US Pivotal Trial Research Articles

CoreValve® transcatheter self-expandable aortic bioprosthesis

Transcatheter aortic valve implantation has been designed to treat patients affected by severe symptomatic aortic stenosis considered extremely high risk for surgical aortic valve replacement. The CoreValve® (Medtronic Inc., MN, USA) is a multilevel self-expanding and fully radiopaque nitinol frame with a diamond cell configuration that holds a trileaflet porcine pericardial tissue valve and anchors the device in the native anatomy. CoreValve was the first percutaneous valve to be granted the CE mark for transfemoral implantation in May 2007 and the CoreValve US Pivotal Trial is actively underway. The CoreValve is available in four sizes (23, 26, 29 and 31 mm) to serve a broad range of patients’ annulus from 18 to 29 mm. All the valves fit into an 18-Fr size catheter. Currently, more than 35,000 patients have been treated in more than 60 countries worldwide from the femoral artery, the axillary artery and, more recently, from a direct aortic approach, with excellent results up to 4-year follow-up.

Cost-Effectiveness Analysis of TAVR

Transcather aortic valve replacement (TAVR) has rapidly gained worldwide acceptance for treating very high-risk patients with symptomatic severe aortic stenosis. Two valve systems are currently in common use worldwide and under trial in the United States. The Edwards SAPIEN valve has completed its PARTNER trial and has been approved for use in nonoperative patients. The Medtronic CoreValve is currently completing its US pivotal trial. Both plan studies of intermediate-risk patients. The use of TAVR in Europe has grown rapidly and is now about 23% of the total aortic valve replacements done in which a tissue valve is chosen (generally patients over 60 to 65 years of age). This technology is used in a patient population that was either not receiving any surgical therapy due to extreme risk or was considered very high risk for conventional surgery. The procedure requires a highly trained TAVR team, advanced imaging, and the devices themselves, which are expensive. Medical device trials are generally designed to establish if the device works as planned. For TAVR in today's world of rising health care costs, the additional question of cost effectiveness is important to address. Fortunately, the PARTNER trial addressed this and the CoreValve trial has built this into the trial design as well. This article examines what is currently known about the cost-effectiveness of TAVR.

Fool me once, shame on you; fool me twice, shame on me! A perspective on the emerging world of percutaneous heart valve therapy

Fool me once, shame on you; fool me twice, shame on me! A perspective on the emerging world of percutaneous heart valve therapy

Apomorphine

This manuscript reviews North American clinical trials examining subcutaneous injection of apomorphine in Parkinson's disease (PD) patients, and the available, cumulative apomorphine safety data for the US. These data provide strong documentation concerning dosing range (2-6 mg/injection), dosing frequency (1-10 injections/day), therapeutic response, and duration and onset of benefit. The US pivotal trial for subcutaneously injected apomorphine demonstrated robust and statistically significant benefit from drug administration when compared to subjects receiving placebo. Interestingly, these changes closely mirrored the response to levodopa in the same population, as measured by Unified Parkinson's Disease Rating Scale and Webster Step Seconds, and suggests that apomorphine may have greater potency than other agonists. A study of subjects ranging from early to advanced disease, conducted at the NIH, demonstrated a decline in duration of response and increased time to response in the advanced group when compared to levodopa naïve subjects, despite the observation that threshold and optimal response dosages did not differ. Pharmacodynamic responses from a single average-dosage administration of 4.2 mg apomorphine in several studies demonstrated a benefit as early as 7.5 minutes with a duration of benefit as long as 90 minutes. Serious adverse events occurred in 16% of the subjects in these studies with the most common adverse events including dyskinesias (21%), hallucinations (11%), and orthostatic hypotension (9%).

Spotlight on glatiramer acetate in relapsing-remitting multiple sclerosis.

Glatiramer acetate (Copaxone) is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS). In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years. Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5% and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-beta for RRMS. The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions. In conclusion, glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-beta. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.

Glatiramer acetate: a review of its use in relapsing-remitting multiple sclerosis.

Glatiramer acetate is a synthetic copolymer composed of a random mixture of four amino acids that modifies the immune response that results in the CNS inflammation, demyelination and axonal loss characteristic of relapsing-remitting multiple sclerosis (RRMS). In three randomised, double-blind trials in patients with RRMS, subcutaneous glatiramer acetate 20 mg/day was significantly more effective than placebo for the primary outcome measure of each trial (mean relapse rate, proportion of relapse-free patients and number of gadolinium-enhancing lesions on magnetic resonance imaging [MRI] scans). The mean relapse rate was significantly reduced at endpoint (approximately one-third less) in the two larger trials (the US pivotal trial [primary endpoint] and the European/Canadian study [tertiary endpoint]) in patients receiving glatiramer acetate compared with those receiving placebo. The rate was 78% less for glatiramer acetate than placebo patients in the pilot trial that investigated a slightly different patient population. Glatiramer acetate significantly decreased disease activity and burden of disease, as assessed in the European/Canadian study using a range of MRI measures. Patients with RRMS treated with glatiramer acetate in the US trial were significantly more likely to experience improved disability (whereas placebo recipients were more likely to experience worsening disability) and their overall disability status was significantly improved compared with placebo recipients. Data from the active-treatment extension of the US trial suggest that glatiramer acetate has sustained clinical benefits up to 8 years. Glatiramer acetate was generally well tolerated; the most commonly reported treatment-related adverse events were localised injection-site reactions and transient post-injection systemic reactions. Both reactions were generally mild and self limiting but were responsible for the majority of withdrawals from treatment (up to 6.5 and 3.5%, respectively). Glatiramer acetate is not associated with the influenza-like syndrome or neutralising antibodies that are reported in patients treated with interferon-beta for RRMS. The cost effectiveness of glatiramer acetate has yet to be definitively determined as assessment of available data is confounded by very different models, data sources and assumptions. Glatiramer acetate has shown efficacy in well controlled clinical trials in patients with RRMS; it reduces relapse rate and decreases MRI-assessed disease activity and burden. It is generally well tolerated and is not associated with the influenza-like symptoms and formation of neutralising antibodies seen with the interferons-beta. Based on available data and current management guidelines, glatiramer acetate is a valuable first-line treatment option for patients with RRMS.