Debulking for In-Stent Restenosis in the Brachytherapy Era: Does it Still Have a Role?

Key words: angioplasty, brachytherapy, laser, restenosis Trials comparing coronary artery stenting to coronary artery bypass grafting (CABG) have shown that repeat revascularization continues to be the main limitation of percutaneous intervention.1–3 Much of this repeat revascularization is related to in-stent restenosis, which itself is a particularly vexing problem with high recurrent restenosis rates.⁴ The most difficult in-stent stenoses to treat are diffuse lesions (> 10 mm).⁵ Balloon angioplasty (PTCA) alone of such lesions has resulted in poor outcomes with target vessel revascularization (TVR) rates up to 63% and recurrent restenosis rates up to 75%.^6–11 Prior to the establishment of brachytherapy as a cornerstone in the treatment of in-stent restenosis, the hope was that debulking agents would assist in this difficult situation. However, there has never been a randomized controlled trial of any debulking device for the management of in-stent restenosis. A variety of devices, including rotational atherectomy (RA), directional coronary atherectomy, cutting balloon angioplasty, and excimer laser coronary atherectomy (ELCA) have been studied and have shown disparate, inconclusive results (Table 1).^12–24Debulking for in-stent restenosis in the pre-brachytherapy era. Sharma et al. reported a single-center series of 100 patients with in-stent restenosis (81% diffuse) treated with RA.¹² They noted a 6-month TVR rate of 26% which is similar to the TVR rates of the radiated patients in the SCRIPPS, WRIST, and GAMMA brachytherapy studies.^25–27 BARASTER was a multicenter registry formed to evaluate RA for in-stent restenosis.¹⁴ It comprised 197 patients with in-stent restenosis treated with RA (46 RA alone, 151 RA + PTCA). These patients were compared to a matched historical cohort (107 patients) treated with PTCA alone at the Mayo Clinic in Rochester, Minnesota, and at Beth Israel-Deaconess Hospital in Boston, Massachusetts. There was not a statistically significant difference in target lesion revascularization (TLR) between the RA/PTCA and the PTCA alone groups (37% vs 47%; p = 0.1). However, patients treated with RA/PTCA had more baseline diffuse in-stent restenosis than the PTCA alone group (82% vs. 61%; p 21 This was not a randomized trial, but the patients appeared well-matched clinically and angiographically. The average lesion length was 16.98 mm in the ELCA group and 17.52 mm in the RA group (p = NS). Similarly, the reference vessel diameters were 2.60 mm and 2.62 mm, respectively (p = NS). The 12-month TLR rates were 26% and 28% in each group (p = NS). There are other small studies of debulking in the pre-brachytherapy era. Overall, these studies of debulking for in-stent restenosis are limited and differ in their results. There have never been any large randomized controlled trials. All the studies include relatively small numbers of patients. Some are multicenter registries, some are single-center prospective cohorts, and some are retrospective series. It is difficult to draw valid conclusions from small nonrandomized studies comparing debulking devices to historical controls. Debulking in the brachytherapy era. The advent of brachytherapy was a milestone in the management of in-stent restenosis. However, while the combination of PTCA and brachytherapy has significantly reduced the recurrence of in-stent restenosis, TVR rates remain in the 17–31% range.^25–29 Moreover, diffuse in-stent restenosis is particularly resistant to brachytherapy.30 Therefore, interest remains in the potential usefulness of debulking devices as adjunctive therapy with PTCA and brachytherapy in the management of diffuse in-stent restenosis. Studies of debulking with brachytherapy are limited. In WRIST, debulking with either ELCA or RA was protocol mandated for diffuse in-stent restenosis. Eighty percent of the WRIST patients received either RA or ELCA (45% RA and 35% ELCA).26 In WRIST SVG, the use of atherectomy was left to the discretion of the operators, and 55% of the radiated patients received adjunctive ELCA.²⁸ Ajani et al. pooled patients from the gamma radiation studies and identified those who received adjunctive treatment with ELCA.³¹ They found 175 such patients, and reported a TVR rate of 27%. Average lesion lengths treated with ELCA were 25 ± 12 mm. For comparison, the overall TVR rates of radiated patients in the WRIST and GAMMA trials were 26.2% and 31.3%, respectively.^26,27 Since the use of ELCA was limited to diffuse in-stent restenosis, the 27% TVR rate is quite impressive, since it is similar to the overall TVR rates. Given the fairly high rate of ELCA and RA use in the gamma radiation studies, one should not assume that similar success rates will be achieved with PTCA/brachytherapy alone. Similarly, the START study was a randomized controlled trial of beta radiation for in-stent restenosis.²⁹ The decision to debulk was left to the discretion of the operators and was used in 47.2% of patients (39.8% RA and 7.4% ELCA). The patients who received atherectomy had similar recurrent restenosis rates to those treated with PTCA and radiation alone. Again, one could presume that those treated with ELCA or RA had more complex lesions. Therefore, the equivalent results may actually support the role of adjunctive debulking with brachytherapy in the treatment of in-stent restenosis. Park et al. reported a series of 50 consecutive patients with diffuse in-stent restenosis (mean lesion length 25.6 mm) treated with RA/PTCA and beta-radiation.³² The patients underwent routine follow-up angiography at 6 months. The binary angiographic restenosis rate was 10.4%. This is extremely impressive given the fact that their mean lesion length was higher than that in the SCRIPPS (12.9 mm), GAMMA (19.0 mm), and START (16.3 mm) trials in which the 6-month restenosis rates of radiated patients were 17%, 32.4%, and 28.8%, respectively.^27,29,33 We identified 32 patients (35 lesions) who presented with in-stent restenosis and were treated with the combination of ELCA/PTCA/brachytherapy from January 2001 to September 2002 at Emory University Hospital. These patients were treated with ELCA (Spectranetics, Colorado Springs, Colorado) and PTCA creating an optimal angioplasty result and subsequently treated with intracoronary beta radiation (Novoste, Norcross, Georgia). The patients’ baseline characteristics are shown in Table 2. Six-month follow-up is available on 24 of the patients, and 12-month follow-up on 22 patients. There were no deaths, myocardial infarctions (MI), or procedural complications. The immediate procedural success rate was 94.3% (33 of 35 cases). ELCA was not successfully applied on two lesions because of inability to pass the laser through the entire lesion. The 30-day major adverse cardiovascular event (MACE) (as defined by death, nonfatal MI, or TVR) rate was 3.1% (1 patient). This patient presented with angina and was found to have an occluded artery proximal to the stent. He was managed with angioplasty and stenting. The 6- and 12-month MACE rates were 8.3% and 9.1%, respectively (Figure 1). This was entirely comprised of TVR (2 patients). The first was the previously mentioned patient, and the second was a patient who presented two months after the procedure and had restenosis. He subsequently underwent CABG. A total of 21 of the 24 (87.5%) patients with at least 6-month follow-up underwent a stress thallium scan or cardiac catheterization. The remaining 3 patients had Class 0 angina during follow-up and were not referred for noninvasive screening or coronary angiography. Figure 2 shows an example of a patient with diffuse LAD in-stent restenosis treated with ELCA, PTCA, and brachytherapy. Repeat angiography at 6 months showed a widely patent stent. Discussion. The usefulness of debulking for in-stent restenosis in the pre-brachytherapy era has been studied with mixed results.^19,22–24 All the studies were small, and none were randomized. Therefore, despite the fact that some studies reported low restenosis and TVR rates, debulking without brachytherapy clearly is contraindicated for the management of in-stent restenosis. However, there may be a role for adjuvant debulking with either RA or ELCA in the current era of brachytherapy. The equivalent results of the patients treated with debulking in the major brachytherapy studies may actually support the role of debulking, because these patients had more complex diffuse in-stent restenosis than those treated with simple PTCA. Additionally, our data and the report by Park et al. show remarkably low TVR rates in patients with diffuse in-stent restenosis treated by ELCA (our series) or RA (the Park series) in addition to PTCA and brachytherapy. In order to properly define the optimal management of diffuse in-stent restenosis, a randomized controlled trial of adjuvant ELCA/RA + PTCA + brachytherapy versus PTCA + brachytherapy is warranted. Without this, interventionalists must approach this problem using the available data. We suggest that debulking for diffuse in-stent restenosis along with PTCA and brachytherapy may improve outcomes in such patients. Acknowledgments. An educational grant from Spectranetics (Colorado Springs, CO) assisted in this study.

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