of 8.1% and 3.6%, respectively (P = .04). Subgroup analyses are summarized in Table 2.
Table 2.
Subgroup analysis of target lesion failure at 2 years.
| BIOFLOW VII (N = 522) | Pa | |
|---|---|---|
| RVDb, mm | .33 | |
| ≤2.75 | 6.3% (14/223) | |
| >2.75 | 4.3% (13/299) | |
| Age, y | .02 | |
| >75 | 10.3% (10/97) | |
| ≤75 | 4.0% (17/425) | |
| Sex | .04 | |
| Women | 8.1% (15/185) | |
| Men | 3.6% (12/337) | |
| Diabetes | .84 | |
| Diabetes | 5.5% (10/183) | |
| No diabetes | 5.0% (17/339) | |
| Lesion lengthc, mm | .78 | |
| >26 | 5.6% (4/72) | |
| ≤26 | 5.1% (23/450) | |
| Stent overlapd | .56 | |
| Nonoverlapping | 5.1% (3/59) | |
| Overlapping | 7.7% (1/13) | |
| Stent diameter, mm | .40 | |
| ≤3.0 | 5.8% (21/363) | |
| >3.0 | 3.8% (6/159) | |
| ACSe | .11 | |
| ACS | 3.8% (11/292) | |
| Non-ACS | 7.0% (16/230) |
Data represented as percentage (n/N).
ACS, acute coronary syndrome; RVD, reference vessel diameter; TLF, target lesion failure.
Only patients with at least 660 days of follow-up or a TLF event through 720 days were included in the analysis.
Fisher’s exact test. P values < .05 indicate evidence of an association between the subgroup and TLF rate.
Patients with at least 1 target lesion with RVD ≤2.75 mm were classified with the small vessel subgroup.
Patients with at least 1 target lesion with lesion length >26 mm were classified with subgroup of lesion length >26 mm.
Only patients with lesions >26 mm in length were included.
ACS was defined as unstable angina or any elevated cardiac enzymes at baseline (preprocedural creatine kinase, creatine kinase myocardial band, or troponin level above normal range).
Discussion
In a postapproval study dedicated to long-term surveillance of clinical outcomes with the Orsiro DES, favorable 2-year outcomes demonstrate durable safety and efficacy in a clinical setting representative of routine clinical practice. The very low rates of TLR and stent thrombosis sustained at 2 years are in alignment with results from other trials dedicated to long-term follow-up with this specific ultrathin strut BP SES.
As previously reported, the 1-year clinical outcomes observed with BP SES in the current study are consistent with those observed in prior randomized trials comparing this and other DES designs.11 Now with extended follow-up through 2 years, the findings of the present study appear consistent with those reported in randomized trials that include long-term follow-up that also demonstrated significantly lower TLR favoring BP SES.2,15, 16, 17 Intended to represent a patient population similar to those included in the BIOFLOW V trial, the 2-year TLR rate of 2.7% observed in the present study are nearly identical to the 2.6% TLR rate in BIOFLOW V.2 In the SORT OUT (Scandinavian Organization for Randomized Trials with Clinical Outcome) IX15 and BIOSTEMI16 (A Comparison of an Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent for Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention) randomized trials, 2-year outcomes of TLR were 2.6% and 2.5%, respectively, with the Orsiro DES being significantly lower than the comparator DES in both trials and again similar to that observed in the present report. The present findings reinforce and extend those of the pivotal BIOFLOW V randomized trial and large-scale SORT OUT studies, demonstrating that the favorable efficacy and safety profile of ultrathin BP SES is maintained in real-world, postmarket US practice across a broad patient population. Similarly, the 3-year TLR rate of 2.8% with Orsiro DES was superior to that of a thicker strut BP DES in late-term follow-up of the BIODEGRADE randomized trial.17
These results are similarly in accord with a broader collection of both observational studies and meta-analyses with longer-term surveillance comparing ultrathin strut DES with contemporary thin-strut DES. Among 74,131 patients treated with current DES in the SCAAR registry and with 2-year follow-up, repeat TLR was significantly lower among those treated with the Orsiro BP SES (N = 4561) than with alternative DES designs (1.6% vs 2.3%, P = .013).18 Furthermore, in a meta-analysis of randomized trials comparing ultrathin strut DES with a contemporary generation thin-strut DES (10 trials, N = 11,658), revascularization with the ultrathin strut DES was associated with significant reductions in TLF (relative risk [RR], 0.84; 95% CI, 0.72-0.99) and MI (RR, 0.80; 95% CI, 0.65-0.99) and numerically lower stent thrombosis (RR, 0.72; 95% CI, 0.51-1.01).8 As an expanded analysis inclusive of additional trials (16 trials, N = 20,701) and with longer-term follow-up (mean 2.5 years), ultrathin DES were associated with significantly lower TLF, a difference driven by lower TLR.9 Finally, among 77 trials (N = 99,039) included in a network meta-analysis, ultrathin strut BP SES were associated with a significant reduction in TLF at 1 year compared with other contemporary thin-strut DES.10 Through a median follow-up of 50 months, ultrathin BP SES ranked with the highest probability as the best performing stent although with attenuation of statistical significance. In addition, BP SES had a significantly lower rate of late-term definite stent thrombosis compared with other DES. Shortened or individualized DAPT duration was common in BIOFLOW VII, with only 42.9% of patients adherent to DAPT at 2 years, yet rates of late and very late stent thrombosis remained low, supporting the safety of the ultrathin BP SES stent in contemporary real-world practice. These findings underscore the compatibility of this stent platform with evolving DAPT strategies that seek to balance ischemic protection and bleeding risk. Altogether, the results of the present study are in line with an evolving body of evidence from several independent studies that support the late-term benefit with BP SES.
Although several studies with varied designs have demonstrated superior safety and efficacy outcomes favoring BP SES, whether these benefits are attributable to an isolated feature specific to this DES is a common question. Instead, demonstrable clinical advantages may represent the combination of multiple design elements rather than a single attribute. The association of thinner stent struts with less inflammation, vessel injury, neointimal proliferation, and thrombus formation than thicker strut stents is well established.19, 20, 21, 22 However, as in the BIOFLOW V trial,1 similar efficacy with BP SES regarding TLF was observed across all vessel sizes (and therefore differential strut thickness) in the present study. These observations suggest that the clinical benefit with this BP SES may not be exclusive to strut thickness alone. Alternatively, complete polymer dissolution (a process completed by 24 months for Orsiro BP SES) may eliminate the stimulus for chronic inflammation, neointimal hyperplasia and atherosclerotic disease progression that has been observed with permanent polymers.23, 24, 25 Dedicated follow-up beyond 2 years in the present report will therefore be insightful regarding the trajectory of late-term events. Nevertheless, comparative trials evaluating ultrathin strut DES and bioresorbable polymers have demonstrated inconsistent findings,26,27 perhaps in part related to patient selection, procedural techniques, or other unmeasured variables. Ultimately, how and whether the specific attributes of complete polymer dissolution and ultrathin strut design translate into improvements in selected clinical outcomes remains speculative.
Study limitations
The present analysis has important limitations for consideration. First, and common to postmarket evaluations, this was an open-label study with no active comparator. Second, the study was not powered for individual clinical end point comparisons at 2 years, although the consistency of results with BP SES in this and prior randomized trials is reassuring. Also, the sample size specific to high-risk patient and lesion subgroups was variable, and differences in subgroups relative to sex and age that were not observed at 1 year (nor in prior BP SES trials) merit further study over time but should be interpreted with caution. Finally, enrollment criteria were intentionally selected to parallel those of the BIOFLOW V trial1 for purposes of comparability with the performance goal. This requirement, in addition to the absence of consecutive patient enrollment, may introduce some selection bias. Although the study population was represented by a high prevalence of patients with acute coronary syndromes and multivessel coronary disease, these results may not be generalizable to an even broader, less selected patient population with lesion complexity and clinical conditions excluded from this analysis. Exclusion of selected patient and lesion complexities that are associated with higher risk may yield lower event rates compared with all-comer trial populations. Dedicated follow-up through 5 years will inform the strength of current results and refine comparisons of outcomes with BP SES from other clinical trials.
Conclusions
In a broader clinical setting among US centers and reflecting current standards of care, the 2-year BIOFLOW VII results demonstrate the durability of efficacy and safety of ultrathin BP SES. Favorably low rates of clinically driven target lesion revascularization and definite late/very late stent thrombosis were observed, consistent with prior trials with ultrathin BP SES.
Acknowledgments
The authors thank Rebecca Sarao and Kristen Reichart who provided analytical and editorial support and Camden Harrell for statistical support and table preparation, under the direction of the first author.
Declaration of competing interest
David Kandzari reports institutional grant/research support from Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, Medtronic CardioVascular, Orbus Neich, and Teleflex, and personal consulting fees/honoraria from Abbott Vascular, Boston Scientific, and Medtronic. John Wang reports consultant honoraria from Edwards Lifesciences, is an advisory board member and speaker for Boston Scientific and a selection committee member for Abbott Vascular. Hector M. Garcia-Garcia reports the following institutional grant support: Biotronik, Boston Scientific, Medtronic, Abbott, Neovasc, Shockwave Medical, Phillips, and Corflow; consultant honoraria from Boston Scientific, Abbott, and Amgen. Robert Stoler reports advisory board honoraria from Biotronik, Medtronic, and Boston Scientific. Santiago A. Garcia reports consultant honoraria from Edwards Lifesciences, Medtronic, Abbott Vascular, Boston Scientific, Anteris, Capstan Medical, B. Braun; proctorship honoraria from Edwards Lifesciences and Abbott Vascular; and equity with Capstan Medical.
Funding sources
This work was supported by Biotronik.
Ethics statement and patient consent
The study protocol was approved by local and central institutional review boards, and all eligible patients provided written informed consent within 24 hours of the index procedure.
Footnotes
Clinical Trials Registration: NCT04175626
References
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