Long term clinical follow up of the phase III randomized trial (START) evaluating the role of beta radiation for the treatment of in stent restenosis

Abstract

The initial enthusiasm for brachytherapy following angioplasty in the treatment of in stent restensosis was tempered by the concern for potential delayed restensosis associated with radiation. This analysis was designed to evaluate the long term outcome of patients treated on the START trial in order to determine whether the initially positive effects of beta radiation were maintained with two year clinical followup. Four hundred and seventy six patients were randomized between radiation (n = 244) and placebo (n = 232) following repeat angioplasty. The Novoste Beta Cath system was used to deliver either 18.4 Gy (for reference vessel sizes of >2.7 mm and <3.35 mm) or 23.4 Gy (for vessel diameters between 3.335 and 4.0) The primary clinical efficacy endpoint was identified as target vessel revascularization (TVR) and the primary safety endpoint was Major Adverse Cardiac Events (MACE) at both 8 months and 2 years. TVR was defined as clinically driven need for repeat revascularization with an in stent restensosis of >50%. MACE was defined as death, MI, any bypass graft surgery, or repeat target lesion target vessel PCI. Clinical outcome data was available for 378 (79%) of the original 476 patients. The primary clinical endpoint continued to show a statistically significant reduction in TVR associated with the use of brachytherapy 36.6% vs. 27.5% (RR 0.7, 95% CI: −9.2%, p = 0.025). Multivariate analysis also revealed younger age and no evidence of calcification were associated with a decrease in TVR rates. Kaplan Meier curves for TVR reveal that the benefit is first identified at approximately 90 days and remains constant beyond the two year point. Freedom from TVR was significantly increased from 62% (placebo) to 72% (beta radiation) [p = 0.02]. Univariate and multivariate analysis revealed that treatment with radiation (p = 0.0347)and pre procedure reference vessel diameter (p = 0.0397) were significant predictors of MACE. Brachytherapy significantly improved freedom from MACE from 59% to 68% (p = 0.035) at two years. Importantly, there were no clinical manifestations of late radiation associated adverse events. The late stent thrombosis rate of 0.4% for treated patients shows no increased risk associated with brachytherapy. Intracoronary brachytherapy remains the only non-surgical therapy proven superior to angioplasty. The long term results of the START trial now confirm it as the first randomized trial to show that beta radiation can significantly reduce the need for repeat interventions and simultaneously decrease the major adverse cardiac events for patients with in- stent restensosis