Longer-Term Outcomes of Paclitaxel Stent Implantation (Full Title Below)

Longer-Term Outcomes of Paclitaxel Stent Implantation as an Initial Treatment Strategy for Sirolimus-Eluting Stent Restenosis

ABSTRACT: Objective. The goal of this study was to determine the long-term clinical outcomes after an initial strategy of paclitaxel-eluting stent (PES) implantation for de novo sirolimus-eluting stent (SES) restenosis. Background. The optimal treatment of drug-eluting stent (DES) restenosis is unknown. Methods. Consecutive patients undergoing PES implantation for SES restenosis were identified. Patients were considered eligible for inclusion if: (1) the initial target lesion for the SES was de novo; (2) the SES restenotic lesion had not been previously treated; and (3) at least 1 year had passed since the PES implantation. Results. A total of 130 consecutive patients with 142 restenotic SES lesions were treated with PES. Mean patient age was 66.4 ± 11 years, diabetes was present in 37.1%, and the target lesion was focal in 67.8%. Over a median of 453 days (range, 365–789 days), out-of-hospital major adverse cardiac events occurred in 33 patients (25.4%). Out-of-hospital death occurred in 2 patients (due to sepsis and cancer), myocardial infarction in 1 patient (0.8%), and target lesion revascularization (TLR) in 30 patients (23.8%). There were no episodes of stent thrombosis. There was no difference in freedom from TLR between lesions with focal or non-focal pattern (log rank p = 0.52), although the time to recurrence was later in focal compared to non-focal lesions (323 ± 26 days versus 216 ± 17days; p = 0.02). Conclusions. An initial treatment strategy of PES implantation for SES restenosis appears safe and provides reasonable outcomes at more than 1-year follow up.

___________________________________________________________________ J INVASIVE CARDIOL 2010;22:216–219 Key words: target lesion revascularization, drug-elutings stents Drug-eluting stents (DES) significantly reduce the incidence of restenosis compared to bare-metal stents (BMS). ^1,2 However, target lesion revascularization (TLR) after DES is not infrequent, given the large absolute number of percutaneous coronary interventions (PCI) with DES and the expansion of DES use to “off-label” indications that are associated with higher restenosis rates. ³ The appropriate treatment of DES restenosis is unknown. Previously reported studies of percutaneous therapies for DES restenosis are limited by their small sample size and limited duration of follow up. Moreover, these studies included lesions that had received multiple interventions prior to initial DES placement, including BMS and brachytherapy, which may influence the risk of recurrent restenosis after treatment for subsequent DES failure. The primary objective of this study was to determine the long-term clinical outcomes after an initial strategy of paclitaxel-eluting stent (PES) implantation for de novo sirolimus-eluting (SES) failure. Secondarily, we sought to determine whether the angiographic pattern of SES restenosis was associated with the rate of, and time to, recurrent restenosis after PES therapy.

Methods

The study was reviewed and approved by the Scripps Clinic Institutional Review Board and followed the guidelines of the revised Declaration of Helsinki. Patient eligibility. All patients at Scripps Clinic who underwent PES implantation for SES restenosis were identified retrospectively. Patients were considered eligible for inclusion if (1) the initial target lesion for the SES was de novo; (2) the SES restenotic lesion had not been previously treated; and (3) at least 1 year had passed since the PES implantation. Stent procedure. All patients received aspirin 325 mg the day of the procedure and daily thereafter. Patients who were not previously on clopidogrel were loaded with a 600 mg dose immediately post procedure. Antithrombin selection and glycoprotein IIb/IIIa use were at the discretion of the operator. All patients were initially instructed to take clopidogrel 75 mg/day for at least 6 months; after changes in clinical guidelines, clopidogrel was prescribed for a minimum of 12 months. Clinical events were identified by telephone contact and review of the medical record. Follow up. Clinical follow up was obtained by telephone contact and review of the medical record and source documentation. Follow-up angiography was not performed unless clinically indicated. Definitions. Technical success was defined by thrombolysis in myocardial infarction (TIMI) flow 3 and 3-fold the upper normal limit, or new Q-waves on ECG. Target lesion revascularization (TLR) was defined as any clinically driven repeat revascularization of the original target lesion in the presence of a diameter stenosis > 50% by coronary angiography. The target lesion was considered to be the area covered by the stent plus 5 mm margins proximally and distal to the edges of the stent. Stent thrombosis (ST) was defined according to the Academic Research Consortium (ARC) definition of definite, probable or possible stent thrombosis. ⁴Angiographic analysis. Quantitative coronary angiography (QCA) was performed using a validated edge-detection program (Cardiovascular Measurement System, Medis Medical Imaging Systems, Neunen, the Netherlands). Quantitative angiographic measurements were obtained in the in-lesion zone (including the stented segment as well as the margins 5 mm proximal and distal to the stent). Lesions were categorized as focal ( 10 mm). ⁵Statistical analysis. The computer-based analysis program SPSS (Statistical Package for the Social Sciences, 12.0 for PC, SPSS, Inc., Chicago, Illinois) was used for statistical calculations. Continuous variables are presented as mean and standard deviation, and categorical variables are presented as counts and percentages. Comparisons of continuous variables were performed using Student t-tests. The chi-square test was used to detect differences in categorical variables, and a Fisher’s exact test was used when any expected cell count was Results Between March 2004 and February 2006, 130 patients underwent PES implantation as the initial treatment for 142 lesions with SES restenosis. Baseline demographic and procedural characteristics are presented in Tables 1 and 2. In-hospital outcomes. Technical success was 100%. In-hospital MACE occurred in 6 patients (4.2%), driven entirely by periprocedural non-Q-wave MI. There were no episodes of Q-wave MI, TLR or acute thrombosis. There were no in-hospital deaths. Clinical outcomes over follow up. Clinical follow up was obtained for all patients over a median of 453 days (range, 365 to 789 days). Angiographic follow up was available for 58 patients (44.6%). There were 2 deaths, both of which were non-cardiac (septic shock and bronchogenic carcinoma). There was 1 non-ST-elevation MI not related to the target vessel, and no ST-elevation MIs. TLR occurred in 30 patients (23.1%). There was a trend towards increased TLR in patients treated for saphenous vein graft restenosis (29%) compared to patients treated for restenosis in native coronary arteries (19%). There were no episodes of ARC-defined definite, probable or possible ST. Overall, MACE occurred in 33 patients (25.4%). Angiographic analysis. Baseline angiographic characteristics are shown in Table 2. The pattern of initial SES restenosis was focal in 68% of patients. There was no difference in survival free of TLR between patients treated for focal versus non-focal SES restenosis (log-rank p = 0.52). However, among the lesions which had recurrent restenosis after PES implantation, a non-focal pattern of initial SES restenosis was associated with a significantly shorter time to recurrence than a focal pattern (216 ± 23 days versus 323 ± 27 days; p = 0.02). Predictors of recurrent events. Characteristics significantly associated with TLR on univariate analysis included were female gender (HR 3.13 [95% CI, 1.59–6.17], p = 0.001), post-procedure minimum luminal diameter (MLD) (HR 0.65 [95% CI, 0.44–0.96], p = 0.03), and age (HR 0.97 [95% CI, 0.94–1.00), p = 0.04) (Table 3). In addition to these variables, the following candidate predictors were entered into the multivariate analysis (p Discussion This is the largest study to examine the longer-term efficacy of PES for the treatment of de novo SES restenosis. The major finding of this study is that an initial strategy of PES for SES restenosis is safe and though associated with a TLR rate of 23% over more than 1 year of follow up. Moreover, the angiographic pattern of SES restenosis does not appear to be a determinant of recurrence after PES implantation, although non-focal lesions were associated with a shorter time to clinically-driven TLR. An initial treatment strategy of PES implantation for SES restenosis appears safe and provides reasonably adequate outcomes at more than 1-year follow up. In keeping with previous reports, we found that the majority (68%) of patients presented with focal SES restenosis. ^6–8 However, contrary to a previous report by Cosgrave et al, we found no association between a non-focal pattern of restenosis and subsequent rate of TLR.9 This discrepancy may be in part explained the type of target lesion studied, the revascularization strategy used, and the duration of clinical follow up. Importantly, we observed that a non-focal pattern of restenosis was associated with shorter time to repeat revascularization as compared to a focal pattern of restenosis. Therefore, an association between the pattern of restenosis and the need for repeat revascularization may be affected by the duration of clinical follow up, with a shorter duration of follow up resulting in apparently better outcomes for focal lesions. Our study highlights the disparity in outcomes after PCI between genders. ¹⁰ However, our study may not have been adequately powered to detect the influence of reference vessel diameter upon the impact of gender, which could partially explain the relationship between female gender and the need for repeat revascularization. Further work needs to be conducted to elucidate the exact mechanisms underlying the disparity in outcomes we observed between genders. The etiology of DES restenosis is likely multifactorial. Factors such as stent underexpansion, polymer disruption during implantation and drug resistance are recognized etiologies of restenosis. Special attention should be placed on achieving an optimal angiographic outcome, since in our current study and other previous studies of DES implantation, smaller post-procedure MLD and greater residual stenosis have been associated with longer-term failure. ^11–13 Sirolimus induces G1 cell cycle arrest and apoptosis by inhibition of the mammalian target of rapamycin (mTOR). Paclitaxel blocks cells in the G2/M phase of the cell cycle by disruption of microtubule arrays necessary to form a normal mitosis. Polymorphisms in the genes that encode for mTOR and the proteins involved in paclitaxel metabolism have been shown to confer drug resistance both in vitro and in vivo. ^14,15 It is logically appealing, therefore, to substitute one drug for the other when treating DES restenosis. Previous studies have shown a trend towards improved outcomes when DES restenosis is treated with a second DES with a differing mechanism of action. ^6,16Study limitations. Our study has several limitations. It was a nonrandomized, retrospective analysis without mandated angiographic follow up. However, a large number of consecutive patients treated with PES for SES restenosis were analyzed. Additionally, routine intravascular ultrasound evaluation of the restenotic SES was not performed to determine if mechanical factors such as stent underexpansion contributed to failure. We also did not compare the efficacy of PES implantation with that of other possible therapies, including balloon angioplasty or repeat SES implantation. There was a strong trend towards increased rates of TLR in saphenous vein grafts which likely failed to achieve statistical significance secondary to limited sample size in this group.

Conclusion

An initial treatment strategy of PES implantation for SES restenosis appears safe and provides adequate outcomes at more than 1-year follow up in complex “real-world” coronary anatomy. The incidence of TLR is not insignificant, however, and further improvement is needed. In our analysis, the initial angiographic pattern of SES restenosis did not predict subsequent PES TLR. Special care should be taken to optimize post-procedural MLD and to minimize post-procedure percent diameter stenosis. Further studies are needed to determine to what extent drug resistance plays a role in DES failure.

References

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___________________________________________________________________ From *Evanston Hospital-Northshore University HealthSystems, Evanston, Illinois, and §Scripps Clinic, La Jolla, California. The authors report no conflicts of interest regarding the content herein. Manuscript submitted November 18, 2009, provisional acceptance given December 16, 2009, final version accepted February 1, 2010. Address for correspondence: Justin Levisay, MD, Northshore University HealthSystems, Evanston Hospital, Evanston, IL 60201. E-mail: JLevisay@northshore.org

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