Clinical experience with the ATS 3f Enable® Sutureless Bioprosthesis

The ATS 3f Enable® Bioprosthesis is a self-expanding valve with a tubular design that allows for decreased leaflet stress and preservation of aortic sinuses. We report the midterm results of a prospective, multicenter clinical study evaluating the safety and efficacy of this stented bioprosthesis in patients undergoing isolated aortic valve replacement with or without concomitant procedures.

The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT)

Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.

Atorvastatin added to interferon beta for relapsing multiple sclerosis: a randomized controlled trial

Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects. The present study evaluated the effect of atorvastatin added to interferon beta-1b in multiple sclerosis (MS) in a multicenter, randomized, parallel-group, rater-blinded study performed in eight Swiss hospitals. Seventy-seven patients with relapsing-remitting MS started interferon beta-1b every other day. After 3 months, they were randomized 1:1 to receive atorvastatin 40 mg/day or not in addition to interferon beta-1b until month 15. The primary endpoint was the proportion of patients with new lesions on T2-weighted images at month 15 compared to baseline at month three. At study end, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.14; 95 % CI 0.36-3.56; p = 0.81). All predefined secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of new Gd-enhancing lesions on T1-weighted images, total brain volume, volume of grey matter, volume of white matter, EDSS, MSFC, relapse rate, time to first relapse, number of relapse-free patients and neutralizing antibodies did not show any significant differences (all p values >0.1). Transient elevations of liver enzymes were more frequent with atorvastatin (p = 0.02). In conclusion, atorvastatin 40 mg/day in addition to interferon beta-1b did not have a beneficial effect on relapsing-remitting MS compared to interferon beta-1b monotherapy over a 12-month period.

Efficacy and safety of certolizumab pegol in an unselected crohn's disease population: 26-week data of the FACTS II survey

Certolizumab pegol (Cimzia, CZP) was approved for the treatment of Crohn's disease (CD) patients in 2007 in Switzerland as the first country worldwide. This prospective phase IV study aimed to evaluate the efficacy and safety of CZP over 26 weeks in a multicenter cohort of practice-based patients.

Extra-articular fractures of the proximal phalanges of the fingers: a comparison of 2 methods of functional, conservative treatment

For nonsurgical treatment of fractures of the proximal phalanges of the triphalangeal fingers, different dynamic casts have been described. The main principle behind these casts is advancement and tightening of the extensor hood, caused by a combination of blocking the metacarpophalangeal joints in flexion and actively flexing the proximal interphalangeal joints. In contrast to established treatment protocols using functional forearm casts, the Lucerne cast allows for free mobilization of the wrist joint. The purpose of the current multicenter study was to compare the results of conservative, functional treatment using 2 different methods, either a forearm cast or a Lucerne cast.

Lipid profiles and outcome in patients treated by intravenous thrombolysis for cerebral ischemia

OBJECTIVE:To determine whether low low-density lipoprotein cholesterol (LDL-C) but not high-density lipoprotein cholesterol (HDL-C) and triglyceride concentrations are associated with worse outcome in a large cohort of ischemic stroke patients treated with IV thrombolysis. METHODS:Observational multicenter post hoc analysis of prospectively collected data in stroke thrombolysis registries. Because of collinearity between total cholesterol (TC) and LDL-C, we used 2 different models with TC (model 1) and with LDL-C (model 2). RESULTS:Of the 2,485 consecutive patients, 1,847 (74%) had detailed lipid profiles available. Independent predictors of 3-month mortality were lower serum HDL-C (adjusted odds ratio [(adj)OR] 0.531, 95% confidence interval [CI] 0.321-0.877 in model 1; (adj)OR 0.570, 95% CI 0.348-0.933 in model 2), lower serum triglyceride levels ((adj)OR 0.549, 95% CI 0.341-0.883 in model 1; (adj)OR 0.560, 95% CI 0.353-0.888 in model 2), symptomatic ICH, and increasing NIH Stroke Scale score, age, C-reactive protein, and serum creatinine. TC, LDL-C, HDL-C, and triglycerides were not independently associated with symptomatic ICH. Increased HDL-C was associated with an excellent outcome (modified Rankin Scale score 0-1) in model 1 ((adj)OR 1.390, 95% CI 1.040-1.860). CONCLUSION:Lower HDL-C and triglycerides were independently associated with mortality. These findings were not due to an association of lipid concentrations with symptomatic ICH and may reflect differences in baseline comorbidities, nutritional state, or a protective effect of triglycerides and HDL-C on mortality following acute ischemic stroke.

Copeptin and risk stratification in patients with ischemic stroke and transient ischemic attack: The CoRisk Study

RATIONALE: Copeptin independently predicts functional outcome and mortality at 90 days and one-year after ischemic stroke. In patients with transient ischemic attack, elevated copeptin values indicate an increased risk of further cerebrovascular events. AIMS: The Copeptin Risk Stratification (CoRisk) study aims to validate the predictive value of copeptin in patients with ischemic stroke and transient ischemic attack. In patients with ischemic stroke, the CoRisk study aims to further explore the effect of treatment (i.e. thrombolysis) on the predictive value of copeptin. DESIGN: Prospective observational multicenter study analyzing three groups of patients, i.e. patients with ischemic stroke treated with and without thrombolysis and patients with transient ischemic attack. OUTCOMES: Primary end-point: In patients with ischemic stroke, the primary end-point includes disability (modified Rankin scale from 3 to 5) and mortality (modified Rankin scale 6) at three-months after stroke. In patients with transient ischemic attack, the primary end-point is a recurrent ischemic cerebrovascular event (i.e. ischemic stroke or recurrent transient ischemic attack). Secondary end-point: In patients with ischemic stroke, the secondary end-points include in-house complications (i.e. symptomatic intracerebral hemorrhage, malignant edema, aspiration pneumonia or seizures during hospitalization, and in-house mortality).

Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke

Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach.

Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson's disease: Concept and standards of the EARLYSTIM-study

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for advanced Parkinson's disease (PD) with disabling motor complications. However, stimulation may be beneficial at an earlier stage of PD when motor fluctuations and dyskinesia are only mild and psychosocial competence is still maintained. The EARLYSTIM trial was conducted in patients with recent onset of levodopa-induced motor complications (<3 years) whose social and occupational functioning remained preserved. This is called 'early' here. The study was a randomized, multicenter, bi-national pivotal trial with a 2 year observation period. Quality of life was the main outcome measure, and a video-based motor score was a blinded secondary outcome of the study. Motor, neuropsychological, psychiatric and psychosocial aspects were captured by established scales and questionnaires. The patient group randomized here is the earliest in the disease course and the youngest recruited in controlled DBS trials so far. The methodological innovation for DBS-studies of this study lies in novel procedures developed and used for monitoring best medical treatment, neurosurgical consistency, best management of stimulation programming, blinded video assessment of motor disability, and prevention of suicidal behaviors.

Prospective comparison of clinical prognostic scores in elderly patients with pulmonary embolism

Background: The Geneva Prognostic Score (GPS), the Pulmonary Embolism Severity Index (PESI), and its simplified version (sPESI) are well known clinical prognostic scores for pulmonary embolism (PE).Objectives: To compare the prognostic performance of these scores in elderly patients with PE. Patients/Methods: In a multicenter Swiss cohort of elderly patients with venous thromboembolism, we prospectively studied 449 patients aged ≥65 years with symptomatic PE. The outcome was 30-day overall mortality. We dichotomized patients as low- vs. higher-risk in all three scores using the following thresholds: GPS scores ≤2 vs. >2, PESI risk classes I-II vs. III-V, and sPESI scores 0 vs. ≥1. We compared 30-day mortality in low- vs. higher-risk patients and the areas under the receiver operating characteristic curve (ROC). Results: Overall, 3.8% of patients (17/449) died within 30 days. The GPS classified a greater proportion of patients as low risk (92% [413/449]) than the PESI (36.3% [163/449]) and the sPESI (39.6% [178/449]) (P<0.001 for each comparison). Low-risk patients based on the sPESI had a mortality of 0% (95% confidence interval [CI] 0-2.1%) compared to 0.6% (95% CI 0-3.4%) for low-risk patients based on the PESI and 3.4% (95% CI 1.9-5.6%) for low-risk patients based on the GPS. The areas under the ROC curves were 0.77 (95%CI 0.72-0.81), 0.76 (95% CI 0.72-0.80), and 0.71 (95% CI 0.66-0.75), respectively (P=0.47). Conclusions: In this cohort of elderly patients with PE, the GPS identified a higher proportion of patients as low-risk but the PESI and sPESI were more accurate in predicting mortality.

Does published orthodontic research account for clustering effects during statistical data analysis?

In orthodontics, multiple site observations within patients or multiple observations collected at consecutive time points are often encountered. Clustered designs require larger sample sizes compared to individual randomized trials and special statistical analyses that account for the fact that observations within clusters are correlated. It is the purpose of this study to assess to what degree clustering effects are considered during design and data analysis in the three major orthodontic journals. The contents of the most recent 24 issues of the American Journal of Orthodontics and Dentofacial Orthopedics (AJODO), Angle Orthodontist (AO), and European Journal of Orthodontics (EJO) from December 2010 backwards were hand searched. Articles with clustering effects and whether the authors accounted for clustering effects were identified. Additionally, information was collected on: involvement of a statistician, single or multicenter study, number of authors in the publication, geographical area, and statistical significance. From the 1584 articles, after exclusions, 1062 were assessed for clustering effects from which 250 (23.5 per cent) were considered to have clustering effects in the design (kappa = 0.92, 95 per cent CI: 0.67-0.99 for inter rater agreement). From the studies with clustering effects only, 63 (25.20 per cent) had indicated accounting for clustering effects. There was evidence that the studies published in the AO have higher odds of accounting for clustering effects [AO versus AJODO: odds ratio (OR) = 2.17, 95 per cent confidence interval (CI): 1.06-4.43, P = 0.03; EJO versus AJODO: OR = 1.90, 95 per cent CI: 0.84-4.24, non-significant; and EJO versus AO: OR = 1.15, 95 per cent CI: 0.57-2.33, non-significant). The results of this study indicate that only about a quarter of the studies with clustering effects account for this in statistical data analysis.

Implant-supported single tooth restoration in the aesthetic zone: transmucosal and submerged healing provide similar outcome when simultaneous bone augmentation is needed

AIM: The aim of this study was to compare the clinical outcomes after 2 years with bone level implants placed to restore a single missing teeth that needed simultaneous augmentation and were treated with a transmucosal or submerged approach. METHODS: This study analyzed a subset of patients included in an ongoing prospective multicenter randomized clinical trial (RCT) involving12 centers where patients were to be followed-up to 5 years after loading. Of the 120 implants that were placed in the original study, and randomly assigned to submerged or non-submerged healing, 52 needed simultaneous augmentation (28 women patients and 24 men patients, between 23 and 78 years of age). Twenty-seven of them received implants with submerged healing (AuS), while in 25 patients the implants were inserted with a non-submerged protocol (AuNS). At the 2-year follow-up visit, radiographic crestal bone level changes were recorded as well as soft tissue parameters included Pocket probing depth (PPD), bleeding on probing (BoP) and clinical attachment level (CAL) at teeth adjacent to the implant site. RESULTS: After 2 years a small amount of bone resorption was found in both groups (0.37 ± 0.49 mm in the AuS group and 0.54 ± 0.76 in the AuNS group; P < 0.001). There was no statistically significant difference between AuS Group and AuNS group for PPD (2.5 vs. 2.4 mm), BOP (BOP + sites: 8.8% vs. 11.5%) and CAL (2.8 vs. 2.4 mm) at the 2-year follow-up visit. CONCLUSIONS: When a single implant is placed in the aesthetic zone in conjunction with bone augmentation for a moderate peri-implant defect, submerged and transmucosal healing determine similar outcome, hence there is no need to submerge an implant in this given clinical situation.

A Double-Blind Randomized Controlled Trial (RCT) of Titanium-13Zirconium versus Titanium Grade IV Small-Diameter Bone Level Implants in Edentulous Mandibles - Results from a 1-Year Observation Period

Background: The use of endosseous dental implants has become common practice for the rehabilitation of edentulous patients, and a two-implant overdenture has been recommended as the standard of care. The use of small-diameter implants may extend treatment options and reduce the necessity for bone augmentation. However, the mechanical strength of titanium is limited, so titanium alloys with greater tensile and fatigue strength may be preferable. Purpose: This randomized, controlled, double-blind, multicenter study investigated in a split-mouth model whether small-diameter implants made from Titanium-13Zirconium alloy (TiZr, Roxolid™) perform at least as well as Titanium Grade IV implants. Methods and Materials: Patients with an edentulous mandible received one TiZr and one Ti Grade IV small-diameter bone level implant (3.3 mm, SLActive®) in the interforaminal region. The site distribution was randomized and double-blinded. Outcome measures included change in radiological peri-implant bone level from surgery to 12 months post-insertion (primary), implant survival, success, soft tissue conditions, and safety (secondary). Results: Of 91 treated patients, 87 were available for the 12-month follow-up. Peri-implant bone level change (-0.3 ± 0.5 mm vs -0.3 ± 0.6 mm), plaque, and sulcus bleeding indices were not significantly different between TiZr and Ti Grade IV implants. Implant survival rates were 98.9 percent and 97.8 percent, success rates were 96.6 percent and 94.4 percent, respectively. Nineteen minor and no serious adverse events were related to the study devices. Conclusion: This study confirms that TiZr small-diameter bone level implants provide at least the same outcomes after 12 months as Ti Grade IV bone level implants. The improved mechanical properties of TiZr implants may extend implant therapy to more challenging clinical situations.

The Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+): rationale and methodology

Venous thromboembolism (VTE) is common and has a high impact on morbidity, mortality, and costs of care. Although most of the patients with VTE are aged ≥65 years, there is little data about the medical outcomes in the elderly with VTE. The Swiss Cohort of Elderly Patients with VTE (SWITCO65+) is a prospective multicenter cohort study of in- and outpatients aged ≥65 years with acute VTE from all five Swiss university and four high-volume non-university hospitals. The goal is to examine which clinical and biological factors and processes of care drive short- and long-term medical outcomes, health-related quality of life, and medical resource utilization in elderly patients with acute VTE. The cohort also includes a large biobank with biological material from each participant. From September 2009 to March 2012, 1,863 elderly patients with VTE were screened and 1003 (53.8 %) were enrolled in the cohort. Overall, 51.7 % of patients were aged ≥75 years and 52.7 % were men. By October 16, 2012, after an average follow-up time of 512 days, 799 (79.7 %) patients were still actively participating. SWITCO65+ is a unique opportunity to study short- and long-term outcomes in elderly patients with VTE. The Steering Committee encourages national and international collaborative research projects related to SWITCO65+, including sharing anonymized data and biological samples.

Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)

Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.