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Four-Year Outcomes of Multivessel Percutaneous Coronary Intervention With Xience V Everolimus-Eluting Stents
Abstract: Objectives. We evaluated the long-term outcomes of multivessel compared with single-vessel percutaneous coronary intervention (PCI) with Xience V everolimus-eluting stents in real-world patients. Background. Treatment options for multivessel disease include PCI, coronary artery bypass grafting, and medical therapy. Patients with multivessel disease are at a higher risk for ischemic complications than those with single-vessel disease. Methods. The XIENCE V USA study was a condition-of-approval, single-arm, prospective study in unselected real-world patients. Patients who underwent multivessel PCI (n = 655) were compared with those who underwent single-vessel PCI (n = 4079). Major clinical outcomes, including mortality, stent thrombosis, and target-lesion failure (TLF), were evaluated at 4 years. Results. At 4 years, mortality was similar in both groups (11.1% in multivessel patients vs 9.8% in single-vessel patients; P=.31). The multivessel PCI group had higher rates of Academic Research Consortium (ARC)-defined TLF (24.3% vs 16.4% in single-vessel patients; P<.001) and ARC-defined definite and probable stent thrombosis (2.43% vs 1.11% in single-vessel patients; P=.02). The independent predictors of ARC-defined TLF at 4 years on multivariable analysis were prior myocardial infarction, number of treated vessels, total stent length, and sex. Conclusion. Despite significant differences in baseline characteristics, long-term mortality rates were similar in both groups. Although ischemic complications were higher in the multivessel PCI group, the overall rates were acceptable, demonstrating the safety and efficacy of Xience V everolimus-eluting stents for the treatment of multivessel disease in a real-world population.
J INVASIVE CARDIOL 2019;31(9):240-246.
Key words: drug-eluting stent, everolimus-eluting stent, percutaneous coronary intervention
Multivessel coronary artery disease (CAD) is a marker of more advanced atherosclerosis and is associated with worse clinical outcomes compared with single-vessel CAD, including increased risk of in-stent restenosis requiring repeat revascularization.1 Both surgical and percutaneous revascularization with drug-eluting stents are reasonable treatment options for multivessel CAD.
The SPIRIT II, III, and IV and COMPARE randomized trials, as well as prospective real-world registries, reported superior clinical outcomes with Xience V everolimus-eluting stent (EES; Abbott Vascular) compared with the Taxus paclitaxel-eluting stent (Boston Scientific), with lower late loss rate, target-lesion revascularization (TLR) rate, and major adverse cardiac events (MACE) rate.2-8 The XIENCE V USA Long-Term Follow-up Cohort, which was a single-arm, prospective, multicenter registry of 5054 unselected patients, reported excellent safety, with a 1-year Academic Research Consortium (ARC)-defined definite and probable stent thrombosis rate of 0.84%.9 The current study reports the long-term outcomes of multivessel PCI compared with single-vessel PCI in the XIENCE V USA registry.
Methods
The details of the enrollment criteria and data collection have been previously described for this study (IDE G050050).9 Patients were included in the study if they underwent PCI exclusively with Xience V EES during the index procedure. There were no exclusion criteria based upon clinical characteristics or angiography criteria. Patients were stratified into two groups: (1) multivessel PCI; and (2) single-vessel PCI. Written informed consent was obtained from all patients and the study complied with the Declaration of Helsinki for investigation in humans. The institutional review board approved the study at each enrolling center. This trial is registered with www.ClinicalTrials.gov (NCT00676520).
Clinical outcomes, including mortality, ARC-defined stent thrombosis, and ARC-defined target-lesion failure (TLF; defined as cardiac death, target-vessel myocardial infarction [MI], and clinically indicated TLR), were evaluated at 4 years. MI, TLF, MACE (defined as cardiac death, MI, and clinically indicated TLR), and target-vessel failure (TVF; defined as cardiac death, any MI, and clinically indicated TVR) were defined by both the ARC and World Health Organization (WHO) criteria.10-12 Stent thrombosis was defined according to the ARC definition.10
Clinical follow-up data were obtained from telephone calls or office visits at 14 days, 30 days, 180 days, 1 year, 2 years, 3 years, and 4 years. A Clinical Events Committee (Cardiovascular Research Foundation; New York, New York) adjudicated all clinical endpoints. The Data Safety Monitoring Board (Axio; Seattle, Washington) reviewed the safety data on a routine basis to ensure public safety.
The Xience V EES is a balloon-expandable coronary stent with a strut thickness of 81 µm and is made of L-605 cobalt-chromium alloy (Multi-Link Vision; Abbott Vascular). Everolimus is blended in a non-adhesive, durable, and biocompatible fluorinated copolymer. The drug-polymer matrix is thin (7.6 µm) and is coated onto the stent (which is prepared with a primer layer) using a multilayer process. The drug matrix releases everolimus (100 µg/cm2 of stent surface) over a period of 3 to 4 months.
Although no specific dual-antiplatelet therapy was mandated per protocol, investigators were encouraged to follow the American College of Cardiology Foundation/American Heart Association/Society for Coronary Angiography and Interventions guidelines, which recommended at least 1 year of treatment duration unless the risk of bleeding was high.13
Statistical analysis. Continuous variables are presented as mean ± standard deviation and compared with the two-sample t-test. Categorical variables are presented as percentages and compared with the Fisher’s exact test. Survival curves for time-to-event variables were constructed with the Kaplan-Meier method, with log-rank test used to compare multivessel and single-vessel PCI. The multivariable model was created using stepwise regression, where variables were entered into the model either through clinical judgment or at the .05 significance level and removed at the .05 level (from the Wald Chi-square statistic). Variables were eligible for inclusion in the multivariable model-building process if the variable was present for 90% of the subjects in the analyses, had a univariate P-value <.05, and if highly correlated with another variable (r>0.5 and P<.05), had the higher level of significance. P-values were from the Wald Chi-square statistic from the final model. A two-sided P-value <.05 was considered statistically significant.
Results
The entire cohort included 5054 patients who had 7075 lesions treated at the time of enrollment. The multivessel PCI group included 655 patients, and the single-vessel PCI group included 4079 patients (Table 1). The multivessel PCI group had a higher prevalence of diabetes mellitus than the single-vessel PCI group (39.6% vs 34.1%, respectively; P<.02) and anemia (10.4% vs 7.7%, respectively; P=.03).
A total of 1605 lesions were treated in the multivessel PCI group and 5005 lesions were treated in the single-vessel PCI group (Supplemental Table S1; supplemental materials available at www.invasivecardiology.com). The multivessel PCI group had more treatment of the left main coronary artery (3.5% vs 1.0%, respectively; P<.001), left circumflex artery (32.0% vs 22.2%, respectively; P<.001), and de novo lesions (93.8% vs 90.4%, respectively; P<.001). The multivessel PCI group had less treatment of the right coronary artery (28.8% vs 36.5%, respectively; P<.001). The mean number of vessels treated in the multivessel PCI group was 2.1 ± 0.2, and 5.3% underwent PCI of 3 or more vessels. The mean number of stents implanted in the multivessel PCI group was 2.8 ± 1.0. The multivessel PCI group had a higher usage of 2.5 mm diameter stents compared with the single-vessel PCI group (35.9% vs 32.3%, respectively; P<.01). The total stent length per patient was longer in the multivessel PCI group compared with the single-vessel group (50.8 ± 23.9 mm vs 26.1 ± 16.5 mm, respectively; P<.001).
At 1-year follow-up, the multivessel and single-vessel PCI groups had similar rates of death (2.7% vs 2.4%, respectively; P=.68) (Table 2). However, the multivessel PCI group had a higher incidence of both ARC-defined MI (8.9% vs 4.7%, respectively; P<.001), WHO-defined MI (3.1% vs 1.7%, respectively; P=.02), TLR (7.7% vs 3.4%, respectively; P<.001), TVR (9.7% vs 4.6%, respectively; P<.001), ARC-defined TLF (13.3% vs 7.1%, respectively; P<.001), and WHO-defined TLF (9.9% vs 5.3%; P<.001) (Figure 1).
At 4-year follow-up, the mortality rate was not significantly different between the multivessel and single-vessel PCI groups (11.1% vs 9.8%, respectively; P=.31) (Table 3). Driven by the 1-year difference, the multivessel PCI group continued to have higher rates of ARC-defined MI (13.7% vs 9.6%, respectively; P<.01), WHO-defined MI (6.1% vs 3.9%, respectively; P=.02), TLR (15.0% vs 8.9%, respectively; P<.001), TVR (19.0% vs 11.9%, respectively; P<.001), ARC-defined TLF (24.3% vs 16.4%, respectively; P<.001), and WHO-defined TLF (20.3% vs 13.9%, respectively; P<.001).
The rates of ARC-defined definite, probable, and possible stenosis were not significantly different between the multivessel and single-vessel PCI groups at 1 year (2.23% vs 1.42%, respectively; P=.16) and 4 years (5.91% vs 4.13%, respectively; P=.06) (Supplemental Table S2). However, the rates of ARC-defined definite and probable stent thrombosis were higher in the multivessel PCI group at 1 year (1.75% vs 0.64%, respectively; P=.01) and 4 years (2.43% vs 1.11%, respectively; P=.02).
The following variables were entered into the stepwise multivariable Cox proportional hazard model for ARC-defined TLF: age, sex, diabetes mellitus, ejection fraction, number of vessels treated, congestive heart failure, prior MI, and total stent length. The multivariable predictors were prior MI, number of treated vessels, total stent length, and female sex (Table 4).
Discussion
In this multicenter, prospective registry, there were no significant differences in all-cause, cardiac, vascular, and non-cardiac death between the two groups at long-term follow-up. Multivessel PCI was associated with higher rates of other non-fatal ischemic complications. Prior MI, number of treated vessels, total stent length, and sex were predictors of long-term adverse clinical events in patients who underwent PCI with Xience V EES.
Multivessel PCI is appealing because it is much less invasive compared with coronary artery bypass grafting (CABG). Patients with multivessel disease often have more comorbidities and are at higher risk for postoperative morbidity and mortality. The EuroScore and the Society of Thoracic Surgeons score incorporate patient comorbidities and provide cardiac operative mortality.14-16 The Syntax score is a well-established and validated method to identify which patients will best benefit from PCI.17 In general, patients with low- and intermediate-risk Syntax scores are good candidates for multivessel PCI, while patients with high scores (>32%) are poor candidates. The EXCEL trial showed that PCI with the Xience EES was non-inferior to CABG in patients with left main coronary artery disease and low or intermediate Syntax scores.18
The ARC-defined definite and probable stent thrombosis rate at 4 years in the multivessel PCI group was 2.43%. The SYNTAX trial reported a 3-year definite or probable stent thrombosis rate of 3.1% with paclitaxel-eluting stents.19 Previous studies have also demonstrated lower stent thrombosis rates with EES compared with paclitaxel-eluting stents, which may be related to improved safety of the thromboresistant fluoropolymer coating.7,20
Stent length was a risk for stent thrombosis.21 We identified that the number of treated vessels and total stent length were predictors of ARC-defined TLF. It is not surprising that the multivessel PCI group had worse clinical outcomes.
Prior MI was identified as a predictor of WHO-defined TLF in our study. This finding was observed in other studies, in which patients with previous MI were at high risk of recurrent events and mortality.22,23
Patients who underwent multivessel PCI had a higher prevalence of diabetes mellitus. Diabetic patients have a greater atherosclerotic burden that is commonly long and diffuse, which may explain the higher rates of ischemic complications in diabetic patients who underwent multivessel PCI.24 The FREEDOM trial demonstrated a higher mortality rate in diabetic patients who underwent multivessel PCI compared with CABG.25
The MI rate was higher in the multivessel PCI group. Surgical revascularization offers greater protection against MI because it bypasses coronary plaques that are susceptible to erosion and fissure. In the present study, previous MI was an independent predictor of TLF.
The ratio of stent number/patient between the multivessel and single-vessel PCI group is 2 (2.8 to 1.4). Similarly, the ratio of stent length/patient was 2 (50.8 mm to 26.1 mm). Despite this, our data support the safety of multivessel PCI, as mortality was similar, and MACE rates are less than expected compared with single-vessel PCI.
The event rates in the multivessel PCI group compare favorably with the other published data. In patients with acute coronary syndrome who underwent multivessel revascularization with sirolimus-eluting, paclitaxel-eluting, and zotarolimus-eluting stent implantation, the composite of death, MI, and revascularization at 3 years was 19.6%.26 The 3-year stent thrombosis rate was 2.2%, compared with the 2.43% at 4 years in our study. In the ARTS II study, multivessel PCI with sirolimus-eluting stents was associated with a major adverse cardiac and cerebrovascular event (MACCE) rate of 10.4% at 12 months.27 In the SYNTAX trial, the 1-year MACCE rates in the CABG and PCI groups were not significantly different in the low Syntax score group (14.7% vs 13.6%, respectively; P=.71) and intermediate Syntax score group (12.0% vs 16.7%, respectively; P=.10).17
Female sex was identified as a predictor of long-term ARC-defined TLF. Previous studies demonstrated worse outcomes in females undergoing PCI.28,29 Worse premorbid factors, smaller coronary diameters, delayed presentations of acute coronary syndromes, and higher rates of vascular access site and bleeding complications may explain the increased safety risk.30
Study limitations. This was a post hoc analysis of a non-randomized study, which may have affected the results due to confounding factors. The decision to perform multivessel or single-vessel PCI was at the discretion of the operator. No comparison with CABG or medical therapy was performed. There was no angiographic core lab to perform quantitative coronary analysis. Surveillance coronary angiography was not required. Differences in baseline characteristic may have contributed to worse outcomes in the multivessel PCI group. Syntax scores were not calculated for patients. Data on completeness of revascularization were not reported.
Conclusion
Patients who underwent multivessel PCI had similar long-term mortality compared with patients who underwent single-vessel PCI. Ischemic complications were higher in the multivessel PCI group. The number of treated vessels was a significant predictor of ARC-defined TLF. Compared with previous published studies, the long-term ischemic complications with multivessel PCI with drug-eluting stents indicated favorable results.
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From 1the Division of Cardiology, UCLA Medical Center, Los Angeles, California; 2Division of Cardiology, St. Francis Hospital, Roslyn, New York; 3Division of Cardiology, UCSD Medical Center, La Jolla, California; 4Division of Cardiology, Seoul National University, Seoul, South Korea; 5Division of Cardiology, Korea University Guro Hospital, Seoul, South Korea; and 6Abbott Vascular, Santa Clara, California.
Funding: The XIENCE V USA study was a condition-of approval postmarket study whose operational expenses were funded by the sponsor (Abbott Vascular). The sponsor, principal investigator, and co-principal investigators actively collaborated with the Food and Drug Administration to design, conduct, and analyze the study. James Hermiller, MD, and Mitchell Krucoff, MD, were the principal investigators for the XIENCE V USA study, but did not review this paper. Abbott Vascular provided the statistical analysis of this study. The corresponding author had full access to the data, and all authors contributed to the preparation of the manuscript.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Shlofmitz reports honoraria from Cardiovascular Systems, Inc. Dr Sudhir is an employee and stockholder in Abbott Vascular. Dr Zhao, Dr Gaborro, and Dr Wang are employees of Abbott Vascular. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 17, 2019, provisional acceptance given March 11, 2019, final version accepted March 20, 2019.
Address for correspondence: Dr Michael S. Lee, UCLA Medical Center, 100 Medical Plaza, Suite 630, Los Angeles, CA 90095. Email: mslee@mednet.ucla.edu
