Abstract: Objectives. To evaluate the safety and efficacy of the Orsiro sirolimus-eluting stent (Biotronik) in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (pPCI). Specific drug-eluting stent (DES) platforms might influence pPCI success rate in the mid-to-long term. Orsiro, a hybrid sirolimus DES with thin struts and a biodegradable polymer, may potentially cause less stent malapposition, stent-induced inflammation, and mechanical damage, improving clinical outcomes. Methods. We retrospectively enrolled all patients who received 1 or more Orsiro DES in the target vessel of pPCI at 9 Italian centers from January 2012 to March 2016. The primary endpoint was a device-oriented composite endpoint (DOCE) of cardiac death, any myocardial infarction clearly attributable to the intervention culprit vessel (TVMI), and ischemic-driven target-lesion revascularization (ID-TLR) at 1-year follow-up. Secondary endpoints were: (1) DOCE at 6-month and 3-year follow-up; (2) any definite/probable stent thrombosis; and (3) any major bleeding. Results. The study cohort comprised 353 patients. At 1-year follow-up, we observed a 3.7% cumulative incidence of DOCE, consisting of 11 cardiac deaths (3.1%), 2 TVMIs (0.6%), and 2 ID-TLRs (0.6%). There was only 1 definite stent thrombosis (0.3%) and 8 bleedings (2.4%). Kaplan-Meier analysis showed DOCE-free survival rates of 96.6% at 6 months, 96.3% at 1 year, and 93.8% at 3 years. Conclusions. Our findings support the real-world safety and efficacy of the Orsiro stent for pPCI.
J INVASIVE CARDIOL 2020;32(12):E331-E337. Epub 2020 November 22.
Key words: device-oriented events, drug-eluting stent, primary PCI
Primary PCI (pPCI) with drug-eluting stent (DES) implantation is the treatment of choice for ST-segment elevation myocardial infarction (STEMI).1 After pPCI, however, stent-related clinical events (such as acute and subacute stent thrombosis) are worse than in stable patents, as the infarct-related lesion is characterized by a thin fibrous cap, a large lipid-laden necrotic core (easily penetrated by stent struts), and an important thrombotic burden. This may lead to reduced neointimal thickness, increased fibrin deposition, and persistent inflammation at follow-up.2 This specific risk was of particular concern for early DES options, and was linked to the non-biocompatible polymers used for drug elution and to the stainless-steel material, which both resulted in particularly thick stent struts.3 More recent cobalt-chromium stent platforms, with reduced stent strut thickness, designed to mitigate vascular injury and to promote endothelialization, have performed consistently better than first-generation DES options, with some signals, although by no means conclusive, pointing to a beneficial role for bioabsorbable polymers.4,5 In any case, there is an ongoing debate and a scarcity of data regarding the short- and long-term impact of the advanced technical characteristics of the balloon-stent-drug complex in pPCI.2
The Orsiro stent (Biotronik) is a hybrid-coating, bioabsorbable-polymer DES characterized by a very low strut thickness (potentially resulting in less stent-induced inflammation and mechanical damage), and a peculiar balloon compliance (potentially causing less stent malapposition).6,7 This platform was demonstrated to be superior to a durable-polymer everolimus-eluting stent in patients with STEMI undergoing pPCI with respect to a composite endpoint of cardiac death, target-vessel myocardial infarction, (TVMI) or clinically indicated target-lesion revascularization (TLR) at 12 months.8
We designed this multicenter registry to evaluate the real-world safety and efficacy of the hybrid Orsiro stent in an unselected population of consecutive STEMI patients undergoing pPCI.
Design and study population. HEROES (Hard Events afteR Orsiro sirolimus-Eluting Stent) is an observational, multicenter, retrospective registry of patients diagnosed with STEMI who received 1 or more Orsiro stents in the target vessel, as per institutional standard of care and at treating physician’s discretion.
All patients receiving at least 1 Orsiro stent at the 9 Italian enrolling centers from January 2012 to March 2016 were included in the registry, without preselection. The HEROES registry was conducted according to the principles of the Declaration of Helsinki, and all institutional review boards approved the study protocol.
Procedures. All percutaneous coronary interventions were performed at high-volume centers (>100 pPCIs/year) adopting structured internal STEMI protocols, in agreement with STEMI European Society of Cardiology guidelines.9 According to local standards, patients undergoing pPCI received aspirin and a loading dose of oral P2Y12 receptor blocker. Data were captured regarding anticoagulation with unfractionated heparin and/or bivalirudin, glycoprotein IIb/IIIa inhibitor use, and manual or rheolytic thrombectomy device use. We assessed clinical data and events during hospital stays, as well as at 6 months, 12 months, and up to 3 years post pPCI via review of clinical notes and regular follow-up visits. Structured telephone interviews were used patients in whom clinical notes were unavailable.
Study endpoints and definitions. All clinical outcomes were defined according to the Academic Research Consortium (ARC).10 The primary endpoint of the study was a device-oriented composite endpoint (DOCE) of cardiac death, any TVMI, and ischemia-driven TLR at 1-year follow-up. Secondary endpoints were DOCE at 6-month and 3-year follow-up, any definite/probable stent thrombosis, and any major bleeding (in hospital, within 7 days post pPCI, and at follow-up).
Patients with multiple Orsiro stents implanted in the same target vessel were included, whereas those implanted with different stent types in the same target vessel were not considered. Patients in whom a deferred stenting strategy had been applied were also included.
Myocardial infarction (MI) was defined according to the Fourth Universal Definition of Myocardial Infarction as evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia.11 TVMI was defined as any MI clearly attributable to the index major coronary artery treated with Orsiro stent implantation during pPCI. Ischemia-driven TLR was defined as any repeated target-vessel revascularization associated with either ischemic symptoms, an abnormal functional study, or both, and ≥50% angiographic coronary stenosis or any revascularization of ≥70% diameter stenosis. Bleedings were defined according to Bleeding Academic Research Consortium (BARC) definitions.12 ST-segment resolution was assessed by the comparison of a 12-lead electrocardiogram performed within 60 minutes after pPCI vs the diagnostic electrocardiogram. ST-segment resolution was defined as complete (>70% of resolution), partial (>30% and <70% of resolution), and none (<30% of resolution).13
Clinical events and study endpoints were adjudicated locally using standard definitions. In case of uncertainties, the principal investigator reviewed medical documentation, discharge summaries, and angiography films, if needed, to assess safety and adverse events.
Study device. The Orsiro stent has a cobalt-chromium L605 backbone (Pro-Kinetic Energy platform) with a double-helix pattern and thin-thickness struts (60 μm for stents with a nominal diameter of ≤3.0 mm, 80 μm for the 2 larger sizes stents). The stent has a circumferential hybrid coating design with active (consisting of limus family drug and of a bioabsorbable polymer matrix) and passive components. The biodegradable coating contains poly-L-lactic acid (PLLA, a solid polymer comprised of an ordered crystalline portion and random amorphous chains, which degrades in approximately 12-15 months into carbon dioxide and water), delivering sirolimus, distributed at a dose of 1.4 μg/mm2 stent surface, over 12-14 weeks. The passive coating (by amorphous and hydrogen-rich silicon-carbide coating) is supposed to reduce the interaction between protein-cell elements and stent metallic surface, decreasing allergenic effect of metal ions, rate of corrosion, and tissue inflammation response.7
Statistical analysis. Categorical variables were expressed as frequencies and percentage. Continuous variables were reported as mean ± standard deviation after testing normal distribution with the Kolmogorov-Smirnov test. Time-to-events analyses to construct survival curves were evaluated with the Kaplan-Meier method. Variables were compared by means of the log-rank test or Breslow test. We performed stratified analyses of the primary endpoint at 1 year for the following subgroups: diabetes, chronic kidney disease, and multiple Orsiro stents implanted in the same target vessel. All tests were significant at P<.05. All analyses were performed with SPSS, version 25.0 (IBM Corporation).
From January 2012 to March 2016, a total of 380 patients with STEMI who received 1 or more Orsiro stents during pPCI were treated at 9 Italian centers. Follow-up was absent or incomplete in 24 patients, and 3 patients were excluded because different stent types were implanted in the same target vessel. Final study population thus included 353 patients.
Baseline clinical features are depicted in Table 1. Overall, the study showed the typical characteristics of a medium-risk STEMI cohort, with many patients being first coronary artery disease presenters (only 1/10 had undergone a previous PCI), a prevalence of middle-aged men (mean age, 64.6 ± 11.8 years; two-thirds men), and a moderate incidence of diabetes (21%) and chronic kidney disease (10%). Consistent with a good mean left ventricular ejection fraction (47.1 ± 9.8% on admission, 51.2 ± 8.6% on discharge), Killip class III-IV was only present in 32 patients (9.1%).
Angiographic and procedural characteristics are summarized in Table 2. Approximately 47.6% of patients had an anterior infarct and 37.4% had an inferior infarct. Transradial approach was employed in most cases, with a good representation of direct stenting technique (>40%). Approximately 42.2% and 28.9% of patients had mechanical thrombectomy and staged revascularization, respectively. Of note, mechanical circulatory support was only needed in 4% of cases. Regarding lesion site, 30.6% of patients had a bifurcation lesion as a culprit, mean lesion length was ~25 mm (consistent with an average stent length of ~33 mm), and multivessel disease was present in 53.3% of patients. Angiographic results were good, with almost all patients reaching Thrombolysis in Myocardial Infarction 2-3 flow post procedure.
Consistent with modern guidelines,9 newer P2Y12 inhibitors were often used, with ticagrelor in more than half of patients, whereas mean dual-antiplatelet therapy (DAPT) duration was, on average, equal to 1 year (Table 3).
Incidence of adverse events at follow-up is depicted in Table 4. Overall, at a mean follow-up of 20.2 ± 13.0 months, we observed 22 deaths (6.6%), of which 16 patients (4.8%) were cardiac deaths (10 during the hospital stay) and 6 (1.8%) were non-cardiac deaths. There were 13 deaths in the first 6 months, and 9 deaths from 12-36 months after pPCI. We also detected 5 MIs (1.5%), of which 4 (1.2%) were TVMIs. We also observed 4 cases (1.2%) of ischemia-driven TLR. Only 1 patient had definite stent thrombosis (0.3%), occurring during hospital stay. There were 8 bleedings after discharge (2.4%), of which 5 (1.5%) were BARC 1, 2 (0.6%) were BARC 2, and 1 (0.3%) was BARC 3a. We observed only 2 strokes (0.6%), with 1 occurring during the first 6 months post pPCI, and 1 occurring during the third year of follow-up.
A total of 295 patients (83.6%) reached the 6-month follow-up, at which point we observed a DOCE rate of 3.4%, with 13 events detected during the observation period and comprising 11 cardiac deaths, 1 TVMI, and 1 ischemia-driven TLR. At 1-year follow-up (reached by 239 patients; 67.7%), the primary endpoint of DOCE was met by 13 patients (3.7% of the initial cohort of 353 patients), comprising 11 cardiac deaths, 2 TVMIs, and 2 ischemia-driven TLRs. At 3-year follow-up (reached by 110 patients; 31.2%), we noted a cumulative DOCE of 6.2%, comprising 16 cardiac deaths, 4 TVMIs, and 4 ischemia-driven TLRs.
Kaplan-Meier analysis showed a DOCE-free survival rate of 96.6% at 6 months, 96.3% at 1 year, and 93.8% at 3 years (Figure 1). Notably, we observed post hoc a significantly higher cumulative incidence of adverse events at 1-year follow-up among diabetics (8.0% vs 2.2%; log rank P=.01) (Figure 2) and chronic kidney disease subgroups (9.4% vs 2.4%; log rank P<.01) (Figure 3).
Patients with multiple Orsiro stents implanted in the same target vessel had a higher cumulative incidence of adverse events at 1-year follow-up vs patients with only 1 stent deployed (7.3% vs 2.0%, respectively; P=.02).
In this retrospective, multicenter registry of STEMI patients treated with pPCI, the ultrathin-strut, biodegradable-polymer, sirolimus-eluting Orsiro stent showed excellent efficacy and safety, comparable with prior studies of the same platform.14-21 Recently, however, the Orsiro stent has been mainly studied in non-acute coronary syndrome patients. Indeed, major randomized trials such as BIOFLOW V14 had STEMI among the exclusion criteria, and the few studies allowing the inclusion of STEMI patients16,17,19,20 had several limitations, with a clear selection bias. Our results, thus, are mainly to be compared with the Orsiro arm of the BIOSTEMI trial,8 a Swiss multicenter randomized trial that incorporates historical data from the previous BIOSCIENCE trial in a Bayesian log Poisson model.
Our patient cohort was slightly older than the BIOSTEMI Orsiro arm (64.6 years vs 62.2 years, respectively) and had a higher prevalence of cardiovascular risk factors, such as diabetes (21.5% vs 11.0%, respectively), hypertension (57.8% vs 43.0%, respectively), history of smoking (52.4% vs 45.0%, respectively), and chronic kidney disease (18.1% vs 12.0%, respectively). Of note, the observed 1-year DOCE rate in the HEROES registry was almost identical (3.7%) to the BIOSTEMI target-lesion failure (TLF) rate (4.0%), and we can safely assume that the small difference between the 2 studies’ definitions in 1 of the components of the primary endpoint (ischemia-driven TLR vs clinically indicated TLR) was of neutral impact. Indeed, the 1-year ischemia-driven TLR rate in our study (1.5%) closely resembles the 1-year clinically indicated TLR rate (1.0%) in the BIOSTEMI Orsiro arm. In addition, the HEROES TVMI rate (0.6%) appears slightly lower than the BIOSTEMI TVMI rate (1.0%). The observed low rate of cardiac death (3.0%), mainly due to in-hospital deaths, is also in line with the BIOSTEMI cardiac death rate (3.0%). It should be noted, however, that the HEROES stent thrombosis rate was lower than the BIOSTEMI Orsiro arm (0.3% vs 2.0%, respectively), with only 1 definite case observed. Regarding bleedings, we observed a low high-grade bleeding rate (only 1 BARC 3A bleeding), compared with the BARC 3-5 bleeding rate of 2.0% in the BIOSTEMI Orsiro arm.
In summary, the HEROES registry findings appear reassuring, supporting in a real-world setting the results obtained in a randomized trial, especially considering the more complex angiographic pattern as compared with the Orsiro arm of the BIOSTEMI trial, with higher rates of multivessel disease (53.3% in the HEROES registry vs 7.7% in the BIOSTEMI Orsiro arm) and bifurcation lesions as culprit (30.6% in the HEROES registry vs 12.0% in the BIOSTEMI Orsiro arm). HEROES results also favorably compare with adverse event rates seen with other last-generation DES in a pPCI setting, as the EXAMINATION (Everolimus-Eluting Stents Versus Bare-Metal Stents in ST-Segment Elevation Myocardial Infarction) trial showed a 5.9% DOCE rate at 1-year follow-up.22 Therefore, it is possible that due to its peculiar features, the Orsiro stent may be linked with lower rates of stent malapposition, stent-induced inflammation, and ultimately, stent-induced vessel damage4,23,24 — issues that play an important role in the heightened risk of adverse events in STEMI patients.25
Study limitations. Our registry has several limitations. First, no randomization was conducted and the data were retrospectively collected. Second, considering that the benefit of biodegradable-polymer stents in terms of stent thrombosis may appear beyond the polymer degradation time, and that median follow-up was only slightly longer than the expected Orsiro bioabsorbable-polymer dissolution time (20.2 months vs 12-15 months), a longer follow-up may have been interesting. Finally, no central angiographic analysis was performed.
In agreement with the recent BIOSTEMI controlled trial findings, the Orsiro stent seems to be effective and absolutely safe compared with other devices. Our STEMI registry endorsed a trend toward low adverse clinical events during follow-up, opening the field to new and more complex future comparative investigations.
From the 1Ospedale Policlinico San Martino Istituto di Ricovero e Cura a Carattere Scientifico per l’Oncologia, DICATOV-CardioThoracic and Vascular, Genova, Liguria, Italy; 2Università degli Studi di Genova Scuola di Scienze Mediche e Farmaceutiche, Policlinico San Martino IRCCS Genova, Liguria, Italy; 3AO Ospedali Riuniti Marche Nord, Pesaro, Italy; 4Ospedale Civico, Palermo, Italy; 5Gemelli Foundation Hospital, Catholic University of the Sacred Heart, Rome, Italy; 6San Giuseppe Moscati Hospital, Aversa, Italy; 7Casilino Hospital, Rome, Italy; 8Bolognini Hospital, Seriate, Italy; 9Misericordia Hospital, Grosseto, Italy; 10European Hospital, Rome, Italy; 11Fatebenefratelli Hospital, Milan, Italy; 12Lorenzo Bonomo Hospital, Andria, Italy.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Porto reports grant support from Astra Zeneca; personal fees from Biotronik, Terumo, Amgen, Stentys, Astra Zeneca, Daaichi-Sankyo, and Bayer personal fees and non-financial support from Abiomed. Dr Canepa reports grant support from Pfizer, personal fees from Pfizer, Novartis, Akcea Therapeutics, and Sanofi Genzyme. The remaining authors report no conflicts of interest regarding the content herein.
Final version accepted May 12, 2020.
Address for correspondence: Prof Italo Porto, University of Genoa, Cardiovascular Unit, Department of Internal Medicine and Specialties (DIMI) Viale Benedetto XV, 10, 16132 Genoa, Italy. Email: firstname.lastname@example.org
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