Sirolimus-Eluting Stents for the Treatment of Bare-Metal In-Stent Restenosis: Long-Term Clinical Follow Up

Significant in-stent restenosis (ISR), i.e., intrastent neo-intimal proliferation following bare-metal stent (BMS) implantation, which determines an angiographic and/or clinically significant stenosis,¹ occurs with an incidence varying between 20–50% in real-life patients,² becoming however even more common in selected higher-risk subjects^3–4 and lesions,^5–6e.g., diabetics, small vessels, or long lesions.^4,7 Indeed, BMS have targeted the underlying issues of elastic recoil and negative remodeling following percutaneous coronary intervention (PCI), however they did not reduce neointimal proliferation, but rather increased it.⁸
After a number of unsuccessful studies appraising systemic agents to prevent or treat restenosis,⁹ and while acknowledging the limitations of repeat balloon-only angioplasty, atherectomy cutting balloon, or stenting,^10–11 brachytherapy was the first established and approved treatment for ISR.¹² However, even intracoronary radiation cannot abolish recurrent restenosis in several patients (especially the higher-risk ones),¹³ and it also brings a major risk of late adverse events (namely, stent thrombosis).¹²
In recent years, drug-eluting stents (DES) have been introduced into practice, and their superiority in the treatment of ISR in comparison to balloon-only angioplasty or brachytherapy has been recently established in randomized trials.^14–16 However, all these pivotal studies and registries were limited by restriction in patient selection and relatively short follow-up periods (e.g., 9 months in the SISR study, a randomized trial design that compared the Cypher™ stent to radiation within a vessel [brachytherapy], and 12 months in the Intracoronary Stenting or Angioplasty for Restenosis Reduction – Drug-Eluting Stents for In-Stent Restenosis [ISAR-DESIRE trial]).^15–18
The aim of the present prospective study was to evaluate the safety and efficacy of SES for the treatment of ISR in unselected real-world patients and to focus on mid- and long-term (>9 months) follow up.

Methods

Patients. The present study included consecutive patients admitted from July 2002 to December 2004 with known coronary artery disease who were previously treated with BMS during percutaneous transluminal coronary angioplasty, who demonstrated ISR and who were treated during their index hospitalization with SES (Cypher, Cordis Corp., Miami, Florida) — the most commonly-used DES at our institution. The patients who met these criteria were enrolled in a dedicated, prospective database. Exclusion criteria to enrollment were a lack of SES implantation, allergy to antiplatelet agents, heparin, contrast agents, or sirolimus, participation in another coronary device study, terminal illness, or a lack of written, informed consent.
Efficacy and safety of the procedure were determined early during the in-hospital stay and at 1-, 6-, 9-, 12-, and 24-month clinical follow up performed by clinical or telephone interviews. All patients were asked to return for angiographic follow-up study at 6 months even if asymptomatic. For patients who agreed to undergo angiographic follow up, quantitative coronary angiography was routinely performed. The study complied with the Declaration of Helsinki regarding investigations in humans. There was no industry involvement in the design, conduct, financial support, or analyses of this study.
Stent implantation. SES were available in diameters ranging from 2.5–3.5 mm and in lengths of 8–33 mm. PCIs were performed following standard techniques. Before or at the time of the procedure, patients received at least 100 mg of aspirin, a 300 mg loading dose of clopidogrel, and unfractionated heparin (70–100 U/kg of body weight). Glycoprotein IIb/IIIa antagonists were used at the operator’s discretion. A 12-lead electrocardiogram was obtained before and after the procedure and before discharge. Levels of creatine kinase, creatine kinase-MB (CK-MB) isoenzyme, and cardiac troponin-T were assessed 4–12 hours and again 16–24 hours after the procedure. Restenotic stents were first dilated at high pressure with semicompliant or noncompliant balloons at high inflation pressure (16–20 atm), but taking care to avoid geographical miss. SES were then either implanted at high pressure (16–20 atm) or initially expanded at moderate-to-high pressure (12–14 atm), and then postdilated with semicompliant or noncompliant balloons at high pressure (16–20 atm). At the time of discharge, all patients were receiving 100 mg of aspirin once daily, as well as 75 mg of clopidogrel daily for at least 3 months.
Study endpoints and definitions. The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE) during the follow-up period defined as a composite endpoint of death, nonfatal myocardial infarction (MI), or target vessel revascularization (TVR). Secondary endpoints were early complications (intraprocedural or in-hospital death, acute or subacute stent thrombosis, stroke, need for urgent coronary artery bypass grafting [CABG], or peripheral vascular complications), and technical success of stent implantation.
In particular, TVR was defined as repeated revascularization within the treated vessel, TLR as revascularization for significant in-stent or in-segment restenosis. MI was defined as Q if featuring new Q-waves in at least two contiguous leads, and an elevated CK-MB fraction, and non-Q-wave if lacking pathologic Q-waves, but with an increase of the CK-MB isoenzyme >3 times the upper limit of normal, with concomitant abnormal troponin-T values. Stent thrombosis was adjudicated only in cases of angiographically documented intraluminal filling defect within the stent resulting in TIMI grade 0 or 1 anterograde flow associated with clinical symptoms or signs of ischemia, and distinguished as acute (≤24 hours), subacute (>24 hours and ≤30 days), or late (>30 days after PCI).¹⁹
Quantitative coronary angiography. Coronary angiograms were digitally recorded at baseline, immediately after stent implantation, and at follow up and were assessed with the Inturis Cardio Viewing software (Philips Medical Image Packing System, Eindhoven, Netherlands). Quantitative measurement (expressed in mm) included the reference vessel diameter (RVD), minimum lumen diameter (MLD), diameter stenosis (defined as [RVD-MLD]/RVD*100), and late lumen loss (defined as the difference between MLD after the procedure and MLD at follow up). Binary angiographic restenosis was defined as stenosis of at least 50% at angiographic follow up. All measurements were in-segment, corresponding to the in-stent tract plus the proximal and distal 5 mm edges.
Statistical analysis. Continuous variables are reported as mean (standard deviation) and categorical variables as n (%). Univariate analyses were performed to assess associations between patient characteristics and clinical events by means of the Student’s t, Chi-squared or Fisher’s exact tests, when appropriate. Relative risk (RR) for the recurrence of events has been calculated for subgroups stratified by the presence of clinical and angiographic characteristics. The Kaplan-Meier method was used to assess freedom from events and survival. All statistical analyses were performed using the SAS System 8.2 version (SAS Institute, Cary, North Carolina).

Results

From July 2002 to December 2004, 138 patients were enrolled in the study (baseline patient clinical characteristics are reported in Table 1). We were able to obtain complete follow-up data on 124 patients (90.0%), with 14 patients lost to follow up (whose clinical characteristics were not significantly different from those of patients who completed follow up). A total number of 180 SES were implanted to treat ISR-diseased vessels (1.3 stents/patient), and 14 patients were treated with 2 consecutive stents on a lesion. Baseline angiographic features are reported in Table 2. Proliferative or diffuse lesions were present in most cases (79% of treated lesions). Procedural characteristics are reported in Table 3.
Procedural and early clinical outcomes. Early complications after stent implantation are listed in Table 4. Very few complications were adjudicated. There was no incidence of intraprocedural or in-hospital death, acute or subacute stent thrombosis, stroke or need for urgent CABG. There was only 1 case of peripheral vascular complication, while 3 patients experienced periprocedural MI (in all 3 cases, a non-Q-wave MI was observed), and 7 cases of a mild rise in CK-MB isoenzyme levels, not significant per the definition for MI. Technical success was achieved in all of the procedures.
Clinical follow up. The median duration of clinical follow up was 13 months, with as many as 51 patients followed up for >24 months. Kaplan-Meier curves and the actuarial rate of recurrence of MACE, all-cause death, TLR or TVR and TLR alone at 3, 6, 9, 12, and 24 months, and the number of patients at risk are reported in Figures 1, 2, 3, and 4.
During follow up, MACE occurred at 3, 6, 9, 12, and 24 months in 4.1%, 5.8%, 11.7%, 14.3%, and 25%, respectively. All-cause mortality accounted for 1.7%, 2.6%, 3.5%, and 4.8% of patients, respectively, for a total number of 5 deaths. Within these patients, cardiac death was observed in 4 patients, all of them with multivessel coronary disease and 2 of them with left ventricular ejection fraction <35% at the time of enrollment, while the remaining patient died because of extra-cardiac causes (cancer). TVR was performed at 3, 6, 9, 12, and 24 months in 2.5%, 4.2%, 8.5%, 11.2%, and 15.9% of patients, respectively, while TLR alone accounted for 2.5% at 3 months, 3.4% at 6 months, 7.7% at 9 months, 9.6% at 12 months, and 11% at 24 months. During follow up, we observed 3 cases of MI (2.2%).
None of the patients required CABG during follow up, nor was any event of angiographic stent thrombosis adjudicated. Thus, the event-free rate during follow up was 94.2% at 6 months, 85.7% at 12 months, and 75% at 24 months.
Angiographic results. Immediate and late angiographic results are shown in Table 5. Follow-up angiography was performed in 63 (45.7%) patients who returned for elective angiography or because of symptoms. The remaining patients did not agree to elective angiographic control, but they did not differ significantly from those who did with respect to the baseline characteristics shown in Table 1 and with respect to events during follow up, as shown in Figure 5 (p = 0.1). The mean length of angiographic follow up was 240 ± 35 days.
Percentage diameter stenosis before stent implantation was 81.8 ± 16.1%. After stent implantation and at angiographic follow up, it was 7.1 ± 7.1% and 23.2 ± 23%, respectively. Acute gain was 2.08 ± 0.5 mm, late loss 0.54 mm ± 0.41 mm, and binary restenosis 10%.
Risk analysis. Risk analysis tested the association between several clinical and angiographic features and risk of MACE, TVR or TLR, and all-cause mortality. We tested the following variables: age, sex, risk factors for coronary artery disease (systemic arterial hypertension, diabetes, diabetes treated with insulin, smoke, hypercholesterolemia, familiar history of coronary artery disease); comorbidities (chronic renal insufficiency, peripheral vascular disease); history of coronary disease (previous acute myocardial infarction; previous coronary artery bypass); left ventricular ejection fraction before stent implantation <50%; single vessel or multivessel disease; type of restenosis (focal, proliferative, diffuse or occlusive restenosis); site of stent implantation; total number of SES implanted for ISR; stent implantation at vessel bifurcation (with single or double stent); ostial lesion. Relative risks with confidence interval at 95% with p-value of significant factors are shown in Table 6.
Factors implicated in a higher risk of MACE were multivessel coronary disease (p = 0.03), nonfocal lesion type (p = 0.037), and left ventricular ejection fraction <50% (p = 0.027). TLR occurred with a higher rate in diabetic patients (p = 0.008), and in patients previously treated with CABG (p = 0.03). All-cause mortality was associated with left ventricular ejection fraction <50% (p = 0.02), need for insulin therapy among diabetic patients (p = 0.02), and previous MI (p = 0.028).

Discussion

The present cohort study, reporting to our knowledge for the first time in the literature on the long-term outlook of patients with ISR treated with SES, has the following implications: (a) SES appear as an effective and safe treatment for BMS ISR, with very high procedural success, and low-, early-, and mid-term clinical adverse events despite the unselected patient population; (b) long-term follow up does not demonstrate a late catch-up phenomenon or risk of late thrombosis, despite the overlapping stent struts, unlike brachytherapy; (c) given these data and those from a shorter term but internally more valid randomized trials,^14,15 SES should be considered the first-line treatment strategy in patients with ISR.
Current research context. Restenosis has recently been recognized as the true Achilles’ heel of coronary stents, especially BMS.²⁰ While DES have shown a major preventive effect on restenosis, BMS are however still largely used because of cost and/or safety issues. Indeed, recent data have suggested a potential increase in adverse events with DES versus BMS, and thus a worldwide increase in BMS usage is likely in the near future.²¹
Given this context, effective management strategies for ISR are pivotal, yet therapeutic means have been limited for several years to repeat balloon-only angioplasty or brachytherapy.¹² This picture has changed drastically in the last decade with the introduction of DES. Indeed, focusing DES usage only on lesions at very high risk of restenosis, such as ISR, has been advocated by several authorities in order to further improve the individual risk-benefit balance of these devices.²² The potential of DES in BMS ISR were first shown in noncontrolled clinical trials^23,24 and observational postmarketing studies.^{17,18,25–27} More recently, at least three dedicated, randomized trials have been reported, showing that DES implantation is superior to both brachytherapy and repeat balloon-only angioplasty.^14–16 In addition, data from the ISAR-DESIRE trial, albeit limited by the relatively small sample size, have suggested the angiographic superiority of SES over paclitaxel-eluting stents in the treatment of ISR, even if this trend has not yet been substantiated in real-life patients.^14,25
However, while currently available data on DES in the management of ISR are homogeneously in favor of these devices, no study to date has reported on their longer-term risk-benefit balance (i.e., >12 months). The present long-term findings supporting the safety and efficacy of SES in unselected patients with ISR, even after >1 year since implantation, thus nicely complement previous data and lend further support to the use of SES.
Indeed, it seems clear that the advantage of DES is their combination of mechanical and biological actions in an effective and efficient manner. The use of mechanical-only interventions, such as repeat balloon angioplasty for a biological self-perpetuating phenomenon such as ISR was not effective. On the other hand, underexpansion of the original stent is a frequent culprit in ISR,²⁸ and thus implanting a DES within the ISR, possibly with high-pressure postdilatation, is key to prevent prolapse or recoil of neointimal tissue and optimize long-term outcomes.^11,28
A major issue concerning SES implantation, and recently fueled by controversial data,²¹ is the early, mid-, and long-term risk of thrombotic events. Indeed, on the basis of both real-world experiences and meta-analyses,^29–31 several questions have been raised about the risk of acute (<24 hours), subacute (<30 days), late (<6 months), and very late (>6 months) stent thrombosis following implantation of DES for ISR. Since the publication of the first usage of SES in ISR,³² including only 16 patients, and with 2 deaths, 2 infarctions, and 1 late thrombosis at 12-month follow up, several other studies have been reported. Our data showed no incidence of thrombosis — acute or subacute — which can be easily explained by the lack of patients previously treated with brachytherapy, and the strict enforcement of high-pressure stent implantation in our group.
Subgroup analysis of our cohort revealed several factors, either clinical or angiographic, which could predict outcome. In particular, the type of lesion found did not predict repeat revascularizations. This confirms the efficacy of SES for the treatment of ISR, regardless of the severity of angiographic disease.

Study limitations. Drawbacks of this work are those typical of noncontrolled clinical investigations.³³ A specific limit of the present study is the lack of randomization and of an otherwise treated control group. In addition, only 56% of enrolled patients underwent angiographic control in our study. This may be regarded as a major limitation, but this percentage is quite similar to the rate of angiographic controls in other studies.^18,34 Subgroup analysis and relative-risk evaluation may also be hampered by the relatively low event rate and by the length of follow up. Ongoing studies and registries will further appraise results of this treatment over a longer follow up, especially for high-risk subgroups (e.g., diabetic patients).

Conclusions

Treatment of bare-metal ISR with SES is safe and effective, even on a longer term than that provided from currently available randomized trials. Few events occurred at short- and mid-term follow up (yielding a yearly MACE rate of 10%), confirming earlier findings of other studies, with a sizable fraction of late events due to nontarget lesion revascularizations. The role of SES in ISR appears especially promising, given that the low rate of need for repeat target revascularization achieved by these devices has never been achieved by any other strategy used for the treatment of ISR.

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