Use of a Sirolimus-eluting Stent to Treat Failure of a Nonpolymer Release Paclitaxel-eluting Stent Implanted for In-stent Resten

Since we have entered the new “drug-eluting stent era,” managing drug-eluting stent (DES) failure has become a real issue for the interventionalists. So far, no approach has been recommended: intracoronary brachytherapy (IBT) might be efficacious, but concerns have been expressed regarding the combination of cytotoxic drugs and radiation, which may result in excessive inhibition of re-endothelisation, aneurysm and a high risk of thrombosis.^1–3 No data are yet available on the use of a DES to treat the failure of another one. We report on a patient with relapsing in-stent restenosis (ISR) after implantation of a paclitaxel DES who was successfully treated using two sirolimus drug-eluting stents. Case Report. A 44-year-old man presented on August 2001 with unstable angina and was found to have severe proximal left anterior descending (LAD) stenosis. He underwent LAD direct stenting using a 3.5 x 15 mm NIR Elite stent (Boston Scientific, Natick, Massachusetts) implanted at 14 atm for 20 seconds, but presented again after three months with recurring angina. He was also found to have another severe stenosis in the region just proximal to the stent. A 3.5 x 8 mm Express (Boston Scientific) bare metal stent was placed at 16 atm for 12 seconds, partially overlapping the first. Six months later, he developed recurring angina and diffuse in-stent restenosis was demonstrated. Coronary bypass surgery was performed, with anastomosis of the left internal mammary artery to the LAD. Unfortunately, the patient’s symptoms were only resolved for a few weeks, and repeat investigation in August 2002 demonstrated failure of the LIMA graft. At this point, the patient was enrolled in a multi-center registry which used non-polymeric paclitaxel DES at concentration of 3.0 µg/mm2. Two Achieve (Guidant, Temecula, California) stents (3.5 x 18 and 3.5 x 23 mm) were placed in the mid-LAD, covering the entire previously stented segment without gaps. The result was optimized with 3.5 mm non-compliant balloon inflations (multiple inflations at a maximum of 14 atm), but no intravascular ultrasound (IVUS) guidance was used. However, symptomatic relief was only temporary and angina recurred after 10 months. An exercise test was positive at moderate workload. Another angiogram performed in September 2003 demonstrated diffuse in-stent neointimal regrowth with a discrete area of severe restenosis visible angiographically in the distal third of the stented segment (Figure 1). IVUS imaging (0.5 mm/second mothorized pullback) was undertaken using the Galaxy system and 40 MHz Atlantis Plus ultrasound catheter (Scimed, Boston Scientific, Natick, Massachusetts). IVUS showed a further area of critical lumen narrowing [minimal lumen area (MLA) less then 4.0 mm2] more proximally (Figure 1). Following abciximab administration, two 3.0 x 23 mm Cypher stents (Cordis, Johnson and Johnson, Miami, Florida) were placed, covering all of the previously stented segment with generous margins. The DES were overlapped, preventing any gap. The result was optimized using IVUS guidance with a 3.5 mm non-compliant NC balloon (Boston Scientific) at high inflation pressure (up to 24 atm for 15 seconds, multiple inflations). A satisfactory result was obtained with an IVUS MLA of 5.3 mm2 (Figure 2), and the patient was discharged with a long-term clopidogrel prescription. Symptoms resolved, and a planned angiographic and IVUS follow-up was scheduled at 6 months. Elective angiography in March 2004 revealed persistence of an excellent angiographic result, and using IVUS, neointima was visible only focally on the inner side of the Cypher stents. No delayed malapposition, stent fracture or other anomalies were detected (Figure 3). After 8 months, the patient is still treated with clopidogrel and aspirin and remains totally asymptomatic. Discussion. The treatment of patients with symptomatic ISR remains highly controversial. In the pre-DES era, the seminal paper by Mehran et al.4 showed how poor clinical and angiographical results were in this subgroup after conventional treatment with balloon angioplasty or atheroablation. Mehran’s classification of ISR as pattern I (including focal lesions 10 mm within the stent), pattern III (ISR > 10 mm extending outside the stent), and pattern IV (totally occluded ISR) has been universally adopted to evaluate the risk of relapsing ISR, as one-year target lesion revascularization (TLR) rates were 19%, 35%, 50%, and 83% in classes I to IV, respectively (p 4 In the past years, almost any treatment modality has been used in the attempt to “cure” restenosis, ranging from cutting balloon angioplasty, which has shown intra-procedural benefit due to the reduction in balloon slippage,⁵ to various debulking techniques,^6,7 or even “re-stenting the stent,”⁸ with consistently disappointing results. At the moment, the only approved and effective treatment would be intracoronary brachytherapy (IBT), which in major trials has been associated with significant reduction in the endpoint of target vessel revascularization compared to balloon angioplasty.⁹ However, although major advances have been achieved in improving its practicality and cost, IBT has currently failed to gain widespread acceptance. The reasons may be various, including the need for a specific cardiology-nuclear medicine team, radioprotection concerns, and the length of the procedure. Also, long-term follow-up data from some of the early trials showed an attenuation of the early benefit following IBT due to “catch-up” late restenosis.¹⁰ A recent metanalysis has shown that any treatment for ISR (including cutting balloon angioplasty and debulking techniques) resulted in the same risk of major adverse cardiac events (in the 30% region), and that IBT was significantly superior to the other modalities only for very high-risk ISR, lesions in which an optimal procedural results could not be achieved, or for very long lesions. Thus, they suggested repeat angioplasty as the treatment option of choice, reserving IBT only for refractory cases.¹¹ Preliminary data exist on the treatment of IBT failure with DES, showing some efficacy, though not the consistently favorable result pattern of efficacy seen in other subgroups, and possibly with an increase in the risk of intra-procedural and late thrombosis.^12,13 No evidence is currently available on the reverse, e.g., treating DES failure with IBT. Recently, a short course of oral sirolimus therapy has emerged as a possible therapeutic alternative when coupled with conventional repeat intervention. TLR rates have still been unacceptably high, well above the single digit zone.¹⁴DES for in-stent restenosis. DES are increasingly used as the first approach to tackle the “Achilles’ heel” of interventional cardiology. Their use in this difficult context is clearly appealing: DES are seen as a more “local” and possibly repeatable treatment, and the interventionalist is not required to learn anything different from the usual technique. However, the evidence supporting this strategy is not strong. Apart from the failure of the stent loaded with paclitaxel-coated polymer sleeves which were attributed to the detrimental effects of the platform,¹⁵ the Brazilian experience using sirolimus-eluting stents in relatively focal ISR could be considered extremely positive (0% MACE and TVR in 25 patients at 8 months).¹⁶ The Rotterdam group reported less impressive results in the more complex setting of diffuse ISR (37.5% MACE at 6 months in 16 patients), including at least one stent thrombosis.¹⁷ In the TAXUS III registry of 26 patients treated with paclitaxel DES, a 16% 6-month restenosis in 26 patients could be observed.¹⁸ Two other single-center experiences with sirolimus DES, only presented as abstracts, suggested better outcome, with recurring ISR in the region of 6–8%.^19,20 In a report from the RESEARCH registry, sirolimus DES appeared to be safe and moderately effective for IBT failure patients,²¹ and the degree of neointimal inhibition assessed by IVUS proved to be similar when the same stents were used either for ISR or de novo lesions.²² A recently published substudy of the DELIVER II trial (which used non-polymeric paclitaxel) showed a late loss of 0.44 ± 0.54 mm, with a disappointing 20% binary restenosis rate.²³ Thus, while many major randomized trials that should provide final answers are still ongoing (e.g. TAXUS V, SISR), it should be noted that the only available data to support such an approach come from non-randomized, very small registries. The role of high-pressure post-dilatation in treating ISR with DES. Another factor to take into account when treating ISR with DES may well be the degree of luminal enlargement obtained. IVUS studies in the pre-DES era had clearly shown that recurrence rates after stenting of a native lesion were correlated with the obtained minimum lumen area (MLA), prompting the “bigger is better” paradigm.²⁴ The near abolition of neointima seen with DES seemed to reduce the need for an aggressive IVUS-guided approach, aimed at maximizing final lumen dimensions. However, analysis of IVUS data from the SIRIUS study (for native lesions)²⁵ and more recently from a registry of DES for ISR26 are concordant in blaming a less than optimal MLA as a major cause for DES failure. A recent paper from our group has shown that suboptimal expansion after initial deployment of the DES is common, being present in 10 of 15 studied patients (66%). High-pressure post-dilatation with a non-compliant balloon resulted in a significant increase in luminal dimensions, including minimum luminal area (4.3 ± 0.3 to 5.6 ± 0.4 mm2, p 27 One of the possible causes is the association of a low MLA with uneven DES strut distribution. In this view, optimization of DES deployment is not only aimed at maximizing lumen dimensions, but also at obtaining an even and symmetrical distribution of stent struts, and thus of the eluted drug. Adequate preparation of the lesion with aggressive predilatation, aimed at cracking calcifications and reducing the differential resistance between plaque areas and adjacent normal arterial wall (perhaps less important in ISR, where neointima is likely to offer the same degree of resistance in all directions) and post-dilatation, both possibly IVUS-guided, might become mandatory steps in the near future. Use another drug-eluting stent when the first fails? Another question raised by this case is the differential efficacy of the two DES. The two drugs used in the commercially available platforms (paclitaxel and sirolimus), while sharing antiproliferative properties on various cell types, exhibit significant diversities in mechanism of action, potency, effect over the cell cycle, and avidity. Although one of the possible causes of the first DES failure in our patient can be related to the absence of polymer in the first DES used, with the drug eluted directly on the stent struts, a differential efficacy of the two drugs on the very aggressive restenosis tendency of the patient cannot be ruled out. This suggests that one of the possible strategies for overcoming DES failure due to idiosyncratic neointimal hyperplasia (provided that mechanical factors are ruled out) might be simply trying another type of DES. This approach may well become the standard and will be facilitated by the introduction of new stents eluted with other antiproliferative agents. Conclusions. We suggest that treating a DES failure with another DES is a possible approach, which proved effective in abolishing recurring ischemia in this very symptomatic young patient. An IVUS-guided high-pressure lumen optimization may have contributed to the positive outcome, however, the efficacy and safety of “DES-stenting the DES” needs to be evaluated in formal clinical trials.

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