Number Of Patient-years Research Articles

Fenfluramine treatment in pediatric patients with Dravet syndrome reduces seizure burden and overall healthcare costs: A retrospective and observational real-world study.

Dravet syndrome is a developmental and epileptic encephalopathy characterized by early onset epilepsy with multiple seizure types often intractable to treatment. Randomized clinical trials have demonstrated how treatment with fenfluramine significantly reduces seizure frequency in patients with Dravet syndrome. The study aims to (1) describe the efficacy and tolerability of fenfluramine in a Danish cohort of patients with Dravet syndrome; and (2) evaluate whether treatment with fenfluramine reduces epilepsy-related hospital contacts administrated by pediatricians or epilepsy-trained nurses. A retrospective registry-based cohort study at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark, enrolled 30 pediatric patients with Dravet syndrome treated with fenfluramine between 2017 and 2023. Thirty patients with Dravet syndrome (aged 3-21 years, 12 females) with a verified pathogenic SCN1A variant were included. They were treated with fenfluramine at a mean duration of 29 months with a mean maintenance dose of 0.5 mg/kg/day. The number of patient-years on treatment was 75 years. At last follow-up, 6 patients had discontinued treatment due to lack of efficacy or adverse effects. In the remaining 24 patients, generalized tonic-clonic seizures were reduced by ≥30% in 83%, by ≥50% in 67%, and by 100% in 25%. Additionally, 71% of the patients were reduced in concomitant anti-seizure medication, and 75% experienced a reduction (mean reduction at 52%, range 11%-94%) in epilepsy-related hospital contacts from baseline to the end of the treatment period. Treatment with fenfluramine effectively reduced seizure frequency and concomitant antiseizure medication in patients with Dravet syndrome. Furthermore, a decrease in epilepsy-related contacts by 80% was observed over 6 years of treatment, which may indicate cost-effective benefits. Patients with Dravet syndrome suffer from severe epileptic seizures that are difficult to treat with medication. Earlier, treatment with fenfluramine (an anti-seizure medication) has been documented to decrease the total number of seizures in patients with Dravet syndrome. This publication summarizes the experiences with fenfluramine in children with Dravet syndrome at the Danish Epilepsy Centre, Filadelfia, Dianalund, Denmark. Our publication also illustrates that treatment with fenfluramine may reduce the patients' number of yearly contacts with doctors and nurses specialized in epilepsy treatment, which may indicate cost-effectiveness.

PRS5 Direct Medical and Mortality Related Costs Among COPD Patients in the United States, 2017-2018

This study aims to provide a nationally representative estimate of the economic burden of chronic obstructive pulmonary disease (COPD) by examining direct medical costs, out-of-pocket costs, frequently used and expensive prescription drugs, and mortality costs among individuals aged >=45 years in the United States (US). Data from the Medical Expenditure Panel Survey (2017-2018) and WONDER online tool were used to estimate the direct medical costs and mortality costs associated with COPD. COPD-related costs were determined for the various service categories by: 1) using the sum of disease-specific medical expenditures (attribution) approach; and 2) calculating the incremental expenditures using a two-part regression-based statistical approach. Mortality costs were determined using the value of statistical life approach. The number of patient-years with COPD over two years in a total sample of 23,590 patient-years was 1,073. Among COPD patients, using the attributable costs approach, the mean annual COPD-related costs per patient were 2018 US $3,385.57 (Standard Error (SE): 276.33). Using the incremental expenditures approach, the mean annual COPD-related costs per patient were $3954.49 (SE: 578.47). The mean out-of-pocket costs for COPD-related expenses among COPD patients was $255.34 (SE: 26.10) per patient-year which contributed to 11.88% of the total prescription drug costs. Further, the 5 most commonly prescribed COPD-related prescription drugs were Spiriva, Symbicort, Ventolin HFA, Proair HFA, and Albuterol. Likewise, the most burdensome COPD-related prescription drugs among COPD patients were in a descending order Spiriva, Symbicort, Advair diskus, Bronchodilator combinations, and Breo ellipta. Mortality related costs associated with a COPD patient were estimated at $1,543.86 billion. This study provides updated estimates of the significant economic burden of COPD among a nationally representative sample of individuals across multiple payers in the US. Our results also quantify the significant mortality related costs of COPD as well as economic burden of comorbidly in COPD in the US.

PDB68 Maximum-Likelihood Estimation of Transition Probabilities between Fibrosis Stages in Nonalcoholic Steatohepatitis (NASH)

NASH is a disease characterized by progression of hepatic fibrosis through five stages, from F0 (no fibrosis) to F4 (compensated cirrhosis). Singh, 2015 estimated a fibrosis progression rate (FPR) between fibrosis stages as the total number of stages progressed from any starting stage divided by the total number of person years of follow up. The FPR has been used in Markov cost-effectiveness models as a proxy for transition probabilities between fibrosis stages (Tapper, 2015; ICER, 2016; ICER, 2020). Gal, 2017 presented a method to calibrate model specific transition probabilities to match detailed study data that gives a better model of disease progression than FPR. This research improves on our previous methodology by leveraging the advantages of maximum-likelihood estimation (MLE). Our model restricted transitions by at most one stage per cycle. The observed data include the number of patients for all 25 combination of initial and final F-stages, and the total number of patient years for each initial stage. The elements of the transition probability matrix were considered as model parameters implying a multinomial distribution across the final stages for each starting stage. The lengths of follow-up periods were available on an aggregated level, therefore the MLE assumed an average follow-up time from each starting stage. The MLE achieved convergence and the resulting transition probabilities were found to be consistent with the estimated FPR, and the probabilities given by our prior calibration method. MLE is recommended to estimate transition probabilities over the use of FPR or the prior calibration method. The method incorporates all available information from the data source and benefits from the favorable statistical properties of MLE. In particular, the MLE method also provides covariance between the estimated parameters that can be used in probabilistic sensitivity analysis required in cost-effectiveness models for HTA submissions.

Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia

BackgroundHomozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown.MethodsWe used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306).ResultsTwenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively.ConclusionsApproximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further.Trial registrationNCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).

Comparative pharmacoeconomic evaluation of the treatment of type 2 diabetes mellitus with insulin degludec and insulin glargine in basal-bolus insulin therapy

Background. Type 2 diabetes mellitus (T2DM) and its complications are the major causes of long-term disability, significant performance loss, and premature mortality. Poor glycemic control, diabetes-related complications, and insulin therapy are associated with a significant increase in diabetes costs. The high cost of insulin analogues restricts reimbursement of their costs in some countries. Comprehensive clinical and economic assessments of different insulin analogues are the useful tool that may help policy-makers to set priorities in medicine provision within the existing system of healthcare funding.
 Aim — to compare the clinical and economic effectiveness of insulin degludec (100 U/mL) and insulin glargine (100 U/mL) in basal-bolus therapy for T2DM.
 Material and methods. Economic evaluation was based on cost effectiveness analysis (CEA), incremental cost-effectiveness ratio (ICER), cost effectiveness modelling (using 5-year time horizon), sensitivity analysis, and economic feasibility assessment. The clinical effectiveness was evaluated based on changes in the HbA1c level, frequency of severe hypoglycemia, and number of patient-years without complications. Only direct medical costs (costs for insulin therapy and treatment of severe hypoglycemia and diabetes-related complications) were analyzed.
 Results. The mean total direct medical costs amounted to 783,789 RUR/patient for degludec (of these, the cost of insulin therapy accounted for 68%) and 730,805 RUR/patient for glargine (of these, the costs for treatment of severe hypoglycemia and diabetes complications accounted for 62.58%). Degludec has a higher efficacy (additional HbA1c reduction by 0.52%), lower rate of severe hypoglycemia, and larger number of complication-free patient-years. Incremental costs (ICER) for degludec amounted to 101,236 RUR/patient (based on a decrease in the HbA1c level) and 353,224 RUR/patient (based on an increase in the number of complication-free patient-years); these values were 14.3- and 4.1-fold lower than the threshold of willingness-to-pay, respectively. Additional analysis of costs in patients with severe hypoglycemia rates of 3 and >3 events/patient/year demonstrated that the estimated mean total costs for insulin degludec were lower by 5 and 23%, respectively, than those for insulin glargine.
 Conclusion. Our findings demonstrate the clinical and cost benefits of insulin degludec in T2DM patients, which supports its broader use in routine clinical practice for achieving the best glycemic control with minimal adverse effects.

Safety and Efficacy of Recombinant Factor XIII (FXIII) in Patients with Congenital FXIII A-Subunit Deficiency, Results from the Mentor™2 Trial

Safety and Efficacy of Recombinant Factor XIII (FXIII) in Patients with Congenital FXIII A-Subunit Deficiency, Results from the Mentor™2 Trial

OC-016 The Risk of Gastrointestinal Bleeding with Non-Vitamin K Antagonist, Oral Anticoagulant Medications. A Systematic Review and Network Meta-Analysis

Introduction The non-vitamin k antagonist (VKA) oral anticoagulants (NOAC) comprise inhibitors of thrombin and factor Xa. They are being increasingly used in patients requiring long-term anticoagulation due to non-inferiority and relative ease of use when compared to VKA and low molecular weight heparin (LMWH). Prospective randomised studies testing the efficacy of NOACs have shown a possible increased risk of gastrointestinal (GI) bleeding. To clarify the risk of GI bleeding we performed a systematic review and Bayesian network meta-analysis. Methods We followed a pre-specified and peer reviewed PRISMA extension guidelines and checklist for reporting systematic reviews and network meta-analyses. A comprehensive search of the literature was performed to identify any study, prospective or retrospective, which compared NOAC with VKA or LMWH and reported on GI bleeding. Studies on all indications for these medications were included. We did not include studies which compared against placebo or antiplatelet medication. We performed a Bayesian random effects regression model. To estimate the effect of NOAC on GI bleeding we calculated incidence rate ratios (IRR) based on the number of patient years exposed to the medication. We grouped medications together by mechanism of action; VKA, LMWH, thrombin inhibitor or factor Xa inhibitor. Pre-planned subgroup analyses were performed on; indication, population, study design, GI bleed definition and NOAC dose. Results We identified 35 studies reporting on 481, 534 patients exposed to 405, 026 patient years of anticoagulant medication. The overall GI bleeding incidence was 1.3 events per 100 patient years. We found no difference in the incidence rate of major GI bleeding when comparing NOAC medications with VKA and LMWH. This results was sustained on sensitivity analyses comparing observational and prospective trial data, the indication for anticoagulation and prophylactic versus therapeutic doses. When analysing all severities of GI bleeding, we found a statistically significant reduction when comparing Xa inhibitors with VKA (IRR 0.20, 95% CrI 0.05–0.65), and thrombin inhibitors (IRR 0.20, 95% CrI 0.05–0.67) respectively. Conclusion We have shown that there is no difference in the risk of major GI bleeding when comparing NOAC, VKA and LMWH anticoagulation medications. There is a significant reduction in all GI bleeding events with the use of factor Xa inhibitors when compared to VKA and direct thrombin inhibitors. Disclosure of Interest None Declared

Susceptibility to seizure-induced sudden death in DBA/2 mice is altered by adenosine

Sudden unexpected death in epilepsy (SUDEP) is rare but is an important public health burden due to the number of patient years lost. Respiratory dysfunction following generalized convulsive seizure is a common sequence of events in witnessed SUDEP cases. The DBA/2 mouse model of SUDEP exhibits generalized convulsive audiogenic seizures (AGSz), which result in seizure-induced respiratory arrest (S-IRA) in ∼75% of these animals, while the remaining DBA/2 mice exhibit AGSz without S-IRA. SUDEP induction may involve actions of adenosine, which is released during generalized seizures in animals and patients and is known to depress respiration. This study examined the effects of systemic administration of agents that alter the actions of adenosine on the incidence of S-IRA in DBA/2 mice. DBA/2 mice that consistently exhibited AGSz without S-IRA showed a significantly increased incidence of S-IRA following treatment with 5-iodotubercidin, which blocks adenosine metabolism. Treatment of DBA/2 mice that consistently exhibited AGSz followed by S-IRA with a non-selective adenosine antagonist, caffeine, or an A2A adenosine receptor subtype-selective antagonist (SCH 442416) significantly reduced S-IRA incidence. By contrast, an A1 adenosine receptor antagonist (DPCPX) was not effective in reducing S-IRA incidence. These findings suggest that preventative approaches for SUDEP should consider agents that reduce the actions of adenosine.

HEALTH ECONOMIC ASSESSMENT OF ANTIRHEUMATIC DRUGS IN PATIENTS WITH REUMATHOID ARTHRITIS PROGRESSED AFTER METOTREXATE

Objective. To perform health economic evaluation of several antirheumatic drugs in patients with rheumatoid arthritis (RA) progressed after DMARDs. Materials and methods. Three consequent line of rheumatoid arthritis therapy in patients progressed after methotrexate were modeled in Russian economic conditions. Markov modelling and CEA accounting for direct medical costs were used. The effectiveness criteria of RA treatment were: patient-years in remission and patient-years in low disease activity. We compared 12 different treatment regimens of second, third and fourth therapy line in patients progressed after methotrexate. Results. The health economic analysis of different RA treatment regimen after progression on methotrexate showed that evaluated regimens do not differs in terms of effectiveness and safety. At the mean time the model account for the patients compliance and showed that the maximum number of patient-years in remission can be reached with etanercept and tofacitinib treatment. Moreover, above mentioned combination in comparison to adalimumab and infliximab showed the positive budget impact. Conclusion. The choice of etanercept and tofacitinib in case of similar economics should be done accounting for individual patient features.

Evaluation and Review of Strategies to Assess Cardiovascular Risk in Clinical Trials in Patients with Type 2 Diabetes Mellitus

This article is a result of the efforts of the American Statistical Association Biopharmaceutical Section Working Group on Safety. With representatives from different institutions, this group reviewed the drugs approved by the United States Food and Drug Administration (FDA) to treat Type 2 diabetes mellitus during 2002–2014 with a focus on the cardiovascular (CV) risk assessment. The main objective of this article is to understand the impact of FDA guidance of 2008 on assessment of CV risk in antidiabetes development programs, which are summarized and displayed in chronological order. Compared to New Drug Applications (NDAs) submitted prior to the FDA 2008 guidance, the number of patient-years significantly increased for NDAs approved in the post-guidance era. To meet guidance requirements on CV risk assessment, meta-analyses and large cardiovascular outcome trials (CVOTs) have been conducted. These CVOTs provide an opportunity to assess safety signals beyond CV risk and assess the benefit/risk ratio better in diabetic patients with a high risk for CV events, but they also present challenges. The advantages and disadvantages of different CV assessment strategies are summarized in this manuscript. Finally, we raise some emerging questions and discuss future opportunities for CV risk assessment research. Supplementary materials for this article are available online.

Systematic Review and Comparison of Clinical Evidence Presented for Orphan Designated Treatments with European Medicines Agency Market Authorisation

ABSTRACT Aim: Conducting large, well-designed clinical trials for treatments indicated for orphan diseases presents certain challenges, including the low prevalence of such diseases. This study assessed the pivotal clinical evidence package presented in the European public assessment report for orphan-designated treatments with a European Medicines Agency (EMA) marketing authorisation. The evidence packages were compared in terms of the size of patient population in relation to the prevalence of the indicated orphan disease. Methods: All treatments reviewed in this study are assigned to anatomical therapeutic chemical (ATC) category ‘L’. This category was focused on because it is the largest ATC category (contains almost 50% of orphan-designated products) and includes all EMA-approved orphan oncology treatments. All treatments reviewed have been approved within the past 6 years and have been evaluated in a controlled trial using at least one survival-based clinical endpoint. Treatments were compared in terms of patient years (accumulated amount of time that patients are followed up), number of patients in the pivotal trial(s), and disease prevalence (information from Committee for Orphan Medicinal Products public summary of opinion). Results: Fourteen treatments fulfilled the inclusion criteria. Mifamurtide (Mepact®) was an outlier with 4,068 patient years; excluding mifamurtide, patient years ranged from 308 to 2,906 years (median 1,796 years). Mifamurtide was also found to have the second smallest eligible patient population (0.5/10,000 persons). The number of patients in the pivotal trial(s) ranged from 162 to 846 patients (median 485 patients); there were 678 patients in the mifamurtide pivotal trial. Conclusions: The low prevalence of orphan diseases often results in trials with low patient numbers and low patient years. The pivotal evidence package for mifamurtide (indicated for the orphan disease osteosarcoma) has both a small eligible patient population and the largest number of patient years. This study provides support for the robustness of the pivotal evidence package for mifamurtide. Disclosure: J.M. Winstone, S. Chadda and S. Ralston: PHMR Associates has received funding from Takeda to conduct the research; P. Sajosi: Peter Sajosi is an employee of Takeda.

Cumulative Radiation Dose in Patients With Hereditary Hemorrhagic Telangiectasia and Pulmonary Arteriovenous Malformations

PurposeTo determine the cumulative effective dose (CED) of radiation from medical imaging and intervention in patients with hereditary hemorrhagic telangiectasia (HHT) who have pulmonary arteriovenous malformations and to identify clinical factors associated with exposure to high levels of radiation. MethodsAll patients with at least 1 pulmonary arteriovenous malformation were identified from the dedicated patient database of a tertiary HHT referral centre. Computerized imaging and electronic patient records were systematically examined to identify all imaging studies performed from 1989-2010. The effective dose was determined for each study, and CED was calculated retrospectively. ResultsAmong 246 patients (mean age, 53 years; 62.2% women) with a total of 2065 patient-years, 3309 procedures that involved ionizing radiation were performed. CED ranged from 0.2-307.6 mSv, with a mean of 51.7 mSv. CED exceeded 100 mSv in 26 patients (11%). Interventional procedures and computed tomography (CT) were the greatest contributors, which accounted for 51% and 46% of the total CED, respectively. Factors associated with high cumulative exposure were epistaxis (odds ratio 2.7 [95% confidence interval, 1.1-6.3]; P = .02), HHT-related gastrointestinal bleeding (odds ratio 2.0 [95% confidence interval, 1.0-3.8]; P = .04) and number of patient-years (P < .0001). ConclusionsPatients with HHT are exposed to a significant cumulative radiation dose from diagnostic and therapeutic interventions. Identifiable subsets of patients are at increased risk. A proportion of patients receive doses at levels that are associated with harm. Imaging indications and doses should be optimized to reduce radiation exposure in this population.

Complications of vagal nerve stimulation for drug-resistant epilepsy: A single center longitudinal study of 143 patients

PurposeTo longitudinally study surgical and hardware complications to vagal nerve stimulation (VNS) treatment in patients with drug-resistant epilepsy. MethodsIn a longitudinal retrospective study, we analyzed surgical and hardware complications in 143 patients (81 men and 62 women) who between 1994 and 2010 underwent implantation of a VNS-device for drug-resistant epilepsy. The mean follow-up time was 62±46 months and the total number of patient years 738. Results251 procedures were performed on 143 patients. 16.8% of the patients were afflicted by complications related to surgery and 16.8% suffered from hardware malfunctions. Surgical complications were: superficial infection in 3.5%, deep infection needing explantation in 3.5%, vocal cord palsy in 5.6%, which persisted in at least 0.7% for over one year, and other complications in 5.6%. Hardware-related complications were: lead fracture in 11.9% of patients, disconnection in 2.8%, spontaneous turn-off in 1.4% and stimulator malfunction in 1.4%. We noted a tendency to different survival times between the two most commonly used lead models as well as a tendency to increased infection rate with increasing number of stimulator replacements. ConclusionIn this series we report on surgical and hardware complications from our 16 years of experience with VNS treatment. Infection following insertion of the VNS device and vocal cord palsy due to damage to the vagus nerve are the most serious complications related to the surgery. Avoiding unnecessary reoperations in order to reduce the appearances of these complications are of great importance. It is therefore essential to minimize technical malfunctions that will lead to additional surgery. Further studies are needed to evaluate the possible superiority of the modified leads.

Effective and sustainable biologic treatment of psoriasis: what can we learn from new clinical data?

The introduction of the biologic agents, adalimumab, etanercept, infliximab and ustekinumab, has provided more options for the short- and long-term treatment of patients with psoriasis. Physicians are now able to achieve and maintain effective disease control in more patients using biologic therapies. Newly published clinical data support the introduction of novel optimization strategies to further improve outcomes in patients with psoriasis. Recent randomized controlled clinical trials have provided data on the efficacy of conventional therapies, including systemic agents, and biologics at specific time points. Switching from methotrexate to a tumour necrosis factor (TNF)-α antagonist after 16 weeks can improve response rates, as demonstrated in a study of patients with moderate-to-severe psoriasis, while the benefit of long-term methotrexate use remains unclear. In a separate study, psoriasis area and severity index (PASI) ≥ 75 response rates were maintained over time (>3 years for adalimumab), suggesting that long-term biologic therapy is an effective and sustainable treatment option for psoriasis. For each individual patient, the benefit of a particular treatment needs to be balanced with the risks. The lack of head-to-head trials of antipsoriatic therapies, particularly biologic therapies, does not help with making individualized treatment decisions. However, a benefit-risk assessment of TNF-α antagonists calculated from an integrated analysis of published literature in moderate-to-severe psoriasis can be used to aid clinical practice. The number needed to treat, number needed to harm and number of patient years of observation to detect an adverse event have been determined for adalimumab, etanercept and infliximab. The benefit-risk profiles generated demonstrated that, during the initial year of treatment, likelihood of success with TNF-α antagonists was several orders of magnitude greater than the likelihood of serious toxicity.

Prevalence of inflammatory bowel disease related dysplasia and cancer in 1500 colonoscopies from a referral center in northwestern Greece

Background and aim To report on the prevalence of inflammatory bowel disease (IBD) related intestinal dysplasia and cancer in northwestern Greece. Patients and methods Single referral center retrospective study. The policy among all gastroenterologists of the area regarding medical treatment, patient follow up and bowel surveillance strategies including risk factors is the same. Results We analyzed 1494 colonoscopies from 696 consecutive IBD patients (494 UC). The follow up time [median , IQR] was 16 [8–23] years and the age at diagnosis was 28 [21–49] years. The number of patient years at risk was 16.219. Disease location for UC was: pancolitis 761 (59%), left sided colitis 455 (35%), and proctitis 69 (6%). Disease location for CD was: colitis 142 (66%), ilieitis 45 (22%) and ileocolitis 21 (10%). Disease activity was in remission in 1240 (83%) of them. In total, 498 (72%) patients were on mesalazine, 169(24%) on immunosuppression and 29 (4%) on biologicals. Biopsies were taken randomly in 1429 (96%) endoscopies and were targeted in 65 (4%) of them. We recorded 69 (9.4%) cases with dysplasia and 10 (1.4%) cases with intestinal cancer (9 in UC). No difference was found for dysplasia and cancer in patients who followed up for 10–20 years or for more than 20 years. Conclusions The prevalence of dysplasia and cancer is increased in UC compared to CD but the prevalence of high-grade dysplasia is comparatively low. Intestinal cancer prevalence is increasing after the first decade and then practically remains stable.

Newer Biological Agents in the Treatment of Rheumatoid Arthritis

Recently, three new biological agents, rituximab, abatacept and tocilizumab, have become available for the treatment of rheumatoid arthritis (RA) in patients with active disease, who have not responded to at least one disease-modifying antirheumatic drug (DMARD). Rituximab is an anti-CD20 monoclonal antibody, abatacept modulates T-cell activation and tocilizumab is an interleukin-6 receptor antagonist. Clinical studies with these agents have demonstrated that they are effective in RA patients with moderate to active disease, who have not responded to treatment with at least one DMARD and/or tumour necrosis factor (TNF) inhibitor. Thus far, there is no convincing evidence to show that one of these three new drugs has a superior efficacy over the others or that they have other benefits compared with the TNF inhibitors. The use of rituximab, instead of another TNF inhibitor, might be an option in patients who have not responded to TNF blockade. Abatacept could also be considered, but this has not yet been formally tested. A practical advantage of tocilizumab is that it may be administered as a first-line biological agent. Adverse events, including (usually mild) infusion reactions, are common. There is a small increased risk of serious infections that appears to be similar to that with TNF inhibitors, although each drug may have its own particular risk profile. Thus far, there is no convincing evidence that the new biological agents are associated with an increased risk of malignancies. However, the number of patient-years studied is still rather limited and, hence, continuous postmarketing surveillance is necessary. Adequate studies directly comparing new biological agents with each other and with other biological agents, such as TNF inhibitors, are not available. Hence, no firm conclusions regarding the benefit-risk profile of these agents versus each other can be reached. However, the benefit for a given new biological agent currently appears to outweigh the risk for an individual RA patient with active disease, despite earlier drug treatment.

Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study

To determine the prevalence of corrected QT interval (QTc) prolongation among patients in opioid maintenance treatment (OMT) and to investigate mortality potentially attributable to QTc prolongation in the Norwegian OMT programme. Two hundred OMT patients in Oslo were recruited to the QTc assessment study between October 2006 and August 2007. The Norwegian register of all patients receiving OMT in Norway (January 1997-December 2003) and the national death certificate register were used to assess mortality. Mortality records were examined for the 90 deaths that had occurred among 2382 patients with 6450 total years in OMT. The QTc interval was assessed by electrocardiography (ECG). All ECGs were examined by the same cardiologist, who was blind to patient history and medication. Mortality was calculated by cross-matching the OMT register and the national death certificate register: deaths that were possibly attributable to QTc prolongation were divided by the number of patient-years in OMT. In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% (n = 8) had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine (n = 27) had QTc results <450 milliseconds. A positive dose-dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. OMT patient mortality, where QTc prolongation could not be excluded as the cause of death, was 0.06/100 patient-years. Only one death among 3850 OMT initiations occurred within the first month of treatment. Of the methadone patients, 4.6% had QTc intervals above 500 milliseconds. The maximum mortality attributable to QTc prolongation was low: 0.06 per 100 patient-years.

Unit Characteristics and Patient Satisfaction

The purpose of this study was to discover if there was relationship between nurse perception of autonomy, control over practice, or relationships with physicians and patient satisfaction with care related to pain management, teaching, or physical care on medical surgical units. The study design was correlational, descriptive, and cross-sectional. The hospital sample was a purposive convenience sample of acute care hospitals in California, with a total of 21 hospitals, 60 medical surgical nursing units, 314 nurses, and 470 patients. Findings indicated that higher patient functional status and having a doctor in the hospital 24 hours/day were related to patient satisfaction with pain management. Lower nurse perception of autonomy, having a doctor in the hospital 24 hours/day, and higher number of patient years of education were related to higher patient satisfaction with teaching. Lower total hours worked by the nurses was related to higher patient satisfaction with physical care.

Hepatocellular Necrosis Associated With Labetalol

Hepatocellular Necrosis Associated With Labetalol

Subtotal obliteration of cerebral arteriovenous malformations after Gamma Knife surgery

Subtotal obliteration of cerebral arteriovenous malformations (AVMs) after Gamma Knife surgery (GKS) implies a complete angiographic disappearance of the AVM nidus but persistence of an early filling draining vein, indicating that residual shunting is still present; hence, per definition there is still a patent AVM and the risk of bleeding is not eliminated. The aim of this study was to determine the risk of hemorrhage for patients with subtotal obliteration of AVMs. After GKS for cerebral AVMs, follow-up angiography demonstrated a subtotally obliterated lesion in 159 patients. Of these, in 16 patients a subtotally obliterated AVM developed after a second GKS was performed for the partially obliterated lesion. The mean age of these patients was 35.2 years at the time of the diagnosis of subtotally obliterated AVMs. The lesion volumes at the time of initial GKS treatment ranged from 0.1 to 11.5 cm3 (mean 2.5 cm3). The mean peripheral dose used in the 175 GKS treatments was 22.5 Gy (median 23 Gy, range 15-31 Gy). To achieve total obliteration of the AVM, 23 patients underwent a new GKS targeting the proximal end of the early filling vein. The mean peripheral dose given in these cases was 23 Gy (median 24, range 18-25 Gy). The incidence of subtotally obliterated AVMs was 7.6% from a total of 2093 AVMs treated and in which follow-up imaging was available. The diagnosis of subtotally obliterated AVMs was made a mean of 29.4 months (range 4-178 months) after GKS. The number of patient-years at risk (from the time of the diagnosis of subtotally obliterated AVMs until either the confirmation of a total obliteration of the lesion on angiography or the time of the latest follow-up angiographic study that still visualized the early filling vein) was a mean of 3.9 years, ranging from 0.5 to 13.5 years, and a total of 601 patient-years. There was no case of bleeding after the diagnosis of subtotally obliterated AVMs. Of 90 patients who did not undergo further treatment and in whom follow-up angiography studies were available, the same early filling veins still filled in 24 (26.7%), and the subtotally obliterated AVMs were subsequently obliterated in 66 patients (73.3%). In 19 patients who underwent repeated GKS for subtotally obliterated AVMs and in whom follow-up angiography studies were available, the AVMs were obliterated in 15 (78.9%) and remained patent in four (21.1%). The fact that none of the patients with subtotally obliterated AVMs suffered a rupture is not compatible with the assumption of an unchanged risk of hemorrhage for these lesions, and implies that the protection from rebleeding in patients with subtotal obliteration is significant. Subtotal obliteration does not necessarily seem to be a stage of an ongoing obliteration. At least in some cases it represents an end point of this process, with no subsequent obliteration occurring. This observation requires further confirmation by open-ended follow-up imaging.