A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (SpA) is a chronic inflammatory disease characterized by back pain and stiffness. The objective of this study was to determine whether golimumab is superior to placebo in patients with nonradiographic axial SpA. METHODS: This phase III, double-blind, randomized, placebo-controlled trial was performed to evaluate subcutaneous golimumab (50 mg) versus placebo in patients ages ≥18 years to ≤45 years who had active nonradiographic axial SpA according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for ≤5 years since diagnosis, high disease activity, and an inadequate response to or intolerance of nonsteroidal antiinflammatory drugs. Patients were randomized 1:1 to receive golimumab or placebo subcutaneously every 4 weeks. The primary end point was 20% improvement according to the ASAS criteria (ASAS20) at week 16. Key secondary end points were an ASAS40 response, ASAS partial remission, 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and change in the Spondyloarthritis Research Consortium of Canada (SPARCC) magnetic resonance imaging (MRI) index for sacroiliac (SI) joint inflammation (SPARCC score). RESULTS: Of the 198 patients randomized, 197 were treated (97 received golimumab, and 100 received placebo). The mean age of the patients was 31 years, and 57.1% were male. At baseline, the mean ± SD BASDAI was 6.5 ± 1.5, the mean ± SD ASDAS was 3.5 ± 0.9, and the mean ± SD SPARCC score was 11.3 ± 14.0. The primary end point, an ASAS20 response, was achieved by significantly more patients in the golimumab group compared with the placebo group (71.1% versus 40.0%; P < 0.0001). An ASAS40 response was also achieved by significantly more patients in the golimumab group compared with the placebo group (56.7% versus 23.0%; P < 0.0001). The incidence of adverse events did not differ meaningfully between groups. CONCLUSION: Patients with active nonradiographic axial SpA treated with golimumab had significantly greater improvement in symptoms compared with patients treated with placebo. Golimumab was well tolerated and had a favorable risk/benefit profile.

Effects of prolonged mechanical ventilation with a closed suction system on endotracheal tube resistance and its reversibility by a closed suction cleaning system.

The study objective was to evaluate endotracheal tubes (ETT) from extubated adult patients and compare them to new, unused, size-matched control tubes for changes in inspiratory resistance (Rinsp) and peak inspiratory pressure (PIP) before and immediately after suctioning with the Airway Medix Closed Suction System (AMCSS) (Biovo Technologies, 2013 Tel Aviv, Israel). Sixteen ETTs were recovered from predominantly medical patients who had required intubation and mechanical ventilation for more than 12 hours. ETTs were evaluated within 4.5 hours of extubation. Readings were taken during square wave flow, at rates of 40 and 60 l/minute. Cleaning of extubated ETTs using the AMCSS was able to restore them to almost original conditions in terms of Rinsp and PIP. The examined ETTs included tubes of various sizes ranging from internal diameter (ID) 7 to 8.5 mm and intubation periods ranging from 12 hours to 21 days. The mean Rinsp for the used and uncleaned ETTs was equivalent to 275% of the Rinsp of sized-matched new and unused ETTs. For 8 mm ID ETTs this was comparable to a measured Rinsp of a 5 mm tube. Following a single cleaning episode with the AMCSS, Rinsp decreased, regaining an effective ETT ID of a 7.5 to 8 mm tube. A single suctioning episode with this device resulted in a significant reduction in Rinsp, virtually restoring original flow variable values. The AMCSS represents a novel technology in closed suction systems, designed to achieve more effective inner lumen cleaning in prolonged mechanical ventilation.

The impact of treatment with risperidone long-acting injection on the Belgian healthcare system: results from a budget impact model.

Substantial evidence from randomised clinical trials has demonstrated that long-acting risperidone (RLAI) is efficacious and well tolerated in patients with schizophrenia. Recently, a long-term naturalistic study of treatment practices in Belgium, the electronic Schizophrenia Treatment Adherence Registry (e-STAR), reported that treatment with RLAI is associated with improvements in adherence and long-term outcomes. The present report describes the results of a budget impact model that analysed the Belgian e-STAR data, together with other available data, over a 3-year time horizon, in order to establish the potential impact of treatment with RLAI on total healthcare costs in Belgium.The model framework combined medical resource utilisation with costs of the population of interest in order to quantify the costs, and cost offsets, of RLAI treatment. For the purpose of this budget impact model, it was assumed that among patients who would discontinue their previous antipsychotic medication, 6.7% of patients would be switched to RLAI. The overall cost savings to the Belgian healthcare system were calculated to be 2.3 million Euros in Year 1, 3.7 million Euros in Year 2 and 4.4 million Euros in Year 3. The majority of these cost-savings resulted from the substantial reduction in hospitalisation costs associated with RLAI treatment. This report indicates that improvements in adherence and long-term outcomes previously demonstrated for RLAI treatment in Belgium may result in substantial cost benefits to the country's healthcare system.

Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A.

OBI-1 is a recombinant B-domain deleted porcine factor VIII (FVIII). FVIII treatment in those with haemophilia A may be complicated by the development of anti-FVIII antibodies (inhibitors) leading to a failure to respond to treatment with human FVIII. To compare the pharmacokinetics and safety of a single dose of OBI-1 with Hyate:C in subjects with haemophilia A and inhibitors, subjects were randomized to receive either Hyate:C followed by placebo or placebo followed by OBI-1 in a double-blind fashion. FVIII levels were assayed using both a one-stage coagulation assay (OSCA) and chromogenic assay. Pharmacokinetic parameters for FVIII were calculated for 6/9 subjects randomized; in three subjects baseline anti-porcine FVIII inhibitors led to a lack of measurable FVIII activity. Mean C(max) appeared higher for OBI-1 (OSCA: 176.00 U dL(-1), standard deviation ± 88.00; chromogenic: 151.00 ± 31.51 U dL(-1)) than Hyate:C (OSCA: 82.3 ± 19.22 U dL(-1); chromogenic: 52.67 ± 13.8 U dL(-1)). Mean AUC also appeared higher for OBI-1 (OSCA: 2082.87 ± 1323.43 U h(-1) dL(-1) ; chromogenic: 1817.28 ± 625.14 U h(-1) dL(-1)) than Hyate:C (OSCA: 1177.8 ± 469.49 U h(-1) dL(-1); chromogenic: 707.61 ± 420.05 U h(-1) dL(-1)). Two infusion-related events occurred: one with Hyate:C, one with placebo. Four of five subjects without anti-porcine FVIII inhibitors at baseline remained porcine FVIII inhibitor negative 29 days after infusion. A single dose of OBI-1 appears to have higher bioavailability than Hyate:C in subjects with haemophilia A without measurable anti-porcine FVIII inhibitors, and is well tolerated. These results should be confirmed in a larger phase 2/3 study.

Factors associated with failure to correct the international normalised ratio following fresh frozen plasma administration among patients treated for warfarin-related major bleeding. An analysis of electronic health records.

This study assessed the frequency and factors associated with failure to correct international normalised ratio (INR) in patients administered fresh frozen plasma (FFP) for warfarin-related major bleeding. This retrospective database analysis used electronic health records from an integrated health system. Patients who received FFP between 01/01/2004 and 01/31/2010, and who met the following criteria were selected: major haemorrhage diagnosis the day before to the day after initial FFP administration; INR ≥2 on the day before or the day of FFP and another INR result available; warfarin prescription within 90 days. INR correction (defined as INR ≤1.3) was evaluated at the last available test up to one day following FFP. A total of 414 patients met selection criteria (mean age 75 years, 53% male, mean Charlson score 2.5). Patients presented with gastrointestinal bleeding (58%), intracranial haemorrhage (38%) and other bleed types (4%). The INR of 67% of patients remained uncorrected at the last available test up to one day following receipt of FFP. In logistic regression analysis, the INR of patients who were older, those with a Charlson score of 4 or greater, and those with non-ICH bleeds (odds ratio vs. intracranial bleeding 0.48; 95% confidence interval 0.31-0.76) were more likely to remain uncorrected within one day following FFP administration. In an alternative definition of correction, (INR ≤1.5), 39% of patients' INRs remained uncorrected. For a substantial proportion of patients, the INRs remain inadequately or uncorrected following FFP administration, with estimates varying depending on the INR threshold used.

Failure to correct International Normalized Ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records.

BACKGROUND: Delayed correction of blood clotting times as measured by the International Normalized Ratio (INR) is associated with adverse outcomes among certain patients with warfarin-related major bleeding. However, there are limited data on the association between INR correction and mortality. OBJECTIVE: To assess factors associated with 30-day mortality and time to death in patients receiving fresh frozen plasma (FFP) for warfarin-associated major bleeding. METHODS: A retrospective database analysis was undertaken with electronic health record data from a large integrated health system. Patients met the following criteria: major hemorrhage diagnosis; INR ≥ 2 on the day before or day of receipt of FFP; and prescription fill for warfarin within 90 days. INR correction (defined as INR ≤ 1.3) was evaluated at the last available test 1 day following the start of FFP administration. Kaplan-Meier curves and Cox proportional hazards models were constructed to assess mortality. RESULTS: Four hundred and five patients met the selection criteria (mean age of 75 years, 54% male), and 67% remained uncorrected at 1 day following the start of FFP administration. Among all patients, 11% died within 30 days of hospital admission. An uncorrected INR was not associated with a higher risk of 30-day mortality for patients overall, but was statistically significant for the subgroup with intracranial hemorrhage (ICH) (adjusted odds ratio 2.55; 95% confidence interval 1.04-6.28). CONCLUSIONS: Among the subgroup of major bleeding patients with warfarin-associated ICH, those not correcting to either INR ≤ 1.3 or INR ≤ 1.5 with the use of FFP have an increased rate of mortality at 30 days.

The association between cytomegalovirus immune globulin and long-term recipient and graft survival following liver transplantation.

The association between cytomegalovirus (CMV) immune globulin (CMVIG) and long-term clinical outcomes has not been well defined. We examined the association between CMVIG and long-term recipient and graft survival in liver transplant recipients. Data were from the Scientific Registry of Transplant Recipients and included recipients transplanted between January 1995 and October 2008; follow-up was through March 2009. All recipients≤80 years of age with primary, single-organ liver transplants, given CMVIG with (n=2350) or without antivirals (n=455), antivirals without CMVIG (n = 32,939), or no CMV prophylaxis (n=28,508) before discharge were included. Kaplan-Meier analysis was used to examine rates of acute rejection (AR), graft loss, and death, over 7 years post transplantation. The adjusted risk of AR, graft loss, and death associated with CMVIG with and without antivirals vs. no prophylaxis was estimated using the Cox proportional hazards regression. In the univariate analysis, CMVIG, with and without antivirals, was associated with increased AR rates, but decreased mortality; CMVIG with antivirals was also associated with decreased graft loss compared with no prophylaxis. From the multivariable model, CMVIG with antivirals was associated with increased risk for AR, but decreased risk for graft loss and death; after adjustment, the association between CMVIG alone and mortality was not significant. CMVIG with antivirals is associated with increased risk of AR but greater long-term patient and graft survival after liver transplantation.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Presurgical pharmacokinetic analysis of a von Willebrand factor/factor VIII (VWF/FVIII) concentrate in patients with von Willebrand's disease (VWD) has limited value in dosing for surgery.

Optimal doses of von Willebrand Factor/Factor VIII (VWF/FVIII) concentrates for surgical procedures in patients with VWD need to be determined. A prospective, multicenter study was performed that included an initial pharmacokinetic (PK) assessment following a standard dose of VWF/FVIII concentrate (Humate-P®) to determine individual PK parameters and guide therapeutic dosing during surgery. Forty one subjects received 60 IU kg⁻¹ VWF: RCo. Median plasma levels, half-life, mean change from baseline and in vivo recovery (IVR) values were determined for VWF:RCo, VWF:Ag, and FVIII: C, and area under the plasma time-concentration curve (AUC), mean residence time (MRT), clearance, volume of distribution and dose linearity were also assessed for VWF:RCo at various time points. Median baseline VWF:RCo level was 13 IU dL⁻¹ (range, 6-124); with a mean change from baseline >100 IU dL⁻¹ immediately after the infusion, decreasing to 10 IU dL⁻¹ at 48 h postinfusion. The group median incremental in vivo recovery (IVR) for VWF:RCo was 2.4 IU dL⁻¹ per IU kg⁻¹, for VWF:Ag 2.3 IU dL⁻¹ kg⁻¹ and for FVIII:C was 2.7 IU dL⁻¹ per IU kg⁻¹. When analysing individual recovery values on repeated infusions, a very weak correlation was observed between presurgery IVR and IVR for both VWF:RCo and FVIII, measured at various times just prior to and after the surgical procedure. Although group median values were fairly consistent among repeated IVR measurements, the intra-individual IVR values for FVIII and VWF:RCo with repeated infusions showed a large degree of variability. IVR values obtained from pharmacokinetic analyses performed in advance of anticipated surgery do not reliably predict postinfusion circulating levels of VWF:RCo or FVIII attained preoperatively or with subsequent peri-operative infusions.

Economic models in type 2 diabetes.

OBJECTIVE: To identify and critically appraise cost-effectiveness models developed to evaluate type 2 diabetes (T2D) treatments and to assess which types of treatment effects they capture. RESEARCH DESIGN AND METHODS: A systematic search was performed in MEDLINE, EMBASE, Centre for Reviews and Dissemination databases at the University of York, and Health Economic Evaluation Database for the period to September 2008. The websites of Health Technology Assessment (HTA) bodies in different countries were also screened for relevant models. For each of the identified original models, details of the structure, data in- and outputs were extracted and the overall quality of the model in terms of the combination of structure, assumptions and data inputs were appraised using published criteria. RESULTS: Seventy-eight articles and 41 HTAs reporting relevant economic evaluations were identified. There were ten models with multiple publications, and a further ten models with one associated publication. The critical review demonstrated that most had the same fundamental structure, used similar micro-simulation techniques and were based on the same key data sources. However, the process for identification of relevant data and their synthesis, and the selection of outcomes lacked transparency. The models differed according to the extent and type of interventions they evaluated and which diabetes complications and treatment-related adverse events were captured. For example, just one model incorporated changes in patient weight, despite the fact that weight gain can be a side-effect of some treatments, and weight loss a potential benefit of others. CONCLUSIONS: Whilst many economic models exist in T2D, most share common features such as the model type. Identified shortcomings are lack of transparency in data identification and evidence synthesis as well as the selection of the modelled outcomes. Future models should aim to include all relevant treatment outcomes, whether these relate to effects on underlying diabetes and its complications or to short- or long-term side effects of treatment.