Intracoronary Radiation for In-Stent Restenosis in Long Lesions: Too Much, Too Little, Too Late?

“It’s not enough if I succeed, everyone else should fail.” - Atila the Hun Since the introduction of stents almost a decade ago, they have become the mainstream for the treatment of patients with coronary artery disease. Nevertheless, restenosis following stent implantation has been the major limitation of stents. Serial intravascular ultrasound studies have shown that restenosis after conventional balloon angioplasty represents a complex interaction between elastic recoil, smooth muscle proliferation and vascular remodeling, whereas restenosis after stent deployment is due almost entirely to smooth muscle hyperplasia and matrix proliferation.1 Despite intensive investigation and preliminary optimistic results in animal models, most pharmacological agents were found to be ineffective in preventing restenosis after balloon angioplasty or stenting when subjected to rigorous, properly conducted clinical trials. Intravascular radiation therapy (IRT) with both, g and b emitting isotopes, is the only proven therapy for in-stent restenosis that has been established to be effective in a series of randomized trials.2 Gamma radiation has deep penetrating energies between 20 keV to 20 MeV which require an excess of shielding whereas, b radiation, which do not require excess shielding, are high-energy electrons emitted by nuclei that contain too many or too few neutrons.3 The main biologic effect of radiation for the prevention of restenosis is to cause cell death of the radiosensitive cells, which are primarily those cells in the process of mitosis following vascular injury. Although previous trials with IRT have shown a definite benefit in short and intermediate-length lesions, only g radiation has been extensively investigated in patients with long and diffuse in-stent restenosis.4 Waksman et al. in the Washington Radiation for In-Stent Restenosis Trial for Long Lesions Studies (Long WRIST) analyzed the effect of 192Ir g radiation in 240 patients with long and diffuse restenosis (lesion length between 36–80 mm).4 In this study, patients were randomized to either placebo (n = 60) or radiation (n = 60, 15 Gy at 2 mm), whereas in the Long WRIST High Dose study, patients were treated with high dose radiation (18 Gy at 2 mm) and either one month of dual antiplatelet therapy (n = 60) or 6 months (n = 60). Mean lesion length was 29 mm in the Long WRIST and 42 mm in the High Dose. At 6-month angiographic follow-up, binary restenosis rates in the stented segment were significantly lower in patients randomized to radiation, See Heuser et al. on pages 641–643 the clinical and angiographic outcomes of a subgroup of 239 patients with lesions >= 15 mm treated with b radiation (n = 128) or placebo (n = 111). Baseline clinical and angiographic characteristics were similar between the two groups with a mean lesion length of 22 mm and a reference vessel diameter of 2.8 mm. At 8-month clinical and angiographic follow-up, there was a significant reduction in major adverse cardiac events in patients randomized to radiation therapy. In-stent binary restenosis rate was 18% in the radiation group compared to 48% in the placebo group (p 20 mm) treated with intracoronary b radiation.7 At an average of 16 months follow-up, there was a 23% rate of restenosis, as shown in Figure 2. Yes, IRT requires appropriate teamwork, awkward shielding, prolonged dual antiplatelet therapy, and foremost, is cumbersome and time-consuming (even with b radiation systems), but lets not forget that IRT is the only therapy proven to be effective in randomized clinical trials and the only approved treatment for the prevention of recurrence of in-stent restenosis. But, how relevant is IRT in the new era of drug-eluting stents? What will be the future of this once-dazzling approach to treat in-stent restenosis? Two preliminary reports of the use of the sirolimus-eluting stent in patients with in-stent restenosis have shown encouraging results. In 16 patients with recurrent in-stent restenosis (lesion length: 18 mm) treated with sirolimus-eluting stents, only three patients developed in-stent restenosis and one patient died at 4-month follow-up.8 The second report analyzed the outcomes of 12 patients with in-stent restenosis treated with sirolimus-eluting stents, the majority of them (n = 11) had failed IRT.9 At an average follow-up period of 8.5 months, four patients out of ten who underwent coronary angiography had restenosis and one patient died.9 These two very preliminary reports suggest that drug-eluting stents may be a simpler and viable alternative for the treatment of in-stent restenosis, if confirmed by ongoing randomized studies. Furthermore, in the European multicenter, randomized, double-blind study of the Sirolimus-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions (E-SIRIUS) trial recently published,10 only 6% of patients assigned to the drug-eluting stent had restenosis, despite the fact that these patients were considered to be at high risk for restenosis, with a mean lesion length of 15 mm and a reference vessel diameter 2.55 mm. There is no doubt that the present study by Heuser et al. is another important milestone for IRT, which has proven to be safe, feasible and effective for the prevention of in-stent restenosis, but it may be too little, too late, as it will have to compete with the ever growing field of drug-eluting stents, even before appropriate randomized studies have been performed. Will brachytherapy be the treatment alternative for patients (and countries) who can’t afford drug-eluting stents, for patients with long segments of in-stent restenosis (“full metal jacket”) and for patients who have peri-drug-eluting stent restenosis? We don’t want to bury IRT alive,11 but it sure has seen better days.

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