Drug-Eluting Stents versus Repeat Vascular Brachytherapy for Patients with Recurrent In-Stent Restenosis after Failed Intracoron
December 2005
Intracoronary radiation therapy (IRT) for in-stent restenosis (ISR) in native coronary arteries and saphenous vein grafts (SVG) has substantially reduced the rate of recurrent restenosis compared with conventional percutaneous coronary intervention (PCI).1–5 However, 20–25% of patients treated with IRT require repeat revascularization to the irradiated site due to restenosis.6,7 The optimal treatment strategy for these patients remains unclear. Repeat conventional PCI has been shown to be safe but is associated with a high recurrence rate.7 Although coronary artery bypass grafting (CABG) may offer a more definitive treatment option, patients may not always be suitable for a repeat surgery that may be associated with high morbidity and mortality rates.
Since the FDA (U.S. Food and Drug Administration) approved the use of drug-eluting stents (DES), they have been shown to be very effective in preventing restenosis in several pivotal clinical trials.8–12 The effectiveness of sirolimus-eluting stents (SES) for the treatment of ISR has been demonstrated in nonrandomized registries.13,14 Recently, two small studies showed encouraging results using SES to treat ISR after brachytherapy failure.15,16 On the other hand, we have demonstrated favorable results using repeat IRT for recurrent ISR in patients who failed brachytherapy.17
The objective of the present, retrospective study was to compare the clinical outcomes of patients who received DES implantation to those of patients who received repeat IRT for the treatment of a previously irradiated site following brachytherapy failure.
Methods
Study population and protocol. A retrospective analysis was performed on 88 patients from our institution with recurrent ISR following previous IRT. Among this cohort, 34 patients received DES implantation (DES group), and in comparison, 54 patients in the repeat IRT group who presented with recurrence of ISR within the previously irradiated segment were treated with conventional PCI with repeat radiation. In the DES group, 27 patients (77.1%) received SES and 8 patients (22.9%) received PES. These 34 patients had a total of 35 lesions, of which 10 lesions (28.6%) were treated with gamma radiation, and 25 lesions (71.4%) were treated with beta radiation during the previous IRT procedure. The mean gamma radiation dose was 16.8 ± 3.1 Gy, and the mean beta radiation dose was 26.4 ± 7.2 Gy. In the repeat IRT group, 43 patients (79.6%) were treated with gamma radiation, and 11 patients (20.4%) were treated with beta radiation during the first IRT. The mean gamma and beta radiation doses were 15.2 ± 1.1 Gy and 26.4 ± 8.3 Gy, respectively. There was no significant difference between gamma and beta radiation doses in both groups.
The criteria for repeat radiation were set in July 2000 for all patients who presented with recurrence of ISR after IRT. Device and radiation system were selected at the discretion of the operator. After an adequate angiographic result was obtained, patients were treated with either: 1) gamma radiation (Ir-192) delivered by the Checkmate system (Cordis, Miami, Florida; n = 2, 3.7%); or 2) beta radiation (Sr/Y-90) delivered by either: (a) the BetaCath system (Novoste, Norcross, Georgia; n = 33, 61.1%); or (b) the Galileo system (Guidant, Santa Clara, California) in a P-32 emitter (n = 19, 35.2%). Manual stepping was not performed with any of the radiation devices. The mean cumulative dose (sum of the first and repeat radiation doses) was 45.6 ± 14.3 Gy. Ten patients (18.5%) received additional bare metal stents.
In the DES group, the mean time between the previous radiation and the DES implantation was 17.4 ± 15.7 months, while the mean time between the first IRT and the repeat IRT in the repeat IRT group was 13.2 ± 9.1 months. There was no significant difference between the above two durations (p = 0.16).
Coronary angioplasty was performed by standard percutaneous techniques using the femoral approach and standard techniques for stent implantation. All patients were pretreated with aspirin 325 mg orally before PCI, and encouraged to take it indefinitely. Clopidogrel 300–600 mg was preloaded before PCI, followed by daily administration of 75 mg; and patients were instructed to continue this regimen for at least 6 months in the DES group and a minimum of 12 months in the repeat IRT group. During PCI, patients received anticoagulation with either bivalirudin (a bolus of 0.75 mg/kg, followed by an intravenous infusion of 1.75 mg/kg/hour) or unfractionated heparin (a bolus of 40 U/kg and additional heparin to achieve an activated clotting time between 250–300 seconds). Glycoprotein IIb/IIIa inhibitors were administrated at the operator’s discretion.
Endpoints and clinical definitions. All patients routinely underwent pre- and postintervention 12-lead electrocardiography (ECG). Creatine kinase (CK)-MB enzymes were routinely obtained from blood samples before PCI and postintervention. Measurements were repeated every 8 hours until the peak value was reached and values began returning to normal (4 mg/dl in our laboratory). Q-wave myocardial infarction (MI) was defined as the presence of new pathological Q-waves in the ECG associated with an elevation of CK-MB two times the upper normal value. Non-Q wave MI was defined as an elevation of CK-MB two times the upper normal value without new Q-waves. Target lesion revascularization (TLR) was defined as a repeat revascularization within the stent or in the 5 mm distal or proximal segments adjacent to the stent. Target vessel revascularization (TVR) was defined as a revascularization driven by any lesion located in the same previously treated epicardial vessel. MACE was defined as death, Q-wave MI and TVR or TLR.
Angiographic success was defined as a final residual stenosis 30 days).
Clinical follow-up. Patients were followed clinically by telephone contact or office visit. Clinical events were recorded at follow-up visits after treatment. Outcomes were measured from the time of DES implantation or the repeat IRT. The mean follow-up time for the DES group was 9.7 ± 4.1 months, and all patients in this group were included in the follow-up. In the repeat IRT group, the mean follow-up time was 10.3 ± 3.5 months, with 92.6% of patients followed up.
Statistical analysis. The results are reported as the mean ± SD for continuous variables and as percentages for categorical variables. The Student’s t test was used to compare continuous variables, and the Chi-square test or Fisher’s exact test was used to compare categorical variables. A probability value of 17
The low occurrence of subacute and late thrombosis in either group can be attributed to prolonged antiplatelet therapy (clopidogrel for at least 6 months in the DES group and for at least 12 months in the repeat IRT group). It is possible that this patient population should be maintained on antiplatelet therapy for 24 months or indefinitely perhaps, especially for patients who received new stents (either DES or bare metal stents), since once vessels undergo radiation, re-endothelialization is delayed and perhaps impaired, as shown in the preclinical experimental work.18
In the present study, DES implantation for ISR recurrence was associated with a high failure rate at the mean follow-up time of 9.7 ± 4.1 months from DES implantation, while repeat IRT had a lower ISR recurrence rate and showed durability at 10 months. Although the effectiveness of SESs for the treatment of ISR has been demonstrated for de novo lesions, it was associated with higher indices of late loss and restenosis,13,14 especially for IRT recurrences. In addition, in the SECURE (Compassionate Use of Sirolimus-Eluting Stents) registry,19 patients with severe coronary artery disease who were poor candidates for conventional revascularization (failed both bypass surgery and vascular brachytherapy) were studied. Among these patients, 72.3% failed previous brachytherapy. The overall recurrence rate at 6 months in this registry exceeded 50%, which was similar to the findings in our study. These results suggest that for this difficult patient population, DES may not be the optimal therapy, and perhaps brachytherapy should continue to be the preferred treatment until a better therapeutic strategy emerges. However, in the recent intravascular ultrasound (IVUS) study of SES implantation for the treatment of recurrent ISR in patients who failed IRT,16 the authors reported a TLR rate of 8% at 6.9 ± 1.2 months follow-up. The possible reasons for their TLR rate being lower than ours are: 1) diabetes was more prevalent in our patients as compared to their patient population (38.2% vs. 20%); or 2) our follow-up time was much longer than theirs (9.7 ± 4.1 months vs. 6.9 ± 1.2 months). Another mechanism to explain why additional DES may be inferior to IRT is related to the ability of the new DES to re-endothelialize in an area that was previously irradiated.
Interestingly, TLR, TVR, and MACE rates in the present study were significantly lower than those in our previous study comparing repeat IRT to conventional PCI to treat failed brachytherapy.17
Possible explanations include: 1) the repeat IRT group in the present study included a different cohort of patients who underwent mainly commercial beta source radiation with higher doses. In addition, to make the two groups more comparable, the repeat IRT group did not include the patients with SVG interventions, who were present in the previous study; 2) the cumulative radiation dose in the present study was higher than that in the previous study (45.6 ± 14.3 Gy vs. 39.5 ± 11.9 Gy); 3) with improved brachytherapy equipment and technology as well as the operators’ skills, the clinical outcomes are improved accordingly; or 4) the improved antiplatelet regimen (clopidogrel for at least 6 months in the DES group and at least 12 months in the repeat IRT group) definitely played an important role in improving clinical outcomes.
Study limitations. The present study carries a few limitations. It is based on two small registries and lacks systematic angiographic follow-up. In addition, it does not reflect the late follow-up outcomes to assess the long-term durability of these strategies. Nevertheless, the study suggests safety for both strategies, and although not randomized, the lower incidence of events with IRT is tempting to favor this strategy over DES for IRT failures in those centers where IRT technology is still available. No definitive conclusions can be drawn from this study on how to treat DES failures; this will require a randomized study to compare the two different treatment strategies: balloon angioplasty plus IRT versus implantation of another DES.
1. Waksman R, White RL, Chan RC, et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165–2171.
2. Waksman R, Ajani AE, White RL, et al. Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts. N Engl J Med 2002;346:1194–1199.
3. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250–256.
4. Popma JJ, Suntharalingam M, Lansky AJ, et al. for the Stents And Radiation Therapy (START) Investigators. Randomized trial of 90Sr/90Y beta-radiation versus placebo control for treatment of in-stent restenosis. Circulation 2002;106:1090–1096.
5. Waksman R, Raizner AE, Yeung AC, et al. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: The INHIBIT randomised controlled trial. Lancet 2002;359:551–557.
6. Ajani AE, Waksman R, Cheneau E, et al. The outcomes of percutaneous coronary intervention in patients with in-stent restenosis who failed intracoronary radiation therapy. J Am Coll Cardiol 2003;41:551–556.
7. Prpic R, Teirstein PS, Reilly JP, et al. Long-term outcome of patients treated with repeat percutaneous coronary intervention after failure of gamma-brachytherapy for the treatment of in-stent restenosis. Circulation 2002;106:2340–2345.
8. Morice MC, Serruys PW, Sousa JE, et al. for the RAVEL Study Group. Randomized study with the sirolimus-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780.
9. Moses JW, Leon MB, Popma JJ, et al. for the SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
10. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: Six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38–42.
11. Colombo A, Drzewiecki J, Banning A, et al. TAXUS II Study Group. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108:788–794.
12. Stone GW, Ellis SG, Cox DA, et al. TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231.
13. Degertekin M, Regar E, Tanabe K, et al. Sirolimus-eluting stent for treatment of complex in-stent restenosis: The first clinical experience. J Am Coll Cardiol 2003;41:184–189.
14. Sousa JE, Costa MA, Abizaid A, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003;107:24–27.
15. Iakovou I, Sangiorgi GM, Stankovic G, et al. Effectiveness of sirolimus-eluting stent implantation for treatment of in-stent restenosis after brachytherapy failure. Am J Cardiol 2004;94:351–354.
16. Schiele TM, Rieber J, Konig A, et al. Comparison of acute and long-term results and underlying mechanisms from sirolimus-eluting stent implantation for the treatment of in-stent restenosis and recurrent in-stent restenosis in patients in whom intracoronary radiation failed as assessed by intravascular ultrasound. Am J Cardiol 2004;94:917–921.
17. Waksman R, Lew R, Ajani AE, et al. Repeat intracoronary radiation for recurrent in-stent restenosis in patients who failed intracoronary radiation. Circulation 2003;108:654–656.
18. Cheneau E, John MC, Fournadjiev J, et al. Time course of stent endothelialization after intravascular radiation therapy in rabbit iliac arteries. Circulation 2003;107:2153–2158.
19. Teirstein PS, Dangas GD, Negoita M, et al. Sirolimus-eluting stents for failed brachytherapy: Updated results from the SECURE registry (Abstr). American Heart Association, Abstract 1924 from Scientific Sessions, 2004.
