New Drug-Eluting Stent Implantation for Recalcitrant In-Stent Restenosis Treated with Drug-Eluting Stents. The Stent-in-Stent Cube (SIS3) Registry

Abstract: The best management for patients with recurrent in-stent restenosis is still not clear. The aim of the present study was to describe the long-term clinical results of re-DES (drug-eluting stent) implantation in patients suffering recurrences after stenting with DES for In-BMS (bare metal stent) restenosis. Methods. All consecutive patients with in BMS restenosis treated with DES and presenting with recurrent ISR (in-DES restenosis) treated with re-DES in 3 tertiary care centers were retrospectively selected and analyzed. Results. In the time period 2005–2009, 40 consecutive patients with recalcitrant ISR were selected. At a mean follow-up of  701 ± 570 days, no patient died. The incidence of target lesion revascularization (TLR) and target vessel revascularization (TVR) was 12.5% and 17.5%, respectively. Survival free from composite endpoint (any death + MI + TLR) was 82% at 2 years. Conclusions. DES implantation for patients with recurrent ISR offers good clinical outcomes at long-term follow up. 

J INVASIVE CARDIOL 2011;23:365–368

Key words: recurrent in-stent restenosis, drug-eluting stents, third metal layer

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Implanting drug-eluting stents (DES) represents an effective therapy for in-stent restenosis.¹ Data derived from studies conducted on patients with restenosis following implantation with bare-metal stents (BMS) showed good results at mid- and long-term for both sirolimus- (SES) and paclitaxel-eluting stents (PES). Notwithstanding, 20% of patients receiving DES for in-stent restenosis (ISR) develop relapses.² The best management for this subset of patients is still not clear. The aim of the present study is to describe the long-term clinical results of a third metal layer (DES) in patients suffering recurrences after stenting with DES for in-BMS restenosis.

Methods

Study population and endpoint. All consecutive patients with in-BMS restenosis treated with DES and presenting with recurrent ISR (in-DES restenosis) treated with re-DES between 2005 and 2009 in 3 tertiary care centers were retrospectively selected and analyzed.

Patients presenting with acute myocardial infaction (MI) and/or cardiogenic shock were excluded from the analysis as well as patients with chronic total occlusions (CTO). All patients received dual antiplatelet therapy according to concurrent guidelines. All data related to hospital admissions, procedures, and outcomes were collected in each center using the hospital recording network. Information regarding the clinical status at latest clinical follow up (FU) available was collected by clinical visits and telephone interviews.

Definitions. In this report, the following events were analyzed cumulatively at latest clinical FU available: cardiac and overall death, MI, target lesion revascularization (TLR), target vessel revascularization (TVR), and stent thrombosis (ST). The occurrence of ST was defined on the basis of the ARC definitions.³Deaths were classified as either cardiac or non-cardiac. Cardiac death was defined as any death due to a cardiac cause, procedure-related deaths, and death of unknown cause. TLR was defined as any repeat intervention (re-PCI or coronary artery bypass graft, CABG) of the target lesion or other complication of the target lesion. TVR was defined as any repeat intervention (re-PCI or CABG) of any segment of the target vessel. MI was defined as the occurrence after hospital discharge of any value of troponin and/or CKMB > upper limit of normal if associated with clinical and/or ECG change. The composite endpoint was defined as the occurrence of  death (CD and non-CD), MI, and TLR. Balloon/vessel ratio was defined as the ratio between the diameter of the non-compliant balloon used for stent postdilation and the diameter of the vessel in the stented segment, before postdilation. Primary endpoint of this study was the incidence of the composite endpoint at long-term FU.

Statistical analysis. Continuous variables are expressed as means ± standard deviation. Categorical variables are expressed as frequencies. Cumulative event rates were evaluated using Kaplan-Meier estimates. Composite endpoint events are reported hierarchically. A two-tailed p-value < 0.05 was considered to be statistically significant. All analyses were performed with SPSS for Windows 13.0.1 (SPSS Inc.).

Results

Baseline clinical and procedural characteristics. Baseline characteristics are summarized in Tables 1 and 2. In the time period 2005–2009, 40 DES implantations in patients with recurrent ISR were performed. Twenty-eight patients (70%) were male, 85% had hypertension, 30% were diabetics and approximately half had a previous MI. Mean left ventricular ejection fraction at discharge was normal (53.4% ± 9.2%). In three quarters of patients, ISR was focal or multifocal. First stent type was BMS for all patients while second and third were DES: SES, PES and everolimus-eluting stent (EES). A “switch” strategy (“hetero”-DES approach) was used in 33 out of 40 patients. In the homo-DES subgroup, 4 out of 7 lesions were treated with SES while the remaining 3 lesions were treated with PES. The percentage of postdilation raised from 40% at the time of first stent implantation to 87.5% at the time of the index procedure, as well as the balloon/artery ratio and the maximal inflation pressure (from 1.01 ± 0.11 to 1.12 ± 0.09 and from 16.5 ± 3.2 atm to 19.6 ± 2.8 atm, respectively). Intravascular ultrasound (IVUS) was performed in 22.5% of patients.

In-hospital and long-term clinical outcomes. Incidence of long-term adverse events is reported in Table 3. Follow-up was available in 100% of patients. At 701 ± 570 days, no patient died, whereas the incidence of MI was 5%. The incidence of TLR and TVR was 12.5% and 17.5%, respectively, while 10% of patient underwent a PCI on a different vessel. No patient underwent CABG. Definite or probable stent thrombosis occurred in 1 patient (2.5%).

No difference was found in the distribution of the events according to stent type: TLR occurred in 2/2/1 (5%/5%/2.5%) patients treated with SES/PES/EES, respectively, and composite endpoint occurred in 3/3/1 (7.5%/7.5%/2.5%) patients treated with SES/PES/EES, respectively.

Data derived from the Kaplan-Meier survival curve are reported in Figure 1. Survival free from composite endpoint (any death + MI + TLR) was 82% at 2 years.

Discussion

The results of the present study show that late clinical outcomes in patients with recurrent ISR treated with new DES implantation is favorable, with a 2-year survival free from death + MI + TLR of 82%.

In-stent restenosis still represents a challenging scenario.^4–6 In the last years, different techniques have been proposed to treat this subset of patients (e.g., POBA, cutting balloon, rotational atherectomy) that did not lead to satisfying clinical and angiographic outcomes.^7,8 In patients with in-BMS restenosis, repeated use of BMS failed to significantly improve long-term outcomes.⁹

In this circumstance, the introduction in clinical practice of DES has generated great expectations. Several observational and randomized trials have demonstrated the safety and efficacy of DES implantation in patients with in-BMS and, more recently, with in-DES restenosis.^10,11 In the ISAR DESIRE 2 trial,² which included 450 patients with SES restenosis requiring re-PCI, the re-DES strategy led to a survival free from death, MI, and TLR of 80% at 1 year FU.

However, in those patients presenting with recurrent in-DES restenosis, the identification of which is the “best treatment” is still a matter of debate. In particular, very little is known about the effects of a third metal layer in the vessel wall on long-term clinical outcomes.

A recent report by F. Alfonso and colleagues conducted on 21 consecutive patients with recurrent ISR treated with DES implantation showed satisfactory long-term angiographic, IVUS, and clinical results, with an event-free survival at 1 year of 90%.¹²

These results, which are in line with the ones obtained in our registry, suggest re-DES strategy to be a good option, though studies with larger sample sizes and with extended FU are necessary to confirm these findings.

In this registry, the implantation of the third stent was almost always followed by postdilation with non-compliant balloons expanded at very high pressures (19.6 ± 2.8 atm) and with a high balloon-artery ratio (1.12 ± 0.09). Post-dilation after first and second stent implantation was performed only in 40% and 70% of cases, with lower balloon artery ratio and lower maximal pressure. Stent under-expansion, which is known to be significantly associated with ISR,¹³ might have played a role in the recurrence of  ISR in this population. It is therefore obligatory to optimize the final result with aggressive dilations performed with non-compliant balloons, especially in severely calcified vessels.¹²

Recurrence of ISR also has been related to drug failure. Hyporesponsiveness to systemic sirolimus infusion is well described in the literature and the existence of a comparable phenomenon after local drug delivery to the coronary vessel wall would not be surprising.^2,14

It is plausible that in these patients the “switch” to a different drug with a different mechanism of action, such as paclitaxel, may lead to a more effective suppression of neointimal hyperplasia.

In our series, 33 out of 40 patients were treated with an “hetero”-DES approach. In particular, patients previously treated with SES received PES, while patients previously treated with PES received either SES or EES. At long-term follow-up, the incidence of TLR was 28.5% in the “homo”-DES group (2/7 patients) and 9% in the “hetero”-DES group (3/33 patients), suggesting the “switch” technique to be preferable.

In this registry, all 7 patients treated with the “homo”-DES approach had 3-vessel disease treated with DES. Therefore, the success at long-term FU of a specific type of DES in the same patient but in other lesions may have influenced the choice of the DES, suggesting to continue with the same drug.   

Strong evidence on this issue is still missing. Data derived from observational and randomized studies are controversial showing a potential benefit of the switch modality in one case,¹⁵ superiority of the “homo”-DES approach in another,¹⁶ and a substantial equivalence of the two strategies in two other studies.^17,18

Effective proven alternatives to recurrent DES implantation to address recalcitrant ISR are not available yet. Drug-eluting balloons showed promising results in cases of BMS restenosis,¹⁹ but their efficacy has still to be confirmed in cases of DES restenosis.

Bioabsorbable DES may have the potential to alter the course and treatment of ISR and will redefine the definition itself of in-stent restenosis, but so far no data are available for their use in this subset of patients.

Limitations. The present study was designed as a retrospective multicenter registry and therefore lacks randomization and intention-to-treat data. The population is small and since no sample size calculations were performed, we acknowledge that our results may be affected by a type II error. 

Moreover, results may be influenced by the heterogeneity of the restenosed stent and the stent used to treat the restenosis.

Conclusion

DES implantation for patients with recurrent ISR offers good clinical outcomes at long-term FU. 

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From the ¹Interventional Cardiology Unit, Mauriziano Hospital, Turin, Italy, ²Degli Infermi Hospital, Rivoli, Italy, and ³Santa Croce Hospital, Moncalieri, Italy.
Disclosure: The authors have completed and returned the ICMJE Form for Dis- closure of Potential Conflicts of Interest. No authors reported conflicts regarding the content herein.
Manuscript submitted April 29, 2011, provisional acceptance given May 11, 2011, final acceptance give June 20, 2011.
Address for correspondence: Emanuele Meliga, MD, PhD, FESC, Interventional Cardiology Unit, Mauriziano Hospital, Largo Filippo Turati 62, 10128, Turin, Italy. Email: emeliga@gmail.com