One-Year Clinical Outcomes of Forty-Eight Millimeter Everolimus-Eluting Stent Implanted in Very Long Lesions: A Propensity-Matched Comparison (The FREIUS Study)

Abstract: Background. Long coronary lesions still remain a challenge, with poor immediate results and suboptimal outcomes when compared to class A/B1 lesions. The presence of overlapped segments of metal struts and polymer might trigger an abnormal inflammatory reaction, resulting in a higher restenosis rate. The aim of our study was to evaluate the safety, feasibility, and cost effectiveness of a 48 mm everolimus-eluting stent (EES) during treatment of very long coronary lesions. Methods and Results. The FREIUS study is a prospective data collection of consecutive patients undergoing 48 mm EES implantation in six high-volume European centers. Each patient was matched through a propensity score to a comparable patient treated with two or more second-generation overlapped drug-eluting stents. The primary endpoint was the combined incidence of cardiac death, target-vessel myocardial infarction, and target-lesion revascularization (device-oriented composite endpoint [DOCE]). The secondary endpoints were all-cause death, each individual component of the primary endpoint, and definite/probable stent thrombosis. From January 2014 to April 2015, a total of 218 patients were treated with at least one 48 mm EES and were compared with 218 matched controls. Overall, 9% of patients reached the primary endpoint. Cumulative survival free from DOCE incidence did not differ between the two groups (7% in the cases vs 10.5% in the controls; P=.10). After multivariable analysis, only clinical presentation with myocardial infarction (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.5-2.1; P=.01) and stent number (HR, 1.4; 95% CI, 1.1-1.8; P=.02) emerged as independent predictors of DOCE. Conclusion. The use of 48 mm EES offers a safe and effective strategy for the treatment of very long coronary lesions.

J INVASIVE CARDIOL 2018;30(4):133-137.

Key words: drug-eluting stent, DES, long coronary lesions, long stent, stent overlap

Improvements in devices and techniques and the extensive use of drug-eluting stent (DES) implantation have progressively extended percutaneous coronary intervention (PCI) to longer and more complex lesions, which were previously referred to surgical revascularization. Nevertheless, clinical results of long stented coronary segments still remain suboptimal when compared to class A/B1 lesions, and this patient subgroup has a higher risk of target-lesion revascularization (TLR).¹ The need for multiple stents, with the consequent overlapping of metal struts and polymer, triggers an abnormal inflammatory reaction and delayed healing, with incomplete endothelialization or neointimal overexpression that finally results in a higher risk of stent thrombosis (ST) or in-stent restenosis (ISR).^2-6 The replacement of the old, thick stainless steel with cobalt-chromium has allowed companies to develop longer stents that still offer satisfactory stent deliverability. One of the first very long DESs available on the market has been the 48 mm Xience Pro everolimus-eluting stent (EES; Abbott Vascular). Its systematic implementation allows the treatment of long coronary lesions, minimizing the need for multiple stents and thus the risk of overlap. Nevertheless, its real clinical benefit and cost effectiveness are still unknown. Thus, we designed this registry to obtain a first description of 1-year performance of this 48 mm EES.

Methods

The Forty-eight millimeteR EverolImus-elUting stent in very-long leSions (FREIUS) study is a prospective data collection of consecutive patients receiving 48 mm EES implantation at six European centers. The list of participating investigators is available in Supplementary Appendix S1 (supplementary materials available online at www.invasivecardiology.com). Data collection started in January 2014 and we included patients enrolled until April 2015. Informed consent was obtained from each patient and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s human research committee.

Study population and study device. Cases were all patients undergoing PCI with implantation of at least one 48 mm EES Xience Pro during the study period (48 mm EES group). Other Xience Pro EES devices could be used if required. Each patient was matched through a propensity score to a comparable patient treated with two or more second-generation DESs (controls) (Supplemental Tables S1 and S2). Eligible patients for matching were extracted from those receiving PCI at the Azienda Ospedaliera Universitaria S. Anna in Ferrara, Italy before the introduction of 48 mm EESs in September 2014 (Supplemental Figure S1). Controls received two or more of the following DESs: Xience V, Xience Prime, or Xience PRO (maximum length, 28 mm; Abbott Vascular); Promus Element or Promus Premier (maximum length, 38 mm; Boston Scientific); or Biomatrix Flex (maximum length, 36 mm; Biosensors Europe SA). The data, including baseline and procedural characteristics and follow-up, were collected in a prospective all-comer registry, as previously reported.^7,8  

Procedure and clinical follow-up. All interventions were performed using standard techniques. Predilation, postdilation, and use of intracoronary imaging were left to the operator’s discretion, as well as the decision of whether to implant a 48 mm EES. After the procedure, all patients were advised to continue dual-antiplatelet therapy (DAPT) with aspirin and P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor according to current guidelines) for 12 months unless there were contraindications. All patients returned for study visits 30 days after hospitalization and PCI procedure, and then 11 months later. During follow-up visits, patients were examined and assessed for adverse events, and 12-lead electrocardiographic recordings were obtained. At all follow-up exams, patients were questioned about their compliance with the study medication. Any interruptions or termination, as well as the reasoning for these decisions, were documented. 

Study endpoints and definitions. The primary endpoint was the combined incidence of cardiac death, target-vessel myocardial infarction (TVMI), and target-lesion revascularization (TLR) (device-oriented composite endpoint; DOCE). TVMI was defined as Q-wave or non-Q wave MI that can be related to the target vessel or cannot be related to another vessel. TLR was defined as either repeat percutaneous or surgical revascularization for a lesion anywhere within the scaffold/stent or the 5 mm borders proximal or distal to the device. The secondary endpoints were all-cause death, each individual component of the primary endpoint, and definite/probable ST, as defined by Academic Research Consortium criteria. All adverse events were recorded and adjudicated by investigators at each center, who collected any relevant documentation (medical records, discharge letters). Two independent investigators (GC, SB) reviewed and verified all data sources. Finally, we estimated the potential impact on procedural costs of 48 mm EES implementation. The estimate of the costs included all material costs during the index PCI procedure. Costs are expressed in United States currency ($). According to average prices at Italian centers, we estimated $471 for one DES, $94 for one balloon (both predilation and postdilation), $59 for one guidewire, and $53 for one guiding catheter.

Statistical analysis. Continuous data were tested for normal distribution with the Kolmogorov-Smirnov test. Normally distributed values were presented as mean ± standard deviation. Otherwise, data were presented as median and interquartile range. Categorical variables were summarized in terms of numbers and percentages. Logistic regression was used to generate a model to calculate propensity scores. The following parameters were considered relevant in the model: age, sex, diabetes mellitus, clinical presentation, culprit vessel, type of lesion (de novo vs in-stent restenosis vs chronic total occlusion), lesion length, and reference vessel diameter. Each patient treated with 48 mm EES was matched with a DES patient through a greedy algorithm based on local optimization using a caliper of 0.2. Continuous variables normally distributed were compared with a paired t-test; otherwise, the Wilcoxon signed-rank test was applied. Categorical variables were compared with the McNemar test. Survival curves were generated by the Kaplan-Meier method, and differences in survival between subgroups were evaluated using the log-rank test. We applied univariable and multivariable Cox proportional hazard regression models to evaluate the relation between clinical and procedural variables and the incidence of DOCE.¹⁴ A 2-sided value of  P<.05 was considered significant. All analyses were performed with Statistica 8 (Statsoft, Inc) and SAS 9.1 system (SAS Institute).

Results

Overall, from January 2014 to April 2015, the implantation of 48 mm EES was attempted in 226 cases. Despite supportive guiding catheter, buddy wire, and adequate and repeated predilation, implantation failed in 8 cases (3.5%). Thus, the final study population included 218 cases and 218 matched controls (Supplemental Table S1). Baseline characteristics of both groups are summarized in Table 1. As expected, patient demographics were comparable between matched groups.

Angiographic and procedural characteristics (Table 2). There were no significant differences regarding angiographic data and quantitative coronary angiographic analysis between the two groups. Similar predilation rates and predilation balloon diameters were observed in both groups. As expected, although lesion length and final total stent length did not differ, the number of implanted stents (both total and mean number) was significantly higher in the control group. The need for ≥3 stents and the occurrence of ≥2 overlaps were significantly higher in the control group. Finally, postdilation (occurrence and balloon diameter) did not differ between groups.

Primary endpoint. A total of 39 patients (9%) reached the primary endpoint. Cumulative survival free from DOCE incidence did not differ between the two groups (7% in the cases vs 10.5% in the controls; P=.10) (Figure 1). At univariate analysis, age, diabetes mellitus, clinical presentation as MI, and stent number were predictors of DOCE. After multivariable analysis, only clinical presentation as MI (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.5-2.1; P=.01) and stent number (HR, 1.4; 95% CI, 1.1-1.8; P=.02) emerged as independent predictors of DOCE.

Secondary endpoints. All-cause mortality was similar in the 48 mm EES and DES groups (4% vs 4%; P=.80). This was also confirmed for cardiovascular mortality (3% vs 3%; P=.80) (Figure 2). Similarly, we did not observe significant difference in the TVMI rate (2% vs 4%; P=.20) (Figure 2). Although the difference was not statistically significant, TLR tended to be lower in the 48 mm EES group vs the control group (4.5% vs 8%; P=.09). Definite/probable ST occurred in 6 patients (1.4%). We did not observe acute ST. All ST occurred after hospital discharge. Subacute ST was observed in 1 patient in the control group, while the remaining 5 cases were late ST.

Estimation of savings. Overall, to perform PCI in the 48 mm EES group, we used 218 guiding catheters, 327 guidewires, and 480 balloons. The numbers did not differ in the control group (215 guiding catheters [P=.90]; 320 guidewires [P=.80]; and 473 balloons [P=.80]). However, the stent number differed significantly (360 in the study group vs 528 in the control group; P<.001). We spent $245,506 (mean, $1126) for cases. Considering the 8 attempts of 48 mm EES implantation that failed, we spent $249,273 (mean, $1143). The expenses for the control group were higher (total, $323,381; mean, $1483). The net benefit for each patient due to 48 mm EES introduction was ~$339 (about one-fourth of the overall expense for procedural materials).

Discussion

To the best of our knowledge, this is the first study designed to evaluate the effectiveness and safety of 48 mm EES in a real-life scenario. In our prospective registry involving six high-volume European centers, we collected data from patients with very long and complex lesions requiring extensive stent implantation. We compared (through a propensity score matching) the immediate success rates and 1-year outcomes of patients receiving at least one 48 mm EES in the culprit lesion vs a similar population treated with overlapping second-generation DESs. 

The results can be summarized as follows: (1) 48 mm EES implantation was successful in almost all cases (97%; 95% CI, 94%-99%); (2) 48 mm EES permits a significant reduction in number of stents and overlaps; (3) 48 mm EES use is safe and tends to reduce TLR; and (4) the systematic use of 48 mm EES allowed a net reduction in periprocedural cost.

Over the last years, DES diffusion led to the treatment of long coronary lesions, with stent overlap occurring in >30% of cases.^8,9 Preliminary studies conducted with first-generation DESs showed an increased risk of ischemic complications in patients treated with ≥1 overlapped DES as compared to those without.^10-12 The mechanisms underlying this clinical finding were higher arterial injury, lower and incomplete endothelialization, and excessive dose of the antiproliferative drug causing vascular toxicity at the site of overlap.¹³ The introduction of second-generation DESs, with more biocompatible polymers and lower doses of antiproliferative agent, seems to have reduced this limitation.^14,15 O’Sullivan et al reported the 3-year clinical outcomes of >3000 patients who underwent PCI with sirolimus-eluting stent (SES) and EES.¹⁶ They found that patients with overlap were at increased risk of adverse events, but this was driven primarily by a higher incidence of events in the SES group. These findings were confirmed by a recently published study that compared angiographic and 1-year clinical outcomes between long single EES (maximal stent length, 38 mm) vs multiple overlapping EESs.¹⁷ The authors confirmed comparable angiographic and 1-year clinical outcomes irrespective of the overlap status. Moreover, with the use of optical coherence tomography, the same group reported a more favorable neointimal response of new-generation DESs in overlapping segments.¹⁸

Our study confirms the safety and efficacy of the 48 mm EES, yet also suggests a potential superiority vs multiple overlapped EESs for the treatment of long coronary lesions. These results might be partially explained by the greater complexity of our study population (higher rate of multivessel disease, acute coronary syndromes, chronic total occlusions, etc) compared with previous studies. Moreover, as opposed to previous data, our registry is the first to include only patients with extremely long segments of coronary lesions (>50 mm vs 30-38 mm in the others). Finally, for the first time, we assessed the cost effectiveness and feasibility of using very long stents vs multiple overlapped EES.

Obviously, although encouraging, these results still have to be confirmed by a properly powered randomized clinical trial. Nevertheless, it is certain that the reduction in cost, together with the safety profile of newer DESs, has increased the interest in long stents. In addition, long stents reduce angiographic miss, the need for multiple stent implantations, and the risk of side-branch closure at the overlap site.¹⁹ It is well recognized that the old “spot-stenting technique” runs the risk of geographic miss and recent studies showed the presence of lipid-core plaques far from the most severe angiographic stenosis.^20-22 In accord with an elegant editorial by Seto and Kern, we believe that if there is no longer clinical or procedural penalty to using long second-generation and third-generation DESs, with a proven potential benefit, at least in terms of cost reduction, then the demand for longer and longer stents will increase over the next few years.²³ 

Study limitations. Our study has several potential limitations. First, it was not a randomized controlled trial. We performed a prospective data collection, which is certainly susceptible to selection bias. Second, only 1 year of follow-up is too short to test a harder endpoint. Finally, a more extensive use of intravascular imaging modalities (ultrasound and/or optical coherence tomography) would have certainly improved the results of our current study.

Conclusion

The use of 48 mm EES implantation offers a safe and effective strategy during treatment of very long coronary lesions. Moreover, the reduction in stents needed to cover long segments allows a net benefit in terms of periprocedural cost reduction.

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From the ¹Department of Interventional Cardiology “Santi Antonio e Biagio e Cesare Arrigo” Hospital, Alessandria, Italy; ²Cardiology Unit, Azienda Ospedaliera Universitaria S. Anna, Ferrara, Italy; ³Interventional Cardiology, “Ospedali Riuniti Marche Nord” Hospital, Pesaro, Italy; ⁴Interventional Cardiology, “Ospedali Riuniti,” Foggia, Italy; ⁵NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom; ⁶Department of Interventional Cardiology, Ospedale Maggiore, Bologna, Italy; ⁷Cardiology Division, Bolognini Hospital, Seriate, Italy; and ⁸Department of Cardiology, University of Eastern Piedmont, “Maggiore della Carità” Hospital, Novara, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 28, 2017, provisional acceptance given September 5, 2017, final version accepted September 22, 2017.

Address for correspondence: Gioel Gabrio Secco, MD, PhD, Interventional Cardiology, “Santi Antonio e Biagio e Cesare Arrigo” Hospital, Via Venezia 16, 15121 Alessandria, Italy. Email: gioel.gabrio.secco@gmail.com