Simultaneous Restenosis of Taxus® and Cypher™ Drug-Eluting Stents

Case Presentation. A 55-year-old African-American male with a past medical history notable for coronary artery disease, insulin-dependent diabetes mellitus complicated by end-organ damage, hypertension and hyperlipidemia presented to our institution for elective diagnostic catheterization to evaluate progressive exertional angina. The patient’s cardiac history dates back to May 2002 when he developed exertional angina. The patient was found to have two-vessel coronary artery disease and underwent bypass grafting of his left anterior descending artery (LAD), second diagonal branch (D2) and second obtuse marginal branch (OM2). In December 2004, he experienced reoccurrence of his anginal symptoms. The symptoms continued to progress, and he underwent catheterization in March 2005 which revealed patent grafts, but multiple flow-limiting lesions in his native coronary arteries (LAD: 75% lesion distal to the LIMA insertion; 75% proximal lesion in a branching first diagonal [D1]; circumflex artery: 95% lesion in mid-vessel). After discussion with the patient, the decision was made to proceed with multivessel angioplasty. He received heparin and integrilin prior to proceeding with direct stenting of his distal LAD with a 3.0 mm x 18 mm Cypher™ stent (Cordis Corp., Miami, Florida); direct stenting of the ostial D1 lesion with a 2.75 mm x 20 mm Taxus^® stent (Boston Scientific Corp., Natick, Massachusetts); and direct stenting of the 95% circumflex lesion with a 2.5 mm x 28 mm Cypher stent. Excellent angiographic results were achieved, and the patient was discharged on clopidogrel. The patient did well for the 2 months following the procedure. Over the next 4 months, however, his symptoms recurred and progressed to Canadian Class III. A subsequent catheterization revealed patent grafts, a new 75% stenosis in the mid-LAD, a focal 95% in-stent restenosis of the 3.0 x 18 mm Cypher stent in the distal LAD (Figure 1A), a focal 75% in-stent restenosis of the 2.75 mm x 20 mm Taxus stent in D1 (Figure 2A), and a focal 95% stenosis at the edge of the 2.5 mm x 28 mm Cypher stent placed in the circumflex artery (Figure 3A). Patient Management. After discussing various treatment options with the patient, he elected to undergo repeat multivessel angioplasty. Prior to beginning the intervention, the patient was administered heparin and received platelet inhibition with clopidogrel, eptifibatide and aspirin. First, using a 6 Fr EBU4 Launcher™ guide catheter (Medtronic, Inc., Minneapolis, Minnesota), both the 75% mid-LAD lesion and the focal 95% in-stent restenosis of the 3.0 x 18 mm Cypher stent in the distal LAD were crossed with a 0.014 inch Asahi soft wire (Abbott Laboratories, Abbott Park, Illinois). Subsequently, this 95% in-stent restenosis was direct-stented with a 3.0 x 16 mm Taxus to 0% residual stenosis (Figures 1A and B). Second, the focal 75% in-stent restenosis of the 2.75 x 20 mm Taxus stent in D1 was crossed with the 0.014 inch Asahi soft wire. The lesion was direct-stented to 0% residual stenosis with a 3.0 x 23 mm Cypher stent (Figures 2A and B). Third, the 75% stenosis in the mid-LAD, having been previously crossed with the 0.014 inch Asahi soft wire, was direct-stented to 0% residual stenosis with a 3.0 x 8 mm Taxus stent. Finally, the focal 95% lesion at the edge of the 2.5 mm x 28 mm Cypher stent in the mid-circumflex was crossed with the 0.014 inch Asahi soft wire. The lesion was direct-stented with a 3.0 x 23 mm Cypher stent to 0% residual stenosis (Figures 3A and B). The patient was admitted overnight for monitoring and eptifibatide infusion. He was discharged the following day. At follow up, the patient had stable Canadian Class I angina, with no intercurrent change in his symptom complex over the preceding 14 weeks. How Would You Treat This Patient? Bernhard Meier, MD, FACC, FESC Professor and Chairman, Cardiology University Hospital 3010 Bern, Switzerland E-mail: bernhard.meier@insel.ch Repeat angioplasty for restenosis, whether in-stent or not, is a low-risk procedure. Even though several lesions needed to be addressed in this case, the preventive usage of a GP IIb/IIIa inhibitor seems unnecessary. Since the patient was already on acetylsalicylic acid and clopidogrel, the only additional medications required at the beginning of the procedure would be 5,000 units of heparin and 2 puffs of nitroglycerine spray. In cases such as this one, I typically use a Medtronic Launcher 5 Fr left Amplatz II (Medtronic, Inc., Minneapolis, Minnesota) catheter, which can be inserted directly through the skin without an introducer and without the need for a cut in the skin. The catheter is placed in the left main coronary artery before removing the 0.035 inch wire that was used for introduction. This avoids kinking in the event that the placement requires a lot of torquing. In fact, the same catheter can be used to check or treat the right coronary artery and for left ventriculography, if required. Since no difficult passages are anticipated, there is no need for a hydrophilic coronary guidewire. For instance, a Forte 0.014 inch coronary guidewire (Boston Scientific Corp., Natick, Massachusetts) could be used for all lesions. The lesions in the diagonal branch, the distal left anterior descending coronary artery and the left circumflex coronary arteries are approached in this order, since the same 2.5 mm balloon (e.g., Maverick, Boston Scientific) can be used for the lesions at increasing inflation pressures (up to over 20 bar if required for size). Simple balloon dilatation would be planned for all of the lesions. Stent implantation would only be performed if the result proved unsatisfactory (> 25% residual stenosis). A zotarolimus-eluting Endeavor stent would make sense, as both the sirolimus-eluting Cypher stent and the paclitaxel-eluting Taxus stent had failed to prevent restenoses in this particular patient. The risk of a re-restenosis after simple balloon angioplasty of a focal restenosis within or close to a previously placed stent (active or passive) is only about 10%. The combined risk for this patient to have to come back for another intervention after simple balloon angioplasty is estimated at about 20%. When no additional stent is placed, the risk of late thrombosis is zero, which is a compelling reason to favor simple balloon angioplasty. John P. Liuzzo, MD, PhD Interventional Cardiology Hackensack University Medical Center Hackensack, New Jersey, USA This is a case study of a 55-year-old male with multiple atherosclerotic risk factors. As was done in this case, the simultaneous use of two different drug-eluting stents (DES) with different pharmacologic mechanisms can lead to restenosis, not just of one, but both types of stents. It is unclear whether the cause of this phenomenon relates to the patient’s risk factors themselves. This phenomenon is likely to be more common than novel and is probably underreported. Technical issues involving stent placement and deployment may represent a significant aspect of the demise of this patient and his increased target lesion revascularizations (TLR). First, it is not clear why the operators chose to use different DESs in the same patient during the initial March 2005 procedure. Were there technical issues with stent delivery, or the lack of a desired stent size for one type, leading to use of the other type? Was it operator preference, or was this patient the subject of study for the simultaneous use of two different drug-eluting stents? The cellular mechanisms of inhibition of endothelial cell and smooth muscle cell migration and/or proliferation are clearly different between the DES types, and clinical trials appear to favor greater TLR reduction with one DES type over the other. I would have preferred to utilize one DES for all arteries initially, rather than mix the two types without reason. More importantly, the technical issues must be discussed. Rather than imply that the patient may be at fault for the in-stent restenosis (ISR), either voluntarily or involuntarily, it is possible that the operator’s technique underlies the mechanism. Was intimal hyperplasia the cause of the lesions seen by angiography? The fact that all three stents, two of one type and one of the other, contained ISR suggests problems with operator technique, or style, rather than a patient phenomenon. It is noted that direct stenting was utilized for all three vessels initially. Frequently, stent-to-vessel size mismatch may occur without predilatation or lesion preparation. If direct stenting is utilized, then postdilatation is frequently required. At what atmospheres were the initial stents deployed? Low inflation pressures and inadequate deployment may lead to ISR. It can only be suggested at this point that intravascular ultrasound (IVUS) should have been utilized either initially to guide placement of the original stents, or to evaluate the DES ISR that was subsequently observed. IVUS may have clarified whether there was stent malapposition, underexpansion, strut fracture or intimal hyperplasia. If the cause of the lesions is mechanical and not drug failure, then the same type of DES may be utilized at the focal area. It may not be necessary to completely cover the inside of one DES type with a long DES of a different type, as the authors almost completely relayered the initial 3.0 x 18 mm LAD with a 3.0 x 16 mm stent. If malapposition or underexpansion occurred, then PTCA alone with high-pressure, noncompliant balloons could have been performed without placement of additional stents. Clearly, malapposition may have occurred, as the initial 2.75 x 20 mm diagonal stent placed was relayered with a larger 3.0 x 23 mm stent, and the 2.5 x 28 mm circumflex stent was relayered with a larger 3.0 x 23 mm stent. Interventional cardiologists need to await future, controlled studies with IVUS evaluations in significant numbers of patients to address the clinical predictors of ISR in patients with simultaneous mixed DES placements. Antonio Colombo MD EMO Centro Cuore Columbus, San Raffaele Scientific Institute Milan, Italy E-mail: info@emocolumbus.it Finding a simultaneous restenosis of two different stents implanted in two different lesions may lead to elaborate conceptual thinking about multiple drug resistance or a vascular response pattern that is totally independent of the drug that was locally applied. We would like to encourage the reader to refrain from such elaborate thinking and conclusions when evaluating a single case report. The patient described in this report represents a high-risk individual in terms of adverse events (myocardial infarction, death and need for reintervention). The presence of insulin-dependent diabetes, multivessel disease and prior CABG represent the most important patient-related factors predisposing the patient to an adverse outcome following percutaneous coronary intervention, even when implanting DES.¹ Despite this baseline high-risk profile and despite the implementation of a “minimalistic” strategy at the time of stenting (no postdilatation, no IVUS guidance), it is remarkable how the implantation of two DES (Cypher, Cordis Corp., Miami, Florida; Taxus, Boston Scientific Corp., Natick, Massachusetts) with the most solid records of effectiveness and performance, was ultimately associated with a benign failure mode: the development of focal restenosis. We do not know if a more aggressive stent implantation technique aiming to optimize and maximize the final lumen is needed, even when implanting DES. We know that an IVUS-guided strategy can be effective in high-risk lesions treated with bare-metal stents.² The question is still completely unanswered when implanting a DES. Despite these legitimate concerns, we should acknowledge that an optimal final result has never been found a negative factor for most follow-up events. The higher CK rise associated with aggressive stent implantation³ may be seen as a possible concern, but is far from being of a high magnitude, and is thus unlikely to be associated with a high incidence of long-term mortality. Similar to bare-metal stents, parameters such as lesion length, stent length, postintervention minimal lumen diameter, preintervention minimal lumen diameter and reference artery size, complex lesions have been found to be predictors of restenosis following DES implantation.⁴ Various studies have shown encouraging results: in over 80% of the cases, the pattern of restenosis following implantation of Cypher or Taxus stents is focal (5 The treatment option utilized in this particular case was to implant additional DES. Our approach is similar. Even if not demonstrated with a dedicated study, the use of a DES different from the one that was associated with restenosis, seems to produce results similar to those when the same DES has been implanted, despite the fact that the lesions treated with a different DES appear to have a higher-risk baseline profile.⁶ The lesson we take from this case report is that failures can occur, even when the most effective devices available are used. These failures are usually treatable and recurrence is usually less severe than was the case in the baseline lesion. These cases are therefore amenable to lasting treatment, even when using the same class of DES that was used in the index procedure and was associated with the first recurrence. I believe that we can optimistically state that DES restenosis is not “DES failure”. A second or sometimes a third attempt is justified, and is usually effective.⁶

References 1. Stankovic G, Cosgrave J, Chieffo A, et al. Impact of sirolimus-eluting and paclitaxel-eluting stents on outcome in patients with diabetes mellitus and stenting in more than one coronary artery. Am J Cardiol 2006;98:362–366. 2. Oemrawsingh PV, Mintz GS, Schalij MJ, et al. Intravascular ultrasound guidance improves angiographic and clinical outcome of stent implantation for long coronary artery stenoses: Final results of a randomized comparison with angiographic guidance (TULIP Study). Circulation 2003;107:62–67. 3. Iakovou I, Mintz GS, Dangas G, et al. Increased CK-MB release is a “trade-off” for optimal stent implantation: An intravascular ultrasound study. J Am Coll Cardiol 2003;42:1900–1905. 4. Lee CW, Park DW, Lee BK, et al. Predictors of restenosis after placement of drug-eluting stents in one or more coronary arteries. Am J Cardiol 2006;97:506–511. 5. Iakovou I, Schmidt T, Ge L, et al. Angiographic patterns of restenosis after paclitaxel-eluting stent implantation. J Am Coll Cardiol 2005;45:805–806. 6. Cosgrave J, Melzi G, Biondi-Zoccai GG, et al. Drug-eluting stent restenosis the pattern predicts the outcome. J Am Coll Cardiol 2006;47:2399–2404.