Oral Rapamycin in the Treatment of Diffuse Proliferative In-Stent Restenosis in a Patient with Small Reference Vessel

Case Report. A 63-year-old man was admitted to our hospital due to recent onset chest pain with radiation to the left arm, which was precipitated by minimum efforts and relieved by rest. He was evaluated at the coronary care unit and treated with aspirin, heparin and intravenous nitroglycerin. The electrocardiogram revealed a T-wave inversion in leads V4, V5, V6, D1, and AVL. His coronary risk factors were diabetes type II treated with an oral hypoglycemic agent, and dyslipedemia treated with statins. He was also a smoker. Physical examination in the Coronary Care Unit was remarkable for a regular heart rate of 72 beats per minute, blood pressure of 130/80 mmHg, a respiratory rate of 15 breaths per minute, height of 1.71 cm, weight of 77 kg, and a body mass index of 26 kg/m2. Neck veins were not distended and no carotid bruits were heard. The heart sounds were normal without any murmurs or gallops. The lung auscultation revealed normal breath sounds. The peripheral pulses were normal. The chest radiograph showed a normal heart image. Considering his risk factors and EKG changes, the patient was referred to our catheterization laboratory for angiography, which showed severe stenoses in the first diagonal (74.2%), mid portion of the right coronary artery (78%), and mid left anterior descending artery (62.5%) (Figure 1); by quantitative coronary angiography analysis, the reference vessel size for LAD and diagonal were 2.5 and 2.0 mm, respectively. Patient Management. We used a femoral approach with 6 French introducer. We elected to proceed with stenting to RCA, first diagonal and balloon dilatation to LAD. The ostium of the RCA was engaged with a 6 French Judkins right 3.5 (JR 3.5, Boston Scientific/Scimed Maple Grove, Minnesota) guiding catheter. The lesion was successfully crossed with a floppy wire GT 1 (Medtronic AVE, Inc.; Santa Rosa, California) and a S 7 3.0 x 12 mm stent (AVE, Galway, Ireland) was deployed at 12 atmospheres (ATM). The left coronary ostium was engaged with a Judkins left 3.5 (JL 3.5 Boston Scientific/Scimed). The first diagonal lesion was crossed with 0.014´´ Hi-Torque Floppy guidewire (Guidant Corporation, Temecula, California) and a 2.0 x 15 mm BIODIVYSIO SV (Biocompatibles, Surrey, United Kingdom) was deployed at 14 ATMs. With another wire 0.014´´ Hi-Torque extra support, we crossed successfully the LAD lesion, dilated with a 2.5 x 12 mm Maverick balloon (Boston Scientific/Scimed) at 8 ATMs, with good results in both arteries (Figure 2). Six months later, the patient had recurrent symptoms with effort angina and a high risk Thallium Stress Test (anterolateral ischemia). In coronary angiography, we noted a restenosis (Figure 3) in the first diagonal branch, treated with a 2.0 x 10 mm cutting balloon (Interventional Technologies Europe Ltd., Donegal, Ireland) plus balloon dilatation with a 2.0 x 12 mm Maverick balloon (Boston Scientific/Scimed). The LAD also showed restenosis treated with a 2.5 x 12 mm Medtronic (Medtronic AVE) deployed at 12 ATMs (Figure 4). No restenosis was observed in RCA. Four months later, the patient was sent to coronary angiography because of rest pain, without EKG changes. The coronary angiography revealed almost complete closure in the LAD stent (in-stent diffuse proliferative restenosis) (Figure 5) with collaterals from the RCA, as well as diffuse restenosis in the diagonal branch. At this time (second restenosis in LAD and diagonal), we decided to include this patient in our Oral Rapamycin protocol (ORAR study Rodriguez A, ACC 2003). We treated the diagonal with balloon PTCA, and re-stented the LAD with 2.5 x 12 mm EXPRESS stent (Boston Scientific/Scimed) deployed at 13 ATMs (Figure 6). The patient received 2 mg of oral rapamycin per day during one month starting with a loading dose of 6 mg immediately after the end of the procedure. Diltiazem 180 mg was added in order to reach an adequate rapamycin blood level (more than 8 ng/ml) which was tested at the third week after PTCA (Rapamycin blood levels in this patient reached 26 ng/ml). At 7 months of follow-up, as part of the study protocol, the patient did a repeat coronary angiography, showing the LAD without restenosis and minor lesion in the diagonal (Figure 7). The patient remains asymptomatic and with normal Thallium Stress Test 11 months after the inclusion in the ORAR trial. How Would you Manage this Case? Tim A. Fischell, MD Heart Center at Borgess Kalamazoo, Michigan This is the case of a complex multivessel intervention in a Type 2 diabetic patient with a high restenosis risk. Stenting of the RCA was successful with an apparently durable long-term result. The LAD and diagonal disease was severe. Recurrent restenosis was observed in the diagonal after treatment with a small vessel Biodivysio stent. The LAD was originally treated with with balloon angioplasty. The LAD suffered restenosis and was retreated with an AVE stent. Four months later the diagonal and the LAD once again had severe restenosis and were treated with PTCA of the diagonal and repeat bare stenting of the LAD. The patient was treated with oral rapamycin and had patency of the LAD and diagonal at 7-month follow-up. Currently, I believe the initial management of this type of patient is relatively straightforward. In our hospital, today, this patient would have initial stenting of the LAD and RCA with CypherTM (Cordis, Miami Lakes, FL.) Bx VelocityTM drug-eluting, sirolimus stents (DES). Given the small distribution and diameter of the diagonal branch, we would likely have performed PTCA (POBA) or possibly cutting balloon angioplasty of the diagonal branch. The clinical restenosis risk for the DES would be estimated to be in the 1-3% range. Importantly, virtually all restenosis seen after this DES treatment is focal restenosis, either from within the stent or at the edge. This type of restenosis could be easily treated with a second, short-length, drug-eluting stent. Should the diagonal cause symptomatic restenosis after the initial balloon angioplasty; we would have also treated that vessel with a CypherTM stent. Given the sequence and timing of treatment in this case, it is reasonable to assume that the operators did not have access to DES at the time that these interventions were performed. In that situation, I would have elected to perform rotablator atherectomy and cutting balloon, combined with brachytherapy for the initial retreatment of the in-stent restenosis of the diagonal. Since stenting had not been done in the LAD, I agree with their initial (first) retreatment of the LAD with bare stenting (again assuming DES was not available). If the LAD bare stent had restenosis, I would have used rotablator and cutting balloon plus brachytherapy to treat the initial in-stent restenosis. The authors’ approach to use oral rapamycin is provocative. In a recent publication by Tierstein, et al., they had a very high (~58%) restenosis rate in patients with recurrent restenosis who were treated with oral rapamycin. Many of the patients had severe side effects or signs of systemic toxicity. Thus, it is possible, in this case, that the apparent good result at 7 months after the final intervention was fortuitous, and unrelated to the oral rapamycin treatment. In fact there is a large, but old, balloon angioplasty literature suggesting that in some cases one can outlast the restenosis process with recurrent PTCA interventions. That is, this one case report is anecdotal and should be carefully interpreted. The overall data reported to date for oral rapamycin is not encouraging, and the drug does have some serious potential toxicity when given systemically. In the long run, I believe that this approach (multiple complex, repeated interventions) will be extremely rare following the widespread, primary use of drug-eluting stents, as we are currently observing in the United States. Robert A. Harrington, MD Duke Clinical Research Institute, Duke University Medical Center Durham, North Carolina This 63-year-old diabetic man presented with an acute coronary syndrome without persistent ST-segment elevation. Given the symptoms occurring with minimal exertion and the widespread T-wave inversion, early cardiac catheterization for risk stratification and the defining of revascularization options was entirely appropriate. The ECG involving the lateral leads suggested that the culprit vessel was the anterolateral branch of the LAD. It was also noted that there was significant, though not critical, narrowing of both the LAD and the RCA. Both the LAD and its AL branch were determined to be on the smaller side. At this point, there are multiple treatment options to consider in this gentleman with two-vessel CAD: treat with immediate PCI the culprit vessel, leaving the other lesions for medical treatment and perhaps revasularization if a stress test is positive; consider coronary artery bypass grafting to the LAD, AL and RCA; consider multivessel PCI of all three angiographic lesions. Given that the majority of the data comparing surgical and percutaneous revascularization suggests no mortality benefit of one approach over the other and that all of the lesions appear quite approachable from a technical perspective, multivessel PCI is quite reasonable. We would have favored stenting all three lesions at the same procedure given the likely restenosis benefits. With the return of symptoms in a patient with a recent (Ron Waksman, MD Washington Hospital Center Washington, DC This case illustrates a diabetic patient who initially presented with three vessel disease involving the left anterior descending (LAD), the first diagonal, and the mid RCA. At that time the patient underwent intervention, which included stenting of the RCA and the first diagonal; and balloon dilatation to the LAD. Six months later the patient presented with restenosis to the diagonal, which was treated with balloon angioplasty and stenting of the restenotic lesion of the LAD. Four months later the patient presented with in-stent restenosis of both the LAD and the diagonal. At this time the authors decided to re-stent the LAD, to once again balloon the in-stent restenosis lesion of the diagonal, and to enroll the patient into an experimental study, which examined the efficacy of oral rapamycin for the prevention of restenosis. The authors report angiographic patency of both the LAD and the diagonal at 7 months. This case raises several questions regarding the treatment of a diabetic patient with three vessel disease. Why not send the patient for CABG and save him the unenviable agony of restenosis? We have learned that CABG is associated with reduction of mortality for diabetic patients with multivessel disease and in addition, the ART study taught us that diabetic patients with multivessel disease may benefit from surgery rather multi stenting in terms of recurrence reduction. Secondly, why not treat the patient who presents with in-stent restenosis with vascular brachytherapy? How many more randomized clinical trials are needed to convince the operator that vascular brachytherapy should be the first line of therapy for patients presenting with in-stent restenosis, especially for those who are diabetic? Literature has certainly supported the efficacy of radiation therapy for the treatment of diabetic patients with in-stent restenosis. Further, the likelihood of recurrent in-stent restenosis in diabetic patients when treated with PCI alone is nearly 80%. Although oral rapamycin may be effective in reducing restenosis, it is still in an early experimental phase. It is not clear whether this therapy is robust enough to control recurrences of in-stent restenosis. The only publication related to this cohort of patients — albeit based on a small cohort — does not support this strategy. I believe that for this patient, the first choice of treatment should have been CABG. Regarding the in-stent restenosis, I believe the patient should have been treated with vascular brachytherapy. Perhaps it would be better to first examine the utility of systemic rapamycin for de-novo lesions and then explore its potential for the treatment of in-stent restenosis. Stanley D. Bleich, MD Cardiology Associates of Jefferson Metairie, Louisiana This is a case of a 63-year-old male patient who presented with significant coronary ischemia and had three-vessel coronary disease, including high-grade lesion in the right coronary and high-grade lesions in the proximal LAD and first diagonal branches. A picture of the RCA or the ventriculogram have not been submitted, and therefore a decision as to percutaneous revascularization versus coronary bypass surgery cannot be made. The investigators, however, did decide to proceed with percutaneous intervention. They mentioned that a stent was placed in the RCA with a successful result. They also placed a stent in the first diagonal branch and balloon angioplasty of the LAD. I do not understand why a stent was placed in the diagonal and the lesion of the LAD was angioplastied. The patient then returned because of in-stent restenosis of the diagonal branches and restenosis of the LAD. At this time, I would have clearly stented the left anterior descending with a drug eluting stent if it was available. In the diagonal branch, I would have used a cutting balloon followed by brachytherapy. The patient then returned four months later with complete closure of the LAD stent with collaterals from the right coronary and restenosis of the diagonal branch. At this point, the patient was randomized to an oral Rapamycin study followed by repeat intervention. If the patient had received brachytherapy of the diagonal previously there was a good chance that he would not have returned with the restenosis at the four-month point. If the LAD had closed as it did in this case, I would have attempted to open it and then follow again with brachytherapy. The investigators randomized this patient into an oral rapamycin trial, which is obviously not available at most institutions and therefore I feel that stenting and brachytherapy would have been the best option. Again, it is important to note that depending on the status of the RCA and the left ventricle this patient might have in fact been best served by coronary bypass surgery which cannot be decided without these missing pictures. In summary, I feel this patient would be best served by stenting of all vessels that could have been stented initially if it was decided that coronary bypass was not the best option. I would have also proceeded with cutting balloon therapy and brachytherapy to treat restenosis.

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