Author + information
- Received September 10, 2012
- Revision received April 12, 2013
- Accepted April 19, 2013
- Published online September 1, 2013.
- Gert Richardt, MD∗∗ (, )
- Matthias Leschke, MD†,
- Mohamed Abdel-Wahab, MD∗,
- Ralph Toelg, MD∗,
- Mohamed El-Mawardy, MD∗,
- Patrick W. Serruys, MD, PhD‡,
- Sigmund Silber, MD, PhD§,
- Stephan Windecker, MD‖,
- Jorge A. Belardi, MD¶,
- Franz-Josef Neumann, MD, PhD#,
- Petr Widimsky, MD, DrSc∗∗,
- RESOLUTE All Comers and RESOLUTE International Investigators
- ∗Herzzentrum, Segeberger Kliniken GmbH, Bad Segeberg, Germany
- †Kliniken Esslingen, Esslingen am Neckar, Germany
- ‡Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands
- §Heart Center at the Isar, Munich, Germany
- ‖Department of Cardiology, Bern University Hospital, Bern, Switzerland
- ¶Cardiovascular Institute of Buenos Aires, Buenos Aires, Argentina
- #Heart Center Bad Krozingen, Bad Krozingen, Germany
- ∗∗Cardiocenter Kralovske Vinohrady, Charles University, Prague, Czech Republic
- ↵∗Reprint requests and correspondence:
Dr. Gert Richardt, Herzzentrum, Segeberger Kliniken GmbH, Am Kurpark 1, 23795 Bad Segeberg, Germany.
Objectives This study sought to assess the clinical safety and effectiveness of the Resolute zotarolimus-eluting stent (R-ZES) in patients with in-stent restenosis (ISR) from 2 large trials.
Background ISR treatment is associated with higher rates of subsequent cardiac events compared with treatment of de novo lesions. Although drug-eluting stents (DES) are an option, second-generation DES are largely untested in the treatment of ISR.
Methods A total of 3,489 patients were pooled from the RAC (RESOLUTE All Comers) trial and the RESOLUTE International (RINT) registry. Two-year clinical endpoints included clinically driven target lesion revascularization (TLR), target lesion failure (TLF), cardiac death (CD), target vessel myocardial infarction (TVMI), combined CD or TVMI (CD/TVMI), and Academic Research Consortium definite and probable stent thrombosis (ST).
Results Overall, 281 patients (8.1%) received an R-ZES for ISR. Two-year TLR and TLF rates were significantly higher in ISR patients than in non-ISR patients (TLR: 12.7% vs. 4.3%, p = 0.003; TLF: 17.4% vs. 9.4%, p = 0.007); however, the CD/TVMI rate was not (6.9% vs. 6.1%, p = 0.711). Seven ISR patients had ST. Two-year outcomes by ISR stent type were similar: bare-metal stent (BMS)-ISR TLR was 12.5% and TLF was 17.2%; DES-ISR TLR was 13.0% and TLF was 18.8%. CD/TVMI was 7.3% and 7.2% for BMS-ISR and DES-ISR, respectively.
Conclusions Using R-ZES to treat ISR appears equally safe in BMS-ISR and DES-ISR, with CD/TVMI rates comparable to 2-year outcomes in other clinical trials. Although revascularization rates are still higher in ISR lesions, the R-ZES offers an effective alternative for treatment of BMS-ISR and DES-ISR.
(Randomized, Two-Arm, Non-inferiority Study Comparing Endeavor-Resolute Stent With Abbot Xience-V Stent [RESOLUTE-AC]; NCT00617084; and RESOLUTE International Registry: Evaluation of the Resolute Zotarolimus-Eluting Stent System in a ‘Real-World’ Patient Population [RINT]; NCT00752128)
Drug-eluting stents (DES) have substantially reduced revascularization rates in de novo lesions, and outcomes have further improved with the advent of second-generation DES. In-stent restenosis (ISR) is historically considered the Achilles heel of percutaneous coronary interventions (PCI) and has been associated with worse outcomes than treatment of de novo lesions. Previous studies have reported target lesion revascularization (TLR) rates around 15% and target vessel revascularization (TVR) rates as high as 22% at 1 year following retreatment of a restenotic lesion (1–5). Moreover, an ISR after DES implantation is regarded as an exceedingly challenging lesion with an even worse outcome than bare-metal stent (BMS)-ISR. Although there are promising observations with drug-eluting balloons (DEB) (5–11) and with certain first-generation DES for treatment of ISR (1), the optimal treatment modality of ISR has yet to be established. In particular, data about ISR treatment with new-generation DES are missing.
The Resolute zotarolimus-eluting stent (R-ZES) (Medtronic Vascular, Santa Rosa, California) is a contemporary thin-strut cobalt-chromium, open-cell stent with a thin biocompatible coating (BioLinx, Medtronic Vascular). The R-ZES has been tested in a global clinical trial program of randomized and observational studies in well-defined patient subgroups using similar rigorous methodologies to provide a comprehensive assessment of DES performance in a wide variety of clinical and anatomic conditions. In aggregate, the studies revealed an excellent efficacy and safety of the R-ZES, which is at least noninferior to the everolimus-eluting stent (12–15).
The RAC (RESOLUTE All Comers) and RINT (RESOLUTE International) studies accrued a high proportion of patients with complex clinical and lesion characteristics, including ISR. Here, we present a pooled analysis of RAC and RINT patients with an ISR treated with the R-ZES to assess the clinical safety and effectiveness of the R-ZES in this population. Considering the possibility of a late catch-up following treatment of ISR, which was most striking after brachytherapy (16,17), our analysis comprised a follow-up period of 2 years. An additional analysis compared the performance of the R-ZES depending on the type of restenosis either following BMS or DES implantation.
Patients and protocol
The design of the RAC and RINT studies, which were both large, multicenter, open-label, prospective clinical trials with minimal exclusion criteria, have been previously described (14,18). Briefly, the RAC trial was a randomized, noninferiority study that compared the R-ZES to the Xience V everolimus-eluting stent (Abbott Vascular, Santa Clara, California) in patients with chronic, stable coronary artery disease or acute coronary syndromes. To be included in the study, patients had to have at least 1 coronary artery stenosis >50% with a reference diameter of 2.25 to 4.0 mm, and there were no restrictions regarding the total number of treated lesions, treated vessels, lesion length, or number of stents implanted. The RINT registry was an observational study of patients with symptomatic coronary artery disease, all of whom received at least 1 R-ZES. Like the RAC trial, the RINT registry had no restrictions on clinical indication (stable angina vs. acute coronary syndromes), number of treated vessels and lesions, lesion type, or lesion length. Both studies were also similar in their exclusion criteria, post-procedure dual antiplatelet therapy, and scheduled follow-up. Exclusion criteria included a known intolerance to a study drug, metal alloys, or contrast media; planned surgery within 6 months after the index procedure; childbearing potential; or concurrent participation in another trial that could affect the study procedures. Post-procedure dual antiplatelet therapy consisted of lifelong daily aspirin (≥75 mg) and daily clopidogrel (75 mg) for at least 6 months. Patient follow-up was performed by telephone or clinic visit at 1, 6, 12, and 24 months and is planned to continue annually for 5 years.
Clinical endpoints and definitions
Similar endpoint definitions were used in the RAC trial and the RINT registry and have been previously described (14,18). The same definitions were used for the endpoints assessed in the present pooled analysis. The principal endpoints for the pooled analysis were: 1) target lesion failure (TLF), defined as a composite of cardiac death (CD), target vessel myocardial infarction (TVMI), or clinically driven TLR; and 2) combined probable and definite stent thrombosis (ST), as defined by the Academic Research Consortium. Using the same endpoints, an additional analysis was performed to evaluate the outcomes of ISR patients by stent type (BMS vs. DES). Events as adjudicated in the RAC trial and RINT registry were utilized for the present pooled analysis, and endpoints were assessed at 1 and 2 years.
All data were analyzed according to the intention-to-treat principle. Descriptive statistics were determined for baseline patient and lesion characteristics, and data are presented as percentage or mean ± SD. The clinical outcomes were compared with propensity score–adjusted p values to adjust for differences in patient characteristics between groups (ISR vs. non-ISR, and BMS vs. DES-ISR). Propensity scores were calculated using logistic regression with treatment group (ISR vs. non-ISR) as the dependent variable and the following baseline characteristics as the independent variables: age, sex, current smoker, prior PCI, hyperlipidemia, diabetes, hypertension, prior myocardial infarction (MI), prior coronary artery bypass grafting (CABG), unstable angina or MI, target vessel=left anterior descending coronary artery (LAD), American College of Cardiology/American Heart Association lesion class B2 or C lesion, moderate/severe calcification, bend >45°, TIMI (Thrombolysis In Myocardial Infarction) flow grade 3, reference vessel diameter (RVD), lesion length, and pre-procedure percent diameter stenosis. Multivariate predictors were calculated using stepwise logistic regression. Variables selected for the multivariate analysis were those with a p value ≤0.2 in the simple logistic regression analysis. In the multiple logistic regression analysis, only those with a p value of ≤0.1 were kept in the analysis. A p value of <0.05 was considered statistically significant.
The cumulative incidence of events was analyzed using the Kaplan-Meier method and is shown with 2-sided 95% confidence intervals and log-rank p values. For each endpoint, treatment groups were compared on time to event using Cox proportional hazards regression. All statistical analyses were performed using SAS version 9.1 or higher (SAS Institute, Cary, North Carolina).
A total of 3,489 patients were included in the pooled analysis. Of these patients, complete data were available for 3,475. Overall, 3,194 patients received an R-ZES to treat a non-ISR lesion, whereas 281 patients (8.1%) received an R-ZES to treat an ISR lesion (91 patients from the RAC trial and 190 patients from the RINT registry). At 1 year, clinical follow-up data were available in 281 ISR patients and 3,169 non-ISR patients; at 2 years, clinical follow-up data were available in 276 ISR patients and 3,127 non-ISR patients. Table 1 compares the baseline demographics of the ISR patients and non-ISR patients. In summary, ISR patients were older, not current smokers, and had more hypertension, hyperlipidemia, insulin-dependent diabetes mellitus, previous MI, and prior CABG. Patients with ISR more often underwent coronary intervention for stable angina than non-ISR patients; nonetheless, nearly half of the ISR cohort presented with an acute coronary syndrome.
Pre- and post-procedure lesion characteristics for the ISR and non-ISR patients are presented in Table 2. For both groups, the most frequent lesion location was the LAD, followed by the right coronary artery (RCA) and left circumflex artery; however, ISR patients had more RCA lesions and fewer LAD lesions than did non-ISR patients. Both groups had similarly complex, class B2/C lesions, although lesions were longer in ISR patients. Pre-procedure thrombus was present twice as often in non-ISR patients. The RVD and minimum lumen diameter were larger and the percent diameter stenosis was smaller in ISR patients compared with non-ISR patients. There was no statistically significant difference in the post-procedure percent diameter stenosis between the 2 groups. Within the ISR group, ISR occurred almost 3 times more often in lesions treated with a BMS than in those treated with a DES.
Table 3 summarizes the clinical outcomes at 1 and 2 years of ISR and non-ISR patients treated with an R-ZES. At 1 year, there were no statistically significant differences in the clinical outcomes between the 2 groups, although a numerical difference was observed in the rate of overall ST (2.1% vs. 1.0%, p = 0.269) and late ST (1.4% vs. 0.2%, p = 0.185) in the ISR and non-ISR cohorts, respectively. At 2 years, however, ISR patients experienced significantly more TVF (18.8% vs. 10.6%, p = 0.017), TLF (17.4% vs. 9.4%, p = 0.007), clinically driven TLR (12.7% vs. 4.3%, p = 0.003), clinically driven TVR (14.5% vs. 5.7%, p = 0.011), and major adverse cardiac events (19.9% vs. 11.1%, p = 0.011). The ST rate was numerically higher in the ISR group (2.5% vs. 1.2%, respectively, p = 0.332), with a marginally significant log-rank p value of 0.058 in the Kaplan-Meier analysis. Nonetheless, rates of death, CD, and TVMI remained similar between the 2 groups. Kaplan-Meier curves illustrating the time to event occurrence for the study's principal endpoints are presented in Figures 1A to 1D.
The proportion of patients on dual antiplatelet therapy at 6 months and 1 year in both the ISR and non-ISR groups was similar (95.3% vs. 95% and 89.4% vs. 89%, respectively). At 2 years, only 41% vs. 35.1% were on dual antiplatelet therapy, but the vast majority of patients (97.3% vs. 95.1%) were receiving aspirin.
Multivariate predictors of TLF
Multivariate analysis identified several independent predictors of TLF in R-ZES–treated patients at 2 years (Table 4). In the total pooled population, predictors of TLF included ISR, prior CABG, vessel bend ≥45°, previous MI, unstable angina, and pre-procedure RVD. In the ISR subgroup, predictors of TLF included prior CABG, unstable angina, and patient age.
Performance of the R-ZES for treatment of a BMS or DES restenosis
Baseline characteristics were similar between patients with a BMS-ISR or DES-ISR treated with an R-ZES (Table 5). Clinical outcomes at 2 years according to ISR stent type were similar (Table 6): for the BMS-ISR subgroup, the rate of TLR was 12.5%, and the rate of TLF was 17.2%; for the DES-ISR subgroup, the rate of TLR was 13.0%, and TLF was 18.8%. Combined CD or MI rates were 7.3% and 7.2% for BMS-ISR and DES-ISR, respectively. Six ST events occurred in the BMS-ISR subgroup, and 1 event occurred in the DES-ISR subgroup.
The occurrence of ISR remains a significant limitation of coronary stent implantation in daily practice. Although DES can effectively reduce the incidence of ISR in a given lesion and patient, the global burden of ISR is not reduced by DES due to the increasing use of coronary stents and the higher complexity of treated coronary anatomies.
We assessed one of the largest datasets on patients with ISR from 2 prospective all-comer trials that were designed with consistent definitions, adjudication methods, and data collection. About 8% of the patients in the pooled analysis presented with an ISR. The rate of ISR patients was lower than in previous DES registries (19–22). The numbers of ISR patients were disproportionally high in the alluded registries, probably because restenotic lesions were regarded as a preferable indication for DES implantation as long as DES were not used in all patients without particular contraindications, which was the case in our cohort. Therefore, our ISR ratio presumably represents a more adequate picture of the contemporary ISR burden, of which approximately one-quarter of the ISR patients had a restenosis after former DES implantation.
Although patients with ISR more often underwent coronary intervention for stable angina than did the non-ISR patients, nearly half of the ISR cohort presented with an acute coronary syndrome. The recognition that a considerable proportion of patients with ISR presented with an acute coronary syndrome is in line with several previous reports, which have disproved the original perception of ISR as a benign clinical issue (3,23,24).
ISR may not only cause MIs, but it also has a higher recurrence rate than de novo lesions, and treatment strategies for ISR are by far less established than in other coronary anatomies. Current guidelines recommend the use of cutting or scoring balloons for lesion preparation followed by DEB treatment or DES implantation (25,26). DES of the first generation were effective in the treatment of a restenosis following BMS or DES (1,4,27–29). We present the first large cohort of patients undergoing ISR treatment with a new-generation cobalt-chromium, thin strut, limus-eluting stent, namely the Resolute stent, which releases zotarolimus from a biocompatible polymer.
The principal finding of our investigation was that the TLF rate nearly doubled in patients with ISR, compared with non-ISR patients, and was mainly driven by a higher TLR rate. The Kaplan-Meier curves of TLR rates divided after 6 months and continuously separated thereafter. Nonetheless, TLR rates of 7.5% after 12 months and 12.7% after 2 years are still in a very reasonable range compared with other studies (3,5,19,24,30). Moreover, PCI of ISR with R-ZES was safe, with no excess of CD or TVMI observed out to 2 years. Notably, the ST events were numerically higher in ISR patients at 1 and 2 years, but the difference did not reach statistical significance. This was also noted among the BMS-ISR compared with the DES-ISR subgroup, with inadequate power to allow meaningful comparison.
The treatment of ISR patients and non-ISR patients with R-ZES resulted in a similar acute angiographic success as documented in a post-procedural diameter stenosis of some 10% in both cohorts. Thus, the higher TLF rate in the ISR cohort was probably not the consequence of an underexpansion of the R-ZES. There was also no obvious major imbalance in risk factors for restenosis in the patient and lesion characteristics of both groups. It rather appears that the ISR per se carries a higher disposition for a TLF, possibly due to the unique biology of an ISR. Consequently, ISR was the strongest independent predictor for TLF in our total study population.
Nevertheless, revascularization rates with R-ZES compare favorably with other contemporary ISR trials (3–5,15,19,21,24). Because longer observation periods are missing in most ISR studies, a comparison of the RESOLUTE pooled data has been confined to 9- and 12-month revascularization rates. Regarding BMS-ISR, our TLR and TVR rates are in line with the sirolimus-eluting stent group in the ISAR-DESIRE (Intracoronary Stenting or Angioplasty for Restenosis Reduction: Drug-Eluting Stents for In-Stent Restenosis) trial (8% TVR), the DEB group in the PEPCAD II (Paclitaxel-Eluting PTCA-Balloon Catheter in Coronary Artery Disease II) study (6% TLR), and the findings in TAXUS V-ISR (Randomized Trial Evaluating Slow-Release Formulation TAXUS Paclitaxel-Eluting Coronary Stent in the Treatment of In-Stent Restenosis) (10.5% TVR at 9 months) (1,5,29). Remarkably, the R-ZES appears to be equally effective in patients with BMS-ISR and with DES-ISR. Treatment of DES-ISR with DEB or another DES was by far less successful in previous studies. In PEPCAD-DES (6), treatment of DES-ISR with DEB resulted in a TLR rate of 15.3% at 6 months. Similar rates were observed in ISAR-DESIRE–II (TLR 16.6% after treatment of DES-ISR with sirolimus-eluting stents and 14.5% after treatment with paclitaxel-eluting stents) (4) and in the study done by Steinberg et al. (3) (TVR 22.2% after DES treatment of DES-ISR vs. 10.3% for BMS-ISR). These previous observations supported the notion that DES-ISR is a particularly resistant lesion with high cardiac event rates after percutaneous retreatment. The excellent outcome in our small DES-ISR subgroup has to be interpreted cautiously. It is, however, conceivable that the R-ZES is more effective than first-generation DES or DEB in the therapy of DES-ISR because a very effective antiproliferative compound was applied without apposition of another thick metal/polymer layer but with preserved stent scaffolding.
Regarding the Kaplan-Meier curves of the cumulative incidence in TLR, there was a continuous rise of events during the entire observation period in the ISR cohort. Nevertheless, this increase did not seem to be overproportional compared with the non-ISR cohort, though a late catch-up phenomenon cannot be entirely excluded (16,17).
Although our study is based on high-quality data, the investigation has all the limitations of a non–pre-specified, post hoc analysis. For instance, no classification of ISR morphology was done, which could have been important for the comparison of ISR in BMS and DES patients, and the number of DES-ISR patients remains low. Furthermore, the present patient-based analysis limits the ability to evaluate outcomes related strictly to ISR lesions. It is unusual to pool the results of a randomized trial with that of a registry. Nevertheless, this variable has been included in the multivariate analyses, and no significant interactions have been observed.
The use of an R-ZES for treatment of ISR was safe, with rates of CD, MI, and ST in line with the overall 2-year events of both clinical trials. Rates of revascularization were higher in ISR compared with non-ISR patients. TVR and TLR rates of the R-ZES, however, are very persuasive in the perspective of other ISR trials. Thus, R-ZES offers an effective alternative for treatment of both BMS-ISR and DES-ISR in this challenging subset of patients.
The authors thank Janice Hoettels and Colleen Gilbert, PharmD, from Medtronic for editorial support, and Minglei Liu, PhD, from Medtronic, for statistical analysis for this paper.
This work was funded by Medtronic. Medtronic also provided editorial support and statistical analysis for this paper. Dr. Richardt has received grant support from Medtronic; occasional speaker's honoraria from Boston Scientific; and serves on an advisory board for Abbott Vascular. Dr. Abdel-Wahab has received grant support from Medtronic; and occasional speaker's honoraria from Boston Scientific. Dr. Toelg has received grant support from Biotronik. Dr. Silber has received grant and travel support and consultant fees from Medtronic. Dr. Windecker is a consultant for Boston Scientific, Medtronic, Abbott Vascular, and Biosensors; and his institution has received research grants from Abbott, Biotronik, Boston Scientific, Biosensors, Cordis, Medtronic, and St. Jude Medical. Dr. Belardi serves on an advisory board and is a consultant for Medtronic. Dr. Widimsky receives occasional speaker's honoraria from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- cardiac death
- drug-eluting stent(s)
- in-stent restenosis
- myocardial infarction
- percutaneous coronary intervention
- Resolute zotarolimus-eluting stent(s)
- stent thrombosis
- target lesion failure
- target lesion revascularization
- target vessel myocardial infarction
- target vessel revascularization
- Received September 10, 2012.
- Revision received April 12, 2013.
- Accepted April 19, 2013.
- American College of Cardiology Foundation
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