Important considerations for trials for peripheral arterial disease: Lessons learned from the paclitaxel mortality signal: A report on behalf of the registry assessment for peripheral interventional Devices (RAPID) Paclitaxel Pathways Program.

The Registry Assessment of Peripheral Devices (RAPID) convened a multidisciplinary group of stakeholders including clinicians, academicians, regulators and industry representatives to conduct an in-depth review of limitations associated with the data available to assess the paclitaxel mortality signal. Available studies were evaluated to identify strengths and limitations in the study design and data quality, which were translated to lessons learned to help guide the design, execution, and analyses of future studies. We suggest numerous actionable responses, such as the development and use of harmonized data points and outcomes in a consensus lean case report form. We advocate for reduction in missing data and efficient means for accrual of larger sample sizes in Peripheral arterial disease studies or use of supplemental datasets. Efforts to share lessons learned and working collaboratively to address such issues may improve future data in this device area and ultimately benefit patients. Condensed Abstract: Data sources evaluating paclitaxel-coated devices were evaluated to identify strengths and limitations in the study design and data quality, which were translated to lessons learned to help guide the design, execution, and analyses of future studies. We suggest numerous actionable responses, which we believe may improve future data in this device area and ultimately benefit patients.

Drug-eluting versus plain balloon angioplasty for the treatment of failing dialysis access: final results and cost-effectiveness analysis from a prospective randomized controlled trial (NCT01174472).

OBJECTIVE: To report the final results and cost-effectiveness analysis of a prospective randomized controlled trial investigating drug-eluting balloon (DEB) versus plain balloon angioplasty (BA) for the treatment of failing dialysis access (NCT01174472). METHODS: 40 patients were randomized to angioplasty with either DEB (n=20) or BA (n=20) for treatment of significant venous stenosis causing a failing dialysis access. Both arteriovenous fistulas (AVF) and synthetic arteriovenous grafts (AVG) were included. Angiographic follow up was scheduled every two months. Primary endpoints were technical success and target lesion primary patency at 1 year. Cumulative and survival analysis was performed. Incremental net benefit (INB) and incremental cost effectiveness ratio (ICER) were calculated and the cost-effectiveness acceptability curve (CEAC) was drawn. RESULTS: Baseline variables were equally distributed between the two groups. At 1 year, cumulative target lesion primary patency was significantly higher after DEB application (35% vs. 5% after BA, p<0.001). Overall, median primary patency was 0.64 years in case of DEB vs. 0.36 years in case of BA (p=0.0007; unadjusted HR=0.27 [95%CI: 0.13-0.58]; Cox adjusted HR=0.23 [95%CI: 0.10-0.50]). ICER was 2198 Euros (€) per primary patency year of dialysis access gained. INB was 1068€ (95%CI: 31-2105€) for a willingness-to-pay (WTP) threshold of 5000€ (corresponding acceptability probability >97%). CONCLUSION: DEB angioplasty may be a cost-effective option that significantly improves patency after angioplasty of venous stenoses of failing vascular dialysis access. Further large-scale randomized trials are warranted.

Eribulin mesylate (Halaven) for breast cancer.

Eribulin mesylate (Halaven-Eisai) has been approved by the FDA for treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapy regimens for metastatic cancer. Prior therapy should have included an anthracycline and a taxane in either an adjuvant or metastatic setting. Other drugs used to treat anthracycline- and taxane-refractory metastatic breast cancer include capecitabine (Xeloda), gemcitabine (Gemzar, and others) and vinorelbine (Navelbine, and others).

Early assessment of tumor response to JAC106, an anti-tubulin agent, by 3'-deoxy-3'-[¹8F]fluorothymidine in preclinical tumor models.

PURPOSE: We determined whether [(18)F]fluorothymidine (FLT) positron emission tomography (PET) can detect early effects on tumor proliferation of JAC106, a new anti-tubulin agent. METHODS: Inhibition of tubulin polymerization and [(3)H]colchicine binding were assessed in vitro. The effects of JAC106 on cytotoxicity, mitotic arrest, [(18)F]FLT uptake, and thymidine kinase 1 (TK1) activity were examined in SW620 and KB-V1 cells. Dose-dependent antitumor effects of JAC106 were monitored by measuring tumor growth and by dynamic [(18)F]FLT PET imaging in mice bearing SW620 and KB-V1 tumors. The proliferation status of tumors was examined. RESULTS: JAC106 potently inhibited tubulin polymerization and decreased the viability of SW620 (p < 0.001, half maximal inhibitory concentration, IC(50) = 3.15 ± 1.4) and KB-V1 (p < 0.01, IC(50) = 21.84 ± 24.59) cells. Exposure to JAC106 induced mitotic arrest starting at 18 h and dose-dependently increased [(18)F]FLT uptake/1 × 10(5) cells (p < 0.05) and TK1 activity and expression in vitro. Administration of 30 mg/kg JAC106 to mice inhibited the growth of SW620 and KB-VI tumors (%T/C 3.34 and 20.6%, respectively). The baseline standardized uptake values (SUV) of SW620 and KB-V1 tumors were 0.96 ± 0.31 and 2.29 ± 0.70, respectively, with a significant difference (p < 0.01). After 3 days of treatment with 30 mg/kg JAC106, the [(18)F]FLT SUVs of SW620 and KB-V1 tumors, normalized to those before treatment, were 77.9 ± 22.4% (p = 0.059) and 43.2 ± 14.0% (p < 0.01), respectively. JAC106 significantly decreased the number of Ki-67-positive cells, TK1 activity, cell fraction in G(0)G(1) phase, and tumor expression of cyclins E, A, and B1 on day 3. CONCLUSION: [(18)F]FLT PET can be used to monitor JAC106 inhibition of tumor growth, beginning 3 days after treatment. Incorporation of [(18)F]FLT PET may be useful in the early clinical development of JAC106.

Update on drug-eluting stents for prevention of restenosis.

Despite the success of coronary stent implantations in the last decade, in-stent restenosis due to neointimal hyperplasia remains a problem to overcome. Neointimal hyperplasia is a vascular response to stent injury and mainly consists of proliferation of smooth muscle cells and deposition of extracellular matrix. Recently, local drug delivery has been advocated as a potential strategy to prevent in-stent restenosis. Unprecedented results have been obtained in early clinical studies on sirolimus-eluting and paclitaxel-eluting stents. Trials using various pharmaceutical coatings on different coronary stents are ongoing. More types of drug-eluting stents are expected on the market in the near future. Meanwhile, the evaluation of drug-eluting stents is entering the second phase in which the safety and efficacy in more complex lesion subsets and different clinical presentations are being investigated. Results including cost-benefit analyses are expected to have a tremendous impact on the practice of interventional cardiology in the next decade.