Intracoronary brachytherapy for treatment of in-stent restenosis

Randomized, double-blind, placebo-controlled trials have demonstrated that intracoronary brachytherapy is more efficacious than placebo in reducing death, myocardial infarction, and target vessel revascularization at long-term follow up of patients with in-stent restenosis. Intracoronary brachytherapy is efficacious in treating totally occluded in-stent restenotic lesions, in treating de novo and in-stent restenotic lesions in saphenous vein grafts, in treating diffuse in-stent restenosis, in treating native coronary ostial in-stent restenotic lesions, in treating patients with diabetes with in-stent restenosis, in treating patients at high-risk for recurrence of restenosis, in treating elderly patients, and in treating patients who failed intracoronary radiation. Beta and gamma intracoronary brachytherapy are equally effective in treating in-stent restenosis. Long-term aspirin and clopidogrel should be administered for at least 1 year to reduce late vessel thrombosis. Inadequate radiation may cause edge stenosis.     

Angiographic and clinical outcome for the treatment of in-stent restenosis with sirolimus-eluting stent compared to vascular brachytherapy

Summary Background With the use of coronary stents for the treatment of coronary artery disease, in-stent restenosis became a major clinical problem. In this non-randomized study, we examined the use of stent-based delivery of sirolimus (rapamycin) for the treatment of in-stent restenosis in comparison to intracoronary -brachytherapy, regarding the clinical effectiveness and the angiographic results for the treatment of in-stent restenosis after 6–9 months. Methods and results Between July 2001 and May 2002, 28 patients (65±11 years) with instent restenosis were treated with intracoronary brachytherapy. Consecutively, between May 2002 and April 2003, 28 patients (65±10 years) with in-stent restenosis were treated with the implantation of a sirolimus-eluting stent (SES). Patients with in-stent restenosis treated by implantation of a SES had significantly lower incidence of in-stent restenosis (1/28 (3.6%) vs 10/28 (36%); p=0.007) and insegment restenosis (4/28 (14%) vs 14/28 (50%); p=0.013) compared to patients treated with brachytherapy. Target lesion and target vessel revascularization rate tended to be lower in the SES group (14 vs 25%) but did not yet reach statistical significance. One patient died in the group treated by implantation of a SES eight months after stenting, one patient suffered from myocardial infarction due to a subtotal in-stent restenosis after brachytherapy. Two patients after brachytherapy underwent surgical revascularization due to recurrent in-stent restenosis similar to the patient with in-stent restenosis after SES implantation. Conclusion In this study we show the feasibility and safety of the treatment of in-stent restenosis by implantation of sirolimus-eluting stents and demonstrate a lower incidence of recurrent in-stent restenosis as well as lower late luminal loss compared to treatment by intravascular brachytherapy.

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Late restenosis following placement of a sirolimus eluting stent for in-stent restenosis

Drug eluting stents (DES) are rapidly replacing intravascular brachytherapy for the treatment of bare metal in-stent restenosis (ISR). To date, there are no long-term follow up data supporting this practise. We report symptomatic repeat in-stent restenosis occurring 27 months after sirolimus eluting stent deployment for de novo in-stent restenosis. This case suggests that in a subgroup of patients with ISR, as with brachytherapy, the drug eluting stent may be simply delaying rather than inhibiting the restenotic process.     

Intracoronary brachytherapy.

Patients presenting with in-stent restenosis have an increased risk of need for repeat intervention. Intracoronary brachytherapy is indicated for these patients to prevent recurrent in-stent restenosis. Three intravascular brachytherapy systems are currently FDA-approved for use in patients: one utilizing gamma-radiation (Cordis) and two using beta-radiation (Novoste and Guidant). Current evidence and labeling do not support using intracoronary brachytherapy for prevention of restenosis in de novo lesions. Brachytherapy is absolutely contraindicated in patients unable to take prolonged combination antiplatelet drugs. Aspirin and a thienopyridine should be taken for 6 months if no new stent is placed and 12 months if a new stent is placed. If possible, new stent implementation should be avoided.     

32P brachytherapy in the treatment of complex Cypher in-stent restenosis

Treatment of in-stent restenosis after implantation of a drug-eluting stent is a critical issue. We provide the first report of the use of intravascular radiation therapy for this purpose in a 73-year-old diabetic patient stented for small-vessel bifurcation; treatment of Cypher diffuse in-stent restenosis with (32)P brachytherapy proved successful at clinical and angiographic follow-up at 7 months. This finding should encourage systematic studies on the safety and efficacy of IRT in this problematic setting.     

Debulking for in-stent restenosis in the brachytherapy era: does it still have a role?

Despite the advent of intracoronary brachytherapy, treatment of in-stent restenosis, particularly diffuse in-stent restenosis, remains problematic. Adjunctive debulking prior to brachytherapy may improve long-term outcomes. We review the literature and report our results of a series of patients treated with excimer laser coronary atherectomy along with balloon angioplasty and brachytherapy for in-stent restenosis. We conclude that adjunctive debulking may improve the long-term clinical outcomes of patients with diffuse in-stent restenosis treated with angioplasty and intracoronary radiation. A randomized controlled trial is warranted.     

Endovascular brachytherapy for treatment of bilateral renal artery in-stent restenosis.

Percutaneous transluminal angioplasty of renal artery stenosis is an attractive alternative to surgical therapy. However, even with endovascular stenting, the overall rate of restenosis is 21%. While brachytherapy for coronary in-stent restenosis has proven efficacy, its use for renal artery in-stent restenosis has not been formally evaluated. We report a case of bilateral in-stent renal artery restenosis treated with endovascular brachytherapy.     

Usefulness of intracoronary brachytherapy for in-stent restenosis with a 188Re liquid-filled balloon

The objective of this randomized pilot trial with 21 patients was to evaluate the effectiveness of a rhenium-188 liquid-filled balloon system to prevent recurrent restenosis after percutaneous transluminal coronary angioplasty for in-stent restenosis. A significant benefit from brachytherapy was seen at 6-month repeat angiography, as well as during the clinical follow-up of 12 months.     

Clinical outcome following combination of cutting balloon angioplasty and coronary beta-radiation for in-stent restenosis: a report from the RENO registry

At present, vascular brachytherapy is the only efficient therapy for in-stent restenosis. Nevertheless, edge restenosis often related to geographical miss has been identified as a major limitation of the technique. The non-slippery cutting balloon has the potential to limit vascular barotraumas, which, together with low-dose irradiation at both ends of the radioactive source, are the prerequisite for geographical miss. This prospective study aimed to examine the efficacy of combining cutting balloon angioplasty and brachytherapy for in-stent restenosis. The Radiation in Europe NOvoste (RENO) registry prospectively tracked all patients who had been treated by coronary beta-radiation with the Beta-Cath System (Novoste Corporation, Brussels, Belgium) but were not included in a randomized radiation trial. A subgroup of patients with in-stent restenosis treated by cutting balloon angioplasty and coronary beta-radiation (group 1, n = 166) was prospectively defined, and clinical outcomes of patients at 6 months were compared with those of patients treated by conventional angioplasty and coronary beta-radiation (group 2, n = 712). At 6-month follow-up, there was a significant difference between groups 1 and 2 in target vessel revascularization (10.2% versus 16.6% respectively; p = 0.04) and in the incidence of major adverse clinical events (MACE) including death, myocardial infarction, and revascularization (10.8% versus 19.2%; p = 0.01). This observation was confirmed by a multivariate analysis indicating a lower risk for MACE at 6 months (odds ratio: 0.49; confidence intervals: 0.27 0.88; p = 0.02). Compared to conventional angioplasty, cutting balloon angioplasty prior to coronary beta-radiation with the Beta-Cath System seems to improve the 6-month clinical outcome in patients with in-stent restenosis.     

Treatment of in-stent restenosis.

Although in-stent restenosis is the result of neointimal hyperplasia, mechanical problems (e.g. stent underexpansion) that occurred during implantation may result in restenosis at follow-up. The treatment of in-stent restenosis, begins with identification of these occult mechanical problems. Thereafter, in-stent restenosis can be treated with PTCA, atheroablation, or additional stent implantation; it is nuclear which technique is superior. Not all in-stent restenosis lesions have a similar risk of recurrence. Recurrence appears to depend on several markers of biologic activity: focal vs diffuse in-stent restenosis, the first episode vs recurrent in-stent restenosis, and early vs late recurrence. Vascular brachytherapy has emerged as the most promising way to treat high-risk lesion subsets.     

The use of brachytherapy to treat renal artery in-stent restenosis

The percutaneous treatment of renal artery stenosis has become the accepted revascularization strategy by most physicians treating this disorder. Unfortunately, as renal artery angioplasty and stent implantation become increasingly prevalent the Achilles heel of angioplasty, in-stent restenosis, also rises. There are currently no data suggestive of the optimal treatment strategy for renal artery in-stent restenosis. However, given the similarities in the pathophysiology between renal artery and coronary artery in-stent restenosis, brachytherapy is considered a reasonable option. This is the strategy that has been suggested and used by a number of operators. This case report describes two examples of renal artery in-stent restenosis treated with angioplasty and brachytherapy.     

Procedural and long-term results of sirolimus-eluting stent in patients at high risk for restenosis

AIM: In-stent restenosis still affects 10-50% of long-term outcome after percutaneous coronary intervention (PCI). Large clinical trials have shown that sirolimus-eluting stents (SES) have reduced restenosis rate to 0-9% in lesions at low-moderate risk. The aim of this study was to evaluate long-term clinical and angiographic outcome of SES in a real world population, at very high risk of restenosis. METHODS: Ninety lesions at high risk of restenosis (lesion length >20 mm, target vessel diameter <2.5 mm, in-stent diffuse restenosis, total occlusions and complex lesions on bypass grafts and bifurcations) were treated in 75 patients. A follow-up was scheduled at 6 months. RESULTS: Restenosis rate was 16.6% with a focal pattern of presentation in most cases. Subacute in-stent thrombosis occurred in 2.2%. Resteno-sis occurred mainly in small vessels, diabetic patients and in vessels previously treated with brachytherapy. CONCLUSION: The treatment of lesions at high risk of restenosis with SES is safe with a low restenosis rate at follow-up. An aggressive and prolonged antiplatelet regimen is mandatory because of high subacute in-stent thrombosis rates.     

Feasibility and safety of intra-coronary Beta irradiation with 144Ce/Pr for prevention of restenosis after percutaneous transluminal coronary angioplasty of in-stent restenotic lesions

BACKGROUND: Endovascular brachytherapy is a proven and efficacious treatment of coronary in-stent restenosis with established long-term benefit. Owing to its complexity and logistic inconveniences, brachytherapy did not find wide acceptance, especially in the current drug-eluting stents era. We conducted a single center, non-randomized pilot trial with 144Ce/Pr, utilizing a new high-energy Beta emitting source, for prevention of restenosis after percutaneous treatment of in-stent restenotic lesions. METHODS AND RESULTS: Thirty consecutive patients presenting in-stent restenosis were enrolled in the study. After conventional balloon angioplasty, 144Ce/Pr was applied to the dilated coronary segment at a dose of 21Gy. Technical feasibility, safety and efficacy of 144Ce/Pr at 9 months clinical and angiographic follow-up were tested. Thirty-seven arterial segments were irradiated with 100% technical success and no in-hospital major adverse cardiac events (MACE). Five MACE were observed (13.5% of the treated segments) during 9 months follow-up, including four target lesion revascularizations and one episode of acute coronary syndrome secondary to sudden late thrombotic occlusion of the irradiated segment. CONCLUSIONS: The study confirmed the safety and the feasibility of the intra-coronary Beta irradiation utilizing the 144Ce/Pr source. It also shows some practical advantages compared to traditional Gamma or other Beta sources. Considering the high-risk restenosis profile of the selected patients (i.e. diffuse in-stent restenosis, bifurcation lesions, small vessels) these results are encouraging in terms of restenosis prevention. Late acute thrombosis remains a problem requiring further improvement.     

Vascular brachytherapy: a new approach to renal artery in-stent restenosis

Renovascular hypertension is frequently the result of atherosclerosis and has been successfully treated with percutaneous angioplasty. Stenting of vessels has helped to significantly lower the rate of restenosis after angioplasty; however, neointimal hyperplasia frequently results in growth of tissue through the stent, causing in-stent restenosis. Similar problems are seen in coronary stenting, and vascular brachytherapy has been shown to effectively prevent repeat in-stent restenosis. While coronary and renal restenoses occur by a common physiologic mechanism, their anatomic differences have prevented widespread adaptation of vascular brachytherapy to renal in-stent restenoses. A number of recent reports have demonstrated efficacy of renal vascular brachytherapy, but thus far, no large-scale, randomized data is available. Herein is reviewed the subject of renal vascular brachytherapy and the studies that are presently used in its justification.     

Effectiveness of drug-eluting stents in patients with bare-metal in-stent restenosis: meta-analysis of randomized trials.

OBJECTIVES: We sought to synthesize the available evidence on the effectiveness of drug-eluting stents for bare-metal in-stent restenosis. BACKGROUND: Although there is clinical evidence that drug-eluting stents are associated with better results than other treatments for in-stent restenosis, they are not yet approved for this indication. Meta-analysis of randomized trials may yield more precise estimates of treatment effects and enable a rapid adoption of effective treatments in clinical practice. METHODS: Data sources included PubMed and conference proceedings. Prespecified criteria were met by 4 randomized studies comparing sirolimus- or paclitaxel-eluting stents versus balloon angioplasty or vascular brachytherapy in 1,230 patients with bare-metal in-stent restenosis. Studies reported the clinical outcomes of efficacy and safety during a minimum of 9 months. The primary outcome was target lesion revascularization. RESULTS: No significant heterogeneity was found across trials, thus showing a similar effect size regardless of the use of balloon angioplasty or vascular brachytherapy as comparators. The risk of target lesion revascularization (odds ratio 0.35, 95% confidence interval [CI] 0.25 to 0.49; p < 0.001) and that of angiographic restenosis (odds ratio 0.36, 95% CI 0.27 to 0.49; p = 0.001) were markedly lower in patients treated with drug-eluting stents. There were no differences between patients treated with drug-eluting stents and those treated with other techniques with respect to the composite of death or myocardial infarction (odds ratio 1.04, 95% CI 0.54 to 2.03; p = 0.55). CONCLUSIONS: Drug-eluting stents are markedly superior to conventional techniques (balloon angioplasty and vascular brachytherapy) and should be considered as first-line treatment for patients with bare-metal in-stent restenosis.     

Clinical trials of intracoronary gamma radiation therapy for in-stent restenosis

The only gamma emitter used in clinical trials for in-stent restenosis is 192Iridium (192Ir). The efficacy of intracoronary gamma radiation therapy in reducing clinical and angiographic restenosis in patients with in-stent restenosis has been established. This review is intended to give an overview of the clinical trials utilizing gamma vascular brachytherapy in patients with in-stent restenosis and give insight into the future of intracoronary radiation therapy.     

Usefulness of the angiographic pattern of in-stent restenosis in predicting the success of gamma vascular brachytherapy

The prognostic role of the angiographic pattern of in-stent restenosis after gamma vascular brachytherapy was assessed from a pooled data set of 4 clinical trials comprising 295 irradiated patients with matched baseline and follow-up angiograms. The binary angiographic restenosis rate increased with worsening in-stent restenosis patterns; however, target lesion revascularization and major adverse cardiac event rates increased for focal, diffuse, and proliferative patterns of in-stent restenosis but not for total occlusions.     

Restenosis: Intracoronary brachytherapy

Opinion statement Though interventional strategies have revolutionized the management of patients with symptomatic coronary artery disease, in-stent restenosis has emerged as the single most important limitation of long-term success following percutaneous coronary intervention. Once present, in-stent restenosis is extraordinarily difficult to treat, with conventional revascularization techniques failing in 50% to 80% of patients. Intracoronary radiation, or brachytherapy, targets cellular proliferation within the culprit neointima. Clinical trials have demonstrated that brachytherapy is a highly effective treatment for in-stent restenosis, reducing angiographic restenosis by 50% to 60% and the need for target vessel revascularization by 40% to 50%. The benefits of intracoronary brachytherapy may be particularly pronounced in certain patient subgroups (eg, those with diabetes, long lesions, or lesions in saphenous vein bypass grafts), but comes at the cost of an increased rate of late stent thrombosis and the need for extended antiplatelet therapy. The role of brachytherapy in the arsenal of the interventional cardiologist will continue to evolve, particularly in light of the unprecedented recent advances with the use of drug-eluting stents for restenosis prevention.     

Delayed restenosis after gamma brachytherapy for in-stent restenosis

Intracoronary brachytherapy is a promising modality for inhibition of in-stent restenosis. However, there is a concern of late progression after brachytherapy. This case report describes delayed restenosis after brachytherapy.     

Comparison of a centered P source wire system with a noncentered Sr/Y brachytherapy system for intracoronary β-radiation following PCI of diffuse in-stent restenosis

BACKGROUND: We investigated the potential impact of differences in effective radiation dose between the centered Guidant 32P source wire system and the noncentered Novoste 90Sr/Y BetaCath system on clinical and angiographic outcomes of intracoronary brachytherapy for the prevention of in-stent restenosis. METHODS: From 10/00 to 05/04, a total of 400 patients underwent percutaneous coronary intervention (PCI) with brachytherapy for diffuse in-stent restenosis at our institution. Following balloon dilatation, patient Group A (n=200) was treated with the centered 32P Galileo source wire system, patient Group B (n=200) was treated with the noncentered 90Sr/Y BetaCath radiation system. In Group A, the prescribed dose of 20 Gy was applied in 1-mm depth of the vessel wall. In Group B, the prescribed dose of 18.4 Gy was applied for visual reference vessel sizes >2.7 and <3.35 mm, 23 Gy for >3.36 and <4.00 mm, and 25.3 Gy for >4.00 mm, each calculated at a distance of 2 mm from the center line of the radiation source. Patients received aspirin and clopidogrel over 12 months. Primary endpoint was target lesion revascularization (TLR) at 6 months. Secondary endpoints were the binary restenosis rate and major adverse cardiac event (MACE) at 30 days and 6 months. RESULTS: At 30 days, one patient of each group underwent PCI at a nontarget lesion (0.5%). At 6 months, MACEs were equally distributed in both groups. Target lesion revascularization at 6 months was 5.9% in Group A and 9.2% in Group B (P=.08). Binary angiographic restenosis rate at 6 months was 5.5% in Group A and 11.2% in Group B (P=.014). CONCLUSION: Intracoronary beta-radiation using the centered 32P source wire system yielded a significant reduction of recurrence rate compared to the noncentered 90S/Y BetaCath system after PCI of diffuse in-stent restenosis. There was a nonsignificant trend toward reduction of TLR among patients treated with the centered 32P source wire system.