Daniela Trabattoni, MD1; Franco Fabbiocchi, MD1; Piero Montorsi, MD1,2; Stefano Galli, MD1; Paolo Ravagnani, MD1; Giuseppe Calligaris, MD1; Giovanni Teruzzi, MD1; Luca Grancini, MD1; Sarah Troiano, MD1; Cristina Ferrari, MD1; Antonio L. Bartorelli, MD1,3
Abstract: Background. The safety and effectiveness of the everolimus-eluting stent (EES) have been previously demonstrated. Aims. To assess very long-term performance and outcomes of the EES in a real-world population. Methods. This single-center registry prospectively enrolled 6893 patients (mean age, 66 ± 9.7 years; 81.4% men) undergoing elective coronary intervention with the EES over a decade. Clinical follow-up (FU) was performed at 1 year and then yearly thereafter. Results. Multiple risk factors were present in 34%. Stable angina was the main stenting indication (78.1%), followed by unstable angina (5.3%) and positive stress test (16.6%) for 1-vessel (44%) or 2/3-vessel disease (56%). Multiple stents (stent/patient ratio: 2.1 ± 0.8) in >1 vessel were implanted in 36.9% (mean stent length, 43 ± 31.3 mm). At 1 year, 80% of patients were on dual-antiplatelet therapy, while only 3% were on therapy at 2 years. A low 1-year major adverse cardiac event (MACE) rate of 5.0% was observed; stent thrombosis (ST) occurred in 19 patients (0.3%), with a prevalence of early (n = 9) over late (n = 4) and very late events (n = 6; 0.08%). Clinically driven target-lesion revascularization/target-vessel revascularization (TLR/TVR) occurred in 3.3% at 1-year follow-up. Long-term FU (3 years) completed in 6210 patients (90.0%) showed a MACE rate of 5.9%, while very long-term FU (>5 years and up to 10 years), available in 3550 out of 4635 exposed patients (76.6%), showed a MACE rate of 8.6%. Independent MACE predictors were stented segment length (odds ratio [OR], 2.1; 95% confidence interval [CI] 1.57-2.82), small vessel stenting (OR, 1.34; 95% CI, 1.08-1.68), and multivessel disease (2-vessel disease: OR, 1.59; 95% CI, 1.21-2.08; 3-vessel disease: OR, 2.26; 95% CI, 1.72-2.97). Conclusions. This large, prospective registry confirms the very long-term safety and efficacy of the EES in unselected real-world and complex coronary lesions.
J INVASIVE CARDIOL 2019;31(5):146-151. Epub 2019 January 15.
Key words: clinical outcomes, drug-eluting stent, everolimus-eluting stent, stent thrombosis
Compared to bare-metal stent (BMS) options, sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) options – often referred to as first-generation drug-eluting stents (DESs) – significantly reduced restenosis and need for target-lesion revascularization (TLR). However, growing concern regarding delayed healing and stent thrombosis (ST) with DES implantation led to the development of second-generation (2G) devices with the aim of increasing safety and efficacy. The everolimus-eluting stent (EES) is a 2G-DES that demonstrated remarkable advantages over first-generation DES options in terms of safety profile and clinical outcomes. A meta-analysis of the SPIRIT trials demonstrated better safety and efficacy profile throughout 3 years for the EES as compared to the PES and durable benefits in the SPIRIT III trial up to 5 years.1 A comprehensive network meta-analysis showed that EES was associated with an ST rate even lower than BMS.2 However, despite excellent safety and efficacy results published to date, longer-term follow-up is required to determine whether EES benefits are sustained in real-world patients and to assess the late safety profile of this 2G-DES.
Thus, the main purpose of this prospective, single-center registry was to evaluate the long-term clinical outcomes of a large population of unselected, consecutive, real-world patients undergoing elective percutaneous coronary intervention (PCI) with the EES in daily practice.
Study design and patient population. Between November 30, 2006 and April 30, 2016, a total of 6893 consecutive patients undergoing elective PCI with the EES were included without any specific restriction on number of treated lesions/vessels or lesion length. We excluded patients with ST-elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (NSTEMI), those treated with EES and other stent types in the same procedure, those treated without stent implantation, those treated exclusively with BMS or other DES, and those participating in investigational studies that had not yet reached their primary endpoint. Procedures were performed according to standard interventional techniques and clinical guidelines. Our institution’s scientific and ethical committees approved the study and all patients provided written informed consent.
Study device. The Xience EES (Abbott Vascular) is a 2G-DES comprised of a cobalt-chromium 81 µm platform, with an open-cell non-linear link design coated with the lipophilic drug everolimus blended into an 8-µm thick durable and biocompatible fluoropolymer layer. Everolimus is a highly lipophilic semisynthetic macrolide immunosuppressant that inhibits mTOR, thereby inducing cell-cycle arrest between the G1 and S phases and inhibition of smooth muscle cell proliferation. About 80% of the drug is released within 30 days after implantation and the remainder within 4 months.
The EES was available in diameters of 2.25 mm, 2.5 mm, 2.75 mm, 3.0 mm, 3.5 mm, and 4.0 mm and lengths of 8 mm, 12 mm, 15 mm, 23 mm, 28 mm, 33 mm, 38 mm, and 48 mm. Throughout the registry period, the Xience Prime and the Xience Alpine stents were used when they became available.
Medication and stenting protocol. A weight-adjusted heparin bolus (100 IU/kg) was given after arterial sheath insertion with additional boluses administered during the procedure to maintain an activated clotting time of 250-300 sec. All patients were pretreated with aspirin and received a 600 mg loading dose of clopidogrel in the catheterization laboratory. After PCI, clopidogrel was prescribed at a dose of 75 mg/day for 12 months,3 while life-long aspirin was recommended. Dual-antiplatelet therapy (DAPT) duration was reduced to 6 months after September 2014 in a minority (10%) of patients.
Stents were selected to cover approximately 3 mm of non-diseased vessel on either side of the lesion. In patients receiving multiple stents for a single lesion, 1-3 mm of stent overlap was performed. Postdilation with non-compliant balloons was recommended, while intravascular ultrasound (IVUS) was endorsed, particularly for the treatment of the left main coronary artery and other complex lesions.
Definitions. Procedural success was defined as <30% residual stenosis (visual estimate) with grade TIMI 3 flow after stenting. Clinical success was defined when no in-hospital death, STEMI, or acute/subacute ST occurred or when there was no need for emergency or elective target-vessel revascularization (TVR), either by coronary artery bypass graft (CABG) or repeat PCI. In-hospital mortality was defined as any death, irrespective of the cause, occurring during the same hospital stay. STEMI was defined as a clinical episode of prolonged chest pain associated with serum creatine kinase increase up to >2x the upper limit of normal and appearance of ≥1 new pathologic Q-waves. NSTEMI was defined as serum creatine kinase MB increase >3x the upper limit of normal from the beginning of the registry (until 2014, when high-sensitivity troponins were made available), and without significant chest discomfort and/or electrocardiographic changes. Major adverse cardiac event (MACE) was defined as death, MI, TVR, and TLR. The primary clinical outcome, which was descriptive in nature, was a composite of all-cause death, MI, or TVR. Secondary clinical outcomes were the components of the primary outcome and target-vessel failure (TVF), defined as the composite of death of any cause, ischemia-driven TLR, and definite or probable ST. Concordant with the Academic Research Consortium (ARC) criteria, all deaths were considered cardiac unless an unequivocal non-cardiac cause was established. The periprocedural period included the first 48 hours and 72 hours after PCI and CABG, respectively. Late events not associated with PCI were considered spontaneous. ST was defined as angiographically defined thrombosis with TIMI flow grade 0/1 or the presence of flow-limiting thrombus accompanied by acute symptoms, irrespective of whether there had been an interceding reintervention.4 Timing of ST was categorized as early (within 30 days after implantation), late (between 30 days and 1 year), or very late (>1 year).5 According to the ARC definition, probable ST was defined as any unexplained death within 30 days or as target-vessel MI without angiographic confirmation of thrombosis or another identified culprit lesion. Possible ST was defined as unexplained death after 30 days. TLR was defined as any repeat target-lesion PCI performed for restenosis. The target lesion was defined as the treated segment from 5 mm proximal and 5 mm distal to the stent edges. TVR was defined as any PCI of any segment of the target vessel. Major bleeding was defined as severe bleeding, large pseudoaneurysm, or arteriovenous fistula at the puncture site requiring transfusion and surgical or interventional repair.
Follow-up. Adverse event occurrence was monitored with outpatient visits scheduled at 30 days, 12 months, and then yearly (median, 69.04 months; range, 0.03-118 months; lower quartile-upper quartile [IQR], 45.4-88.8 months) and recorded prospectively. Of note, as a large tertiary referral center, most repeat revascularizations (either PCI or surgical) are usually performed at our institute and recorded prospectively in our database. Medical records from other hospitals were reviewed for patients who were hospitalized elsewhere for adverse events, while referring physicians were contacted in case additional information was needed. Data from the civil registry were collected for a more precise death analysis on long-term follow-up. This allowed a high level of data collection and source documentation.
Statistical methods. Continuous data are expressed as means with standard deviations and compared with Student’s t-test. Qualitative data are presented as frequencies and/or percentages. P-values are derived by the two-sided tests and considered statistically significant if <.05. Kaplan-Meier curves were calculated to show the temporal trend of the main outcomes considered and stratified according to the number of diseased vessels treated (Figure 1). The identification of independent MACE predictors was assessed by Cox’s regression model. Results of the analysis were summarized as odds ratio (OR) with 95% confidence interval (CI).
Between November 2006 and April 2016, a total of 14,886 consecutive and unselected patients underwent PCI at our institute; 47% were men. Clinical and angiographic characteristics were similar among patients regardless of DES type utilized. Of the 6893 consecutive patients treated with EES, 81.4% were men. Table 1 shows their baseline characteristics. PCI indications were stable angina (78.1%), silent ischemia (16.6%), and unstable angina (5.3%). In 7% of patients, an EES was deployed for unprotected left main stenosis. Patients were often treated for multivessel disease with multiple stents (55%) and received long stented segments (total stent length/patient, 43 ± 31.3 mm; range, 8-252 mm) with a stent-patient ratio of 2.1 ± 0.8. Lesion predilation was performed in 84% and high-pressure postdilation (16.6 ± 2.5 atm) with non-compliant balloons was performed in 80.0%, while IVUS guidance was used in 32.0%. The composite endpoint of in-hospital MACE was observed in 2.7%. Six patients died (4 from cardiogenic shock, 1 from ventricular fibrillation, and 1 from sepsis). Postprocedural STEMI occurred in 9 patients (0.1%) and NSTEMI occurred in 169 patients (2.4%). Early ST was observed in 9 patients (0.1%) (definite ST in 8 patients and probable ST in 1 patient). We observed a low 1-year cumulative MACE rate of 5.0%. Cumulative ST rate was 0.37% in the entire population treated over the same study period (0.3% among the 6893 EES patients and 0.4% among the remaining 7993 patients who received non-EES DES options).
Overall, ST occurred in 19 EES patients (0.3%), with a prevalence of early (9) over late (3 definite, 1 probable) ST events. Very late (>1 year) ST occurred in 6 patients (0.08%). The rate of clinically driven TLR/TVR was 3.3%, while in 289 patients (4.1%), staged procedures or non-TVR/non-TLR PCIs were performed during 1-year follow-up. Eighty percent of patients were on DAPT at 1 year, while only 3% were on DAPT at 2 years.
Three-year complete follow-up data were available for 6210 patients (90.0%) and showed a 5.9% cumulative MACE rate (Table 2). These results were similar to those obtained both acutely and at 1-year and 3-year follow-up in the overall population. The cumulative 5-year MACE rate, available in 4380 patients (87.0%), was 9.6% (Table 3). Long-term clinical follow-up (>5 years and <10 years), completed in 3550 patients (72.0%), showed a cumulative MACE rate of 8.6% (Table 4).
The independent predictors of MACE were stented segment length (OR, 2.1; 95% CI, 1.57-2.82), small vessel stenting (OR, 1.34; 95% CI, 1.08-1.68); 2-vessel disease (OR, 1.59; 95% CI, 1.21-2.08), and 3-vessel disease (OR, 2.26; 95% CI, 1.72-2.97). The temporal MACE trends stratified according to the number of diseased vessels treated are shown in Figure 1.
The aim of this article is to report the long-term safety and efficacy of the EES in a large, single-center registry of all-comers undergoing elective PCI. The EES showed a remarkably low rate of late and very late ST, TLR, TVR, and MACE at 1-year, 5-year, and >5-year follow-up. The very low MACE rate is clinically significant. Indeed, it is a composite measure of safety (cardiac death and MI) and stent efficacy (TLR) and is more specific to the EES performance than TVF, which includes TVR remote from the target lesion (an event not affected by EES implantation). These findings confirm and extend previous results of the SPIRIT trials, suggesting an even greater benefit of the EES in more complex patients and lesions. Notably, our registry has the longest follow-up in the largest unselected real-world patient population to date. This is of major importance to determine whether the benefits previously observed with the EES are sustained and to assess the late safety profile, because it is known that the incremental risk of ST with DES may emerge beyond 1 year.6 Indeed, the only five randomized trials comparing first-generation DES versus 2G or newer-generation DES with 5-year follow-up demonstrated that the primary endpoint at 1 year was not a predictor of the long-term outcome in terms of safety and efficacy.7-10
The SPIRIT trial program compared the EES initially to BMS and then to PES in a series of studies (SPIRIT FIRST, II, III, and IV). In patients with simple lesions and low-risk profiles, the SPIRIT FIRST trial11 showed significantly lower mean in-stent luminal loss at 6 months in the EES group vs the group treated with the identical BMS counterpart (Vision). A similar lower neointimal hyperplasia level was demonstrated by IVUS. The randomized SPIRIT II3,12 and III trials13,14 evaluated EES vs PES in a larger number of patients and similarly demonstrated a significant reduction in the primary endpoint of in-stent late loss at 6 months and 8 months, respectively. Although they were not primary endpoints, 1-year clinical follow-up of SPIRIT II patients showed lower rates of MACE (2.7% vs 9.2%; P=.04) and ST (0.0% vs 1.3%) for EES compared to PES.13 At 2 years, TLF was also numerically but not statistically lower (6.6% vs 11.0%; P=.31).15 Although there was no difference in the secondary endpoint of TVF, SPIRIT III demonstrated a significant reduction in MACE at 9 months and 1 year with EES compared to PES (4.6% vs 8.1% [P=.03] and 6.0% vs 10.3% [P=.02], respectively).14 The clinical advantage of the EES was confirmed at 2 years with numerically lower cardiac death rate (1.1% vs 1.3%; P=.75) and MI rate (3.3% vs 5.9%; P=.08) and a significant reduction in TLR (6.1% vs 11.3%; P<.01).16 Moreover, TVF rate (11.3% vs 16.4%; P=.04) and MACE rate (7.7% vs 13.8%; P<.01) were all significantly lower at 3-year follow-up.17
The results of the large-scale SPIRIT IV trial further support the clinical superiority of EES compared to PES in higher-risk patients and in more complex lesions, showing a significantly lower rate of the primary endpoint of TLF with EES compared to PES (4.2% vs 6.8%; P<.01 for superiority). This was driven primarily by a significant reduction of ischemia-driven TLR (2.5% vs 4.6%; P<.01).17 Although all-cause mortality and cardiac death rates were similar, EES was associated with a significant reduction of MI (1.9% vs 3.1%; P=.05) and ST at 1 year (0.29% vs 1.06%; P<.01).
The more recent SPIRIT V Clinical Evaluation consists of two concurrent studies, the SPIRIT V diabetic study, a prospective, randomized, multicenter trial comparing outcomes after stenting with EES vs PES specifically in diabetic patients undergoing non-emergent PCI18 and the SPIRIT V registry, a prospective, single-arm, multicenter registry evaluating EES performance in the real-world setting.19 In the SPIRIT V diabetic study, EES resulted in significantly better inhibition of intimal hyperplasia and similar composite rate of death, MI, and TLR compared with PES at 1 year (16.3% vs.16.4%).18 In the SPIRIT V registry, implantation of a maximum of 4 EESs in vessels with a diameter between 2.25-4.0 mm and a length of ≤28 mm by visual estimation was performed in patients with multiple and complex de novo lesions. The primary composite endpoint of all death, MI, and TVR at 30 days was 2.7%, which is comparable to the rate observed in the more controlled SPIRIT II and SPIRIT III trials, which enrolled patients with restricted inclusion and exclusion criteria.19 At 1 year, cardiac death, overall MI, and TLR rates were 1.1%, 3.5%, and 1.8%, respectively, while the cumulative rate of definite and probable ST was 0.66%.
It is noteworthy that the cumulative 1-year MACE rate (5.0%) and ST rate (0.2%) observed in even more complex lesions and patients of our registry compare favorably with the results of the SPIRIT V registry. Our very low rate of definite ST is also in agreement with the 12-month definite ST rates of the EES patients enrolled in the COMPARE20 and RESOLUTE21 randomized trials (0.4% and 0.3%, respectively). Indeed, the results of the COMPARE trial, a single-center prospective randomized trial comparing PES to EES in 1800 all-comer real-world patients, suggest an even greater benefit of EES over PES when unselected patients with potentially more complex lesions than those enrolled in the SPIRIT trials are treated.20 The primary endpoint of death, MI, and TVR at 12 months was observed in 9.1% of PES patients and in 6.2% of the EES group. The randomized comparison in the RESOLUTE trial showed similar TLF rates in the zotarolimus-eluting stent (ZES) and EES groups, but a higher rate of definite ST in the ZES arm within the first 12 months (1.2% vs 0.3%).21 At 5-year follow-up, ZES and EES showed similar efficacy and safety in these patients who had minimal exclusion criteria. However, albeit not significant, definite/probable ST rate was numerically higher in ZES-treated patients (2.8% vs 1.8%).21
Similar to our study, the single-center X-SEARCH (Xience Stent Evaluated at Rotterdam Cardiology Hospital) registry22 evaluated the clinical outcomes of the EES with unrestricted use in a smaller population of consecutive patients (n = 649) with de novo coronary lesions. EES patients were compared with those treated previously with BMS, SES (RESEARCH registry), and PES (T-SEARCH registry). EES-treated patients were older and more often had MI and complicated lesions. At 6 months, EES was superior to BMS for TVR and MACE, showed similar clinical outcomes to SES, and in line with the SPIRIT trials, had lower MACE rate than PES. Our long-term safety results are also in accordance with data from the SORT OUT IV (Randomized Clinical Comparison of the Xience V and the Cypher Coronary Stents in Non-selected Patients With Coronary Heart Disease) trial,23 which compared the 5-year outcomes for EES vs SES. This study randomized 2771 patients and showed a significantly lower MACE rate at 5 years in EES-treated patients that was attributable mainly to a lower rate of late definite ST (0.2% vs 1.4%).23 Of note, our prolonged follow-up suggests that late neointimal “catch-up” phenomenon, which was previously observed in a subset of SPIRIT II EES-treated patients undergoing serial angiography,15 does not translate into increased revascularizations and clinical events.
The low ST rate in EES-treated patients observed in several randomized trials and confirmed at long-term follow-up by our large registry in a real-world population is remarkable. The outstanding EES safety observed to date may be attributable to the different characteristics of the drug and the polymer as compared to first-generation DES options. Indeed, preclinical studies of stent healing showed that more rapid endothelialization, a surrogate of ST risk, reduced expression of platelet-endothelial cell adhesion molecule-1 and increased messenger ribonucleic acid levels of vascular endothelial growth factor at 14 days with EES as compared to SES or PES.24 Another factor that may play a role is the tight adhesion of albumin to the highly hydrophobic fluoropolymer that displaces thrombogenic proteins, such as fibrinogen.25 However, the individual contribution of the EES platform, polymer, and drug cannot be isolated in their influence on less ST and intimal hyperplasia, which translates into lower rates of TLR and absence of catch-up phenomenon over long-term follow-up. Another contributing factor to the acute and long-term safety and efficacy results of our registry might have been the accurate stent implantation technique with high rates of lesion predilation and stent postdilation with non-compliant balloons and liberal use of IVUS, particularly in complex lesions.
Study limitations. This study has several limitations. First, it is a single-center, non-randomized, and observational registry. Second, since the study was conducted at a large tertiary referral center, the results may not be generalizable to other populations. Third, we included in the analysis only patients undergoing elective PCI because a low percentage of patients are referred to our center for treatment of acute coronary syndromes. Fourth, the very low rates of MI reported after PCI may indeed depend on the MI definition used, which was not based on troponin levels, but on CK-MB increase >3x the upper limit of normal. Fifth, the analysis was based mainly on clinical evaluation and angiography was performed only in selected cases due to clinical requirements. Consequently, the TLR and TVR rates may have been under-represented. However, absence of routine angiographic follow-up may have allowed more accurate assessment of the clinical efficacy, avoiding unnecessary TLR due to the “oculostenotic reflex” phenomenon. Sixth, lack of independent study monitors is also a limitation. However, we believe that the approach used for event detection, combined with an all-comer study design, allowed us to assess the efficacy of elective PCI performed with EES implantation in a context reflecting every-day clinical practice. Seventh, despite the high level of clinical follow-up completion, we cannot exclude occurrence of events in patients lost to follow-up.
This large, elective, PCI registry confirms the very long-term safety and efficacy of an EES over more than a decade of follow-up and demonstrates optimal results in an unselected stable-coronary population including high-risk patients with complex coronary artery disease.
Acknowledgment. The authors would like to thank Fabrizio Veglia, PhD, and Alice Bonomi, MSD, for their statistical expertise.
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From the 1Centro Cardiologico Monzino, IRCCS, Milan, Italy; 2Department of Clinical Sciences and Community Health, Cardiovascular Section, University of Milan, Milan, Italy; and the 3Department of Biomedical and Clinical Sciences “Luigi Sacco,” University of Milan, Milan, Italy.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bartorelli reports personal fees from Abbott Vascular. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted October 3, 2018, provisional acceptance given October 10, 2018, final version accepted October 30, 2018.
Address for correspondence: Daniela Trabattoni, MD, FESC, FACC, Centro Cardiologico Monzino, Via Parea 4, 20138 Milan, Italy. Email: email@example.com