Overcoming the Challenges of Conducting Early Feasibility Studies of Medical Devices in the United States.

Initial clinical studies of new medical technologies involve a complex balance of research participant benefits versus risks and costs of uncertainty when novel concepts are tested. The Food and Drug Administration Center for Devices and Radiological Health has recently introduced the Early Feasibility Study (EFS) Program for facilitating the conduct of these studies under the Investigational Device Exemption regulations. However, a systematic approach is needed to successfully implement this program while affording appropriate preservation of the rights and interests of patients. For this to succeed, a holistic reform of the clinical studies ecosystem for performing early-stage clinical research in the United States is necessary. The authors review the current landscape of the U.S. EFS and make recommendations for developing an efficient EFS process to meet the goal of improving access to early-stage, potentially beneficial medical devices in the United States.

Cost-effectiveness of transcatheter aortic valve replacement compared with surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results of the PARTNER (Placement of Aortic Transcatheter Valves) trial (Cohort A).

OBJECTIVES: The aim of this study was to evaluate the cost-effectiveness of transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (AVR) for patients with severe aortic stenosis and high surgical risk. BACKGROUND: TAVR is an alternative to AVR for patients with severe aortic stenosis and high surgical risk. METHODS: We performed a formal economic analysis based on cost, quality of life, and survival data collected in the PARTNER A (Placement of Aortic Transcatheter Valves) trial in which patients with severe aortic stenosis and high surgical risk were randomized to TAVR or AVR. Cumulative 12-month costs (assessed from a U.S. societal perspective) and quality-adjusted life-years (QALYs) were compared separately for the transfemoral (TF) and transapical (TA) cohorts. RESULTS: Although 12-month costs and QALYs were similar for TAVR and AVR in the overall population, there were important differences when results were stratified by access site. In the TF cohort, total 12-month costs were slightly lower with TAVR and QALYs were slightly higher such that TF-TAVR was economically dominant compared with AVR in the base case and economically attractive (incremental cost-effectiveness ratio <$50,000/QALY) in 70.9% of bootstrap replicates. In the TA cohort, 12-month costs remained substantially higher with TAVR, whereas QALYs tended to be lower such that TA-TAVR was economically dominated by AVR in the base case and economically attractive in only 7.1% of replicates. CONCLUSIONS: In the PARTNER trial, TAVR was an economically attractive strategy compared with AVR for patients suitable for TF access. Future studies are necessary to determine whether improved experience and outcomes with TA-TAVR can improve its cost-effectiveness relative to AVR.

Updating an institutional chest pain algorithm: incorporating new evidence on emerging pharmacotherapy.

Clinical treatment pathways are useful to ensure that evidence-based medicine is consistently applied in hospital systems and have been shown to improve patient outcomes. Such pathways need to be regularly updated and revised by incorporating new evidence from clinical trials to ensure optimal clinical care. In 2011, we published the Columbia University Medical Center/New York Presbyterian Hospital - Clinical Pathways for Acute Coronary Syndromes and Chest Pain. This algorithm includes primary percutaneous coronary intervention for all patients with ST-segment elevation myocardial infarction and an early invasive approach for patients with non-ST-segment elevation myocardial infarction. Since our last chest pain algorithm update, the novel antiplatelet agent ticagrelor has been introduced in the United States, resulting in an important revision of our acute coronary syndrome clinical pathways. Herein, we present our updated chest pain algorithm and provide rationale for the changes that we have made to our protocol.

Zotarolimus-eluting stents in patients with native coronary artery disease: clinical and angiographic outcomes in 1,317 patients.

Early studies of a cobalt-based alloy stent coated with the novel antiproliferative agent zotarolimus and a phosphorylcholine polymer have demonstrated significant reductions in angiographic restenosis and target vessel revascularization compared with bare metal stents. However, the generalizability of the angiographic outcomes and clinical benefit of zotarolimus-eluting stents (ZESs) to a more real-world patient population is undetermined. Clinical and angiographic outcomes in 1,317 patients treated with the ZES in the first 4 trials of the Endeavor ZES (Medtronic Vascular, Santa Rosa, CA) clinical trials program were pooled for systematic analysis. Protocol-specified follow-up angiography was performed at 8 or 12 months for a subset of 750 of these patients, and clinical follow-up was performed at 9 months after the index procedures in all patients. Diabetes mellitus was present in 22.5% of patients, the mean reference vessel diameter was 2.73 mm, and the mean lesion length was 14.59 mm. At 8 months (12 months for ENDEAVOR I), mean +/- SD in-stent late luminal loss was 0.61 +/- 0.49 mm. In-stent late luminal loss was greatest in larger caliber (>2.9 mm) vessels (0.65 +/- 0.49 mm) and longer (>16.3 mm) lesions (0.70 +/- 0.52 mm) but did not statistically vary according to diabetic status. At 9 months, overall rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE) were 4.9% and 7.7%, respectively. The rate of TLR at 12 months was not significantly different relative to diabetes and lesion length >16.3 mm (7.2% and 7.7%, respectively), although TLR was significantly more common when reference vessel diameter was <2.5 mm (8.5%; p = 0.013). At 24 months, overall rates of TLR and MACE were 6.5% and 9.9%, respectively. The overall 24-month rate of stent thrombosis was 0.3%, with no events occurring >14 days after the procedure. Despite varied clinical and angiographic characteristics, treatment with the ZES is associated with consistently low rates of TLR and overall major adverse events, including stent thrombosis. Although these findings indicate the efficacy and safety of the ZES over the time course of the first 4 ENDEAVOR clinical trials, additional ongoing study with more open patient inclusion criteria (including long lesions, small vessels, bifurcations, etc) will be important for discerning whether comparable clinical outcomes can be extended to lesion subsets of higher complexity.

The relation between clinical features, angiographic findings, and the target lesion revascularization rate in patients receiving the endeavor zotarolimus-eluting stent for treatment of native coronary artery disease: an analysis of ENDEAVOR I, ENDEAVOR II, ENDEAVOR II Continued Access Registry, and ENDEAVOR III.

The clinical and angiographic factors that predict clinically driven target lesion revascularization (TLR) in patients treated with the zotarolimus-eluting stent (ZES) are not known. Accordingly, the differences between ZES-treated patients who required TLR and ZES-treated patients who did not require TLR were examined in 1,306 patients enrolled in 4 pivotal trials of the Endeavor ZES (Medtronic Vascular, Santa Rosa, CA) for the treatment of symptomatic native coronary artery disease. TLR was performed in 64 patients (4.9%) by 9 months, with most cases (89.1%) occurring after 30 days. ZES-treated patients who required TLR had a greater incidence of 2- or 3-vessel disease (p <0.01), more stents implanted (p = 0.05), and lower device (p = 0.04) and procedure (p <0.01) success rates than ZES-treated patients who did not require TLR. The stents implanted in ZES-treated patients who later required TLR were also longer (p = 0.02) and smaller in diameter (p <0.01). Most angiographic outcomes at 8 months (12 months for ZES-treated patients in ENDEAVOR I) were worse for ZES-treated patients who later required TLR. At 9 months, 10.9% of the ZES-treated patients who required TLR had had myocardial infarctions, compared with 2.2% who did not require TLR (p = 0.001). Multivariate analysis identified older age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.00-1.06), male sex (OR, 1.79; 95% CI, 0.88-3.65), and longer lesion length (OR, 1.03; 95% CI, 0.99-1.07) as risk factors for TLR after ZES implantation (with a C statistic of 0.61, suggesting a modest discriminatory value). These data provide insight into the clinical and angiographic factors that predict TLR at 9 months in ZES-treated patients, making possible the focused surveillance of selected ZES-treated patients who might be at greater risk of TLR.

Estrogen-eluting, phosphorylcholine-coated stent implantation is associated with reduced neointimal formation but no delay in vascular repair in a porcine coronary model.

Estrogen can inhibit intimal proliferation and accelerate endothelial regeneration after angioplasty. This suggests that estrogen may prevent in-stent restenosis. Unlike other therapies to prevent restenosis, estrogen may also not delay endothelial regrowth, thereby avoiding the risk of late stent thrombosis. The purpose of this work was to determine the effect of a 17beta-estradiol-eluting stent on neointimal formation in a porcine model. Each artery of six pigs was randomized to either a control, low-dose, or high-dose 17beta-estradiol-eluting stent. All animals were sacrificed at 30 days for histopathological analysis. There was a 40% reduction in intimal area in the high-dose stents compared with control stents (2.54 +/- 1.0 vs. 4.13 +/- 1.1 mm(2), for high dose vs. control, respectively; P < 0.05). There was complete endothelial regeneration at 30 days and similar inflammatory response to stenting on histopathology in all the stent groups. This is the first study to show that 17beta-estradiol-eluting stents are associated with reduced neointimal formation without affecting endothelial regeneration in the pig model of in-stent restenosis. Estrogen-coated stents may have a potential benefit in the prevention and treatment of in-stent restenosis.