Clinical Outcomes in the Percutaneous Coronary Intervention of In-Stent Restenosis With Everolimus-Eluting Stents

Abstract: Background. Although percutaneous coronary intervention with everolimus-eluting stent (EES) implantation for native coronary artery disease has favorable results compared to first-generation drug-eluting stents, outcomes with EES for the treatment of in-stent restenosis (ISR) are unknown. Methods. The Xience V USA is a prospective multicenter registry evaluating outcomes in patients treated with EES. Here, we present the 12-month clinical outcomes in patients who received EES for the treatment of ISR and non-ISR. The primary outcome was the composite of target lesion failure (cardiac death, target vessel myocardial infarction (MI), or target lesion revascularization). Secondary outcomes were MI, target lesion revascularization (TLR), and stent thrombosis (ST). Results. In this registry, a total of 383 patients (64.4 ± 11.4 years; 68.4% male) received revascularization for single-vessel ISR and 4832 patients (64.4 ± 11.0 years; 69.0% male) received revascularization for non-ISR lesions. At 1 year, target lesion failure was 10.9% in the ISR group and 4.9% in the non-ISR group. MI, TLR, and definite ST rates were higher in the ISR group (MI, 2.2% ISR group and 1.6% non-ISR group; TLR, 10.3% ISR group and 2.9% non-ISR group; definite/probable ST, 1.98% ISR group and 0.36% non-ISR group). However, these differences ceased to exist when case-control matched patients in the non-ISR group were studied (target lesion failure, 8.8% ISR vs 7.4% non-ISR; cardiac death or MI, 2.7% ISR vs 1.4% non-ISR; TLR, 7.8% ISR vs 7.1% non-ISR; and definite/probable ST, 1.03% ISR vs 0.69% non-ISR). Conclusion. The treatment of ISR with EES appears to be safe and efficacious at 1 year. Compared to the non-ISR group, target lesion failure was much higher, indicating a higher risk profile of these patients. However, these differences ceased to exist with case-controlled matching. 

J INVASIVE CARDIOL 2014;26(9):420-426

Key words: drug-eluting stents, restenosis, in-stent restenosis

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Drug-eluting stent (DES) implantation for the treatment of native coronary artery disease improves clinical outcomes by decreasing the rate of in-stent restenosis (ISR) and need for repeat revascularization compared to bare-metal stent (BMS) use.¹ However, the optimal treatment strategy for ISR remains unclear.² Plain balloon angioplasty compared with cutting balloon angioplasty results in similar and high rates of repeat ISR and target lesion revascularization (TLR).³ Balloon angioplasty alone studied in propensity-matched⁴ and in a randomized fashion versus sirolimus-eluting stent (SES) implantation⁵ did not show any differences in clinical outcomes. However, percutaneous coronary intervention (PCI) with SES was superior to balloon angioplasty alone in the RIBS-II trial.⁶ Vascular brachytherapy initially showed promise,^7,8 but randomized controlled trials showed the superiority of DES over this modality.^9,10 The high restenosis rate, occurrence of thrombosis, and the lack of availability have led to a decrease in use of vascular brachytherapy. 

Although second-generation DESs are frequently used for the treatment of ISR, there is a paucity of data evaluating the effectiveness of this strategy.^11,12 EESs are effective for the treatment of native vessel disease and have an excellent safety profile, and might provide similar outcomes in ISR patients.¹³ Therefore, we undertook this study to evaluate the efficacy and safety of EES implantation for the treatment of ISR.

Methods

Design. Patients undergoing PCI with Xience V EES (Abbott Vascular) in the Xience V USA trial were enrolled into a large registry. Xience V USA is a prospective, open-label, multicenter, observational, single-arm trial designed to further evaluate the safety of the EES in clinical practice. A total of 8061 patients who underwent EES implantation were enrolled from 192 sites in the United States. The study had two enrollment phases: July 2008 to December 2008 with 5062 patients and the second enrollment phase from August 2009 to February 2010 with 2999 patients initiated to support the Food and Drug Administration (FDA) dual-antiplatelet therapy (DAPT) initiative. 

All patients who could provide written informed consent and were treated only with EES during the index procedure were eligible. There were no additional clinical descriptors or angiographic exclusion criteria for either enrollment phase. Stent implantation was performed according to each site’s standard practice. Periprocedural pharmacotherapy was also determined by site-based clinical practice, and staged procedures were permitted. Antiplatelet therapy for at least 1 year was recommended in patients who were not at high risk of bleeding per guidelines, but antiplatelet therapy was not otherwise mandated by protocol per se. There were no protocol-required treatments or tests, except that postprocedure cardiac enzyme collections were required during the second enrollment phase per FDA request. 

All patients were clinically followed at 14 days, 30 days, and 6 months either by telephone contact or office visit. The 1-year visit was conducted in the office. There was no mandatory angiographic follow-up in this study. Planned follow-up in patients from the first enrollment phase will continue for 5 years from the index procedure and will be reported annually. Eligible patients who were enrolled during the second enrollment phase were randomized to different DAPT arms at 1 year and will be followed at 15, 24, 30 and 33 months according to the long-term DAPT study. The remaining patients from the second enrollment phase will not be followed any further.

From these pooled data, we extracted patients who underwent PCI for the treatment of ISR and non-ISR lesions. Of these, we evaluated patients in whom a single lesion was treated and performed as a non-staged procedure. The patients were only counted once for each type of event and each time period. 

The primary endpoint of the study was target lesion failure (TLF) at 1 year, defined as the composite of cardiac death, target vessel myocardial infarction (MI), or target lesion revascularization (TLR). The secondary endpoints were MI, TLR, and definite stent thrombosis (ST). The criteria for TLF, MI, and stent thrombosis were consistent with the Academic Research Consortium (ARC) guidelines.¹⁴

Statistical analysis. Due to the relatively small sample size of the ISR subset in contrast to the non-ISR subset, a case-control matching strategy was used for the adjusted analysis. In this strategy, first the propensity score (probability of being in the ISR subset) is built based upon baseline characteristics, and then each ISR patient is matched to a non-ISR patient through the proximity of propensity scores (PS) via a Greedy Match algorithm. The variables that were used for PS building through logistic regression include age, gender, smoking status, diabetes, hypertension, hypercholesterolemia, previous CABG, previous PCI, Canadian Cardiovascular Society (CCS) class 3 or 4, previous MI, acute MI, renal insufficiency, left ventricular ejection fraction (LVEF) <30%, number of diseased vessels, B2C lesion, left main, number of vessels treated, graft lesion, Thrombolysis in Myocardial Infarction (TIMI) score, vessel (right coronary artery [RCA], left circumflex [LCX], or left anterior descending [LAD]), bifurcation, ostial lesion, calcification, percent diameter stenosis (%DS) at baseline, and lesion length <22 mm. After applying the Greedy Match algorithm, a total of 317 ISR patients out of the 383 overall ISR patients were matched. The Greedy 5χ1 digit match algorithm was applied for a 1 to 1 match between case and controls. Cases were first matched to controls on 5 digits of the PS. For those that did not match, cases were then matched to controls on 4 digits of the PS. This continued down to a 1-digit match on PS for those that remained unmatched. The non-matched ISR patients (n=66) are the result of missing propensity scores due to incomplete data for certain baseline variables.

Results

Baseline clinical and procedural characteristics — all patients. The baseline characteristics of the 383 patients who underwent PCI with EES for the treatment of ISR as well as those from the 4832 non-ISR patients are listed in Table 1. The ISR group versus the non-ISR group had significantly higher rates of diabetes (40.1% vs 35.0%), hyperlipidemia (94.4% vs 82.0%), hypertension (92.7% vs 82.7%), positive family history of CAD (56.8% vs 49.8%), history of MI (48.0% vs 27.7%), and unstable angina (35.7% vs 27.8%), respectively. Of the 383 patients with ISR, 242 had prior DES implantation (63.2%) and 141 patients had prior BMS implantation (36.8%).

Angiographic analysis (visual estimation) revealed lesion length of 16.0 ± 11.0 mm, a preprocedure minimal lumen diameter of 0.82 ± 0.83 mm, and a preprocedure diameter stenosis of 85.6 ± 10.6% (Table 2). Postprocedure, the mean minimum lumen diameter was 3.10 ± 0.64 mm, with a final diameter stenosis after stent deployment of 1.21 ± 4.84%. 

Clinical outcomes — all patients. Clinical follow-up was available in 359/383 patients (93.7%) at 1 year. 

The primary endpoint of 1-year TLF rate was 10.9% in the ISR group, significantly greater than the rate of 4.9% observed in the non-ISR group (Table 3). In ISR patients, TLR was 10.3%. Cardiac death and MI occurred in 3.1%, cardiac death in 1.1%, and the rate of definite/probable ST was 1.98% (Table 3) in ISR patients. When compared to the ISR patients, the non-ISR patients had lower rates of TLF (4.9%), cardiac death or MI (2.6%), TLR (2.9%), and definite/probable ST (0.36%) (Figure 1A). 

Baseline clinical and procedural characteristics — case-matched patients. In order to reduce bias based on the higher risk profile of the ISR patient group, non-ISR patients were case-matched to ISR patients. The case-matched baseline characteristics are shown in Table 4. As shown, key risk factors between the ISR and non-ISR groups are not significantly different in the case-matched groups in most characteristics. However, the case-matched ISR group had significantly fewer males (69.7% vs 78.9%), higher rates of unstable angina (34.4% vs 26.5%), and fewer patients with LVEF <30% (3.4% vs 8.3%) as compared to non-ISR patients. There were no differences in procedural characteristics in the case-matched groups (data not shown).

Clinical outcomes — case-matched patients. Following case-matching of baseline risk factors, clinical outcomes between case-matched ISR patients and non-ISR patients were not significantly different (Table 5). There were similar rates of TLF, cardiac death or MI, TLR, and definite/probable ST in non-ISR patients as compared to ISR patients (Figure 1B).

Discussion

Of the 5215 patients treated for a single lesion in the Xience V USA trial, 383 cases (7.3%) were ISR lesions. These patients demonstrated higher baseline risk factors and demonstrated, as would be expected, worse clinical outcomes following stenting with EES. Following the application of propensity score matching with the Greedy Match algorithm, the results discussed herein demonstrate that treatment of ISR with EES is a safe and effective treatment, with low rates of TLF at 1-year follow-up in real-world patients.

Xience  V USA is a prospective, single-arm, post-market database of all-comers receiving EES and reported to have very low rates of ST (0.84%) and the composite of cardiac death and MI (6.5%) at 12 months.¹⁵ The 1-year TLR rate of PCI with SES for the treatment of BMS-ISR was 8%, which compares similarly to patients in this study.¹⁶ The non-case matched outcome in the patients undergoing PCI of ISR appears to be much worse compared to patients undergoing native vessel PCI. In a substudy of the ARRIVE registry, patients with ISR treated with paclitaxel-eluting stent (PES) compared to native vessel disease had significantly higher risk of mortality (8.6% vs 4.2%; P<.001), ST (4.0% vs 1.4%; P<.001), and target vessel revascularization (16.0% vs 10.9%; P=.01) at a follow-up of 2 years.¹⁷ The incidence of TLR with EES is 4.3%, and ISR appears to be a powerful multivariate predictor of cardiovascular outcomes.¹⁸

Second-generation DESs have shown promising results when compared to their first-generation counterparts in the treatment of native-vessel coronary artery disease, especially in decreasing the risk of restenosis and need for repeat revascularization.^19-22 However, the effectiveness and safety of EES in the treatment of ISR has not been evaluated in a randomized trial. Available non-randomized data support the safety of EES for the treatment of ISR. In a retrospective analysis of 156 consecutive patients who were treated for ISR of SES, no significant differences were found at 12 months between EES and SES in TLR rate (7.7% vs 9.4%, respectively), and major adverse cardiac events (7.7% vs 10.3%, respectively).²³ In patients with ISR of BMS, the TLR rate was higher with PES compared with EES at 1 year (11.5% vs 2%; P=.02), although there were no significant differences in TLR, MI, death, major adverse cardiac events, and ST at long-term follow-up.¹²

The optimal stent for the treatment of ISR is also unknown. Everolimus-eluting stents have shown a superior safety profile compared to other DESs; however, their outcomes in ISR has not been compared in a randomized fashion.¹³ In the randomized ISAR-DESIRE 2 trial, PCI with SES and PES provided similar efficacy and safety for the treatment of ISR of SES.²⁴ The TLR rates were 16.5% in the SES group and 15% in the PES group. The TLR rate in our study was 6.7% at 12 months, suggesting at least non-inferiority of EES compared to first-generation DESs for the treatment of ISR, although head-to-head comparisons are needed to make a more definitive conclusion. 

Study limitations. This was a single-arm, retrospective, observational analysis, and there are obvious limitations such as lack of randomization, comparison arm, and prospective analysis. And because these patients have baseline characteristics that were not compared or analyzed in a multivariate model, comparing outcomes with other published data results in unmeasured confounding variables. Our study included treatment with EES of ISR of both DES and BMS. Finally, the study lacked quantitative coronary angiographic analysis, but since the primary endpoint is a clinical one, this is not a major limitation and does not affect the findings of the study.

Conclusion

Treatment of ISR with EES is safe and effective, with acceptable rates of TLF. Ultimately, a prospective randomized trial is needed to identify the ideal revascularization strategy for these patients.

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From the ¹UCLA Medical Center, Los Angeles, California; ²UC San Diego Medical Center, La Jolla, California; ³Seoul National University Medical Center, Seoul, South Korea; ⁴Dong-A University Medical Center, Busan, South Korea; ⁵Mount Sinai Hospital, New York, New York; ⁶St Vincent Heart Center of Indiana, Indianapolis, Indiana; ⁷Duke University Medical Center, Durham, North Carolina;  and ⁸Abbott Vascular, Santa Clara, California.

Funding: This study was sponsored by Abbott Vascular.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lee reports consultant and honoraria/speaker’s fees from St Jude Medical, BSCI, Medtronic, Abiomed, and Janssen. Dr Mahmud reports honoraria from Abbott Vascular for Educational Programs. Dr Hermiller reports consultant/honoraria/speaker’s bureau fees from Abbott Vascular, BSCI, Medtronic, St Jude, and the Medicines Company.Dr Krucoff reports research grants from Abbott Vascular, Biosensors International, Boston Scientific, Cordis, Medtronic, Terumo, St Jude Medical, Angel Medical Systems, Edwards Lifesciences, and Cappella; consultant/honoraria/speaker’s bureau fees from Abbott Vascular, Biosensors International, Boston Scientific, Cordis, Medtronic, Terumo, St Jude Medical, Angel Medical Systems, Guided Delivery Systems, Edwards Lifesciences, Cardiac Dimensions, Inc, and Cappella. Dr Rutledge is an employee and stockholder of Abbott Vascular. 

Manuscript submitted January 17, 2014, provisional acceptance given February 10, 2014, final version accepted March 17, 2014.

Address for correspondence: Dr Michael S. Lee, 100 Medical Plaza, Suite 630, Los Angeles, CA 90095. Email: mslee@mednet.ucla.edu