Cost-utility evaluation of vortioxetine in patients with Major Depressive Disorder experiencing inadequate response to alternative antidepressants in the United Kingdom.

BACKGROUND: Patients frequently require several lines of therapy for treatment of major depressive episodes. This economic analysis details the management of patients who responded inadequately due to lack of efficacy or intolerability to two previous antidepressants in the UK. METHODS: The model included a decision tree and a Markov component. Health states considered in the decision tree were remission, response, no response, withdrawal due to adverse events, relapse, recovery, and recurrence. The time horizon was 24 months. Patients were on third-line treatment for up to a 3-month acute phase and a 6-month maintenance phase. As third-line efficacy data were not available, inputs were calculated by adjusting original second-line data to third-line based on proportionate reductions observed in STAR*D. Equivalent efficacy was assumed for all comparators. Healthcare resource use and utilities were based on UK estimates. RESULTS: Vortioxetine was a cost-effective treatment option at a threshold of £20,000/QALY vs. escitalopram, citalopram, sertraline, and was associated with more health benefits, less costs (was dominant) versus relevant third-line comparators venlafaxine and duloxetine. Agomelatine was found not to be a cost-effective option. The 22-month maintenance phase treatment scenario results were similar to the 6-month base case. LIMITATIONS: Third-line efficacy data were not available. This highlights the need for studies in patients receiving third-line treatment. CONCLUSION: This model provides an overview for the management of patients receiving third-line treatment where limited evidence currently exists. Vortioxetine, with its novel mechanism of action, is expected to be a dominant treatment option versus relevant comparators in the UK.

Cost-effectiveness of sofosbuvir for the treatment of chronic hepatitis C-infected patients.

The efficacy of treatment for hepatitis C genotype 1 infection has significantly improved with the introduction of first-generation protease inhibitors. However, there remains a need for effective treatments for patients infected with other genotypes, for nonresponders and patients unsuitable for interferon. Sofosbuvir is the first nucleotide polymerase inhibitor with pan-genotypic activity. Sofosbuvir-based regimens have resulted in >90% sustained virological response across treatment-naïve genotype 1-6 patients in five phase III clinical trials of sofosbuvir administered with ribavirin or pegylated interferon and ribavirin. This analysis evaluates the cost-effectiveness of sofosbuvir within the current licensed indication, for genotype 1-6 in the UK. A Markov model followed a cohort of 10 000 patients over lifetime, with approximately 20% initiating treatment for compensated cirrhosis. Sofosbuvir-regimens were compared to telaprevir, boceprevir, pegylated interferon and ribavirin, or no treatment. Costs and outcomes were discounted at 3.5%. The cost perspective utilized costs applicable to the National Health Service in the UK. Sofosbuvir proved to be cost-effective in most patient populations with incremental cost-effectiveness ratios (ICERs) at £11 836/QALY and £7292/QALY against telaprevir and boceprevir, respectively. In genotype 3, sofosbuvir had a weighted ICER of £18 761/QALY. Sofosbuvir-based regimens are a cost-effective option for the majority of hepatitis C-infected patients in the United Kingdom although the incremental cost-effectiveness varies by genotype and regimen. Sofosbuvir and ribavirin is an alternative regimen for patients unsuitable for interferon.

Patients' preferences and health utility assessment with SF-6D and EQ-5D in patients with chronic hepatitis C treated with sofosbuvir regimens.

BACKGROUND: Health utilities measure patients' preferences for a health state. AIM: To assess health utilities for sofosbuvir-containing therapy for chronic hepatitis C. METHODS: The SF-6D utility scores were derived from the SF-36 instrument administered at baseline, during and post-treatment to participants of the previously reported clinical trials of sofosbuvir. EQ-5D utility scores were also approximated from the SF-36 using a regression model. RESULTS: Nine hundred and ninety-four patients were enrolled. Baseline SF-6D and EQ-5D scores were 0.66 ± 0.13 and 0.71 ± 0.22, respectively (the POSITRON trial), 0.71 ± 0.16 and 0.76 ± 0.23 (FISSION), 0.70 ± 0.14 and 0.75 ± 0.22 (FUSION), 0.72 ± 0.15 and 0.79 ± 0.22 (NEUTRINO). In all studies, SF-6D and EQ-5D scores were highly correlated with each other. (r = 0.83-0.87, P < 0.0001). After 12 weeks, patients receiving sofosbuvir + ribavirin (POSITRON) had similar utility scores to placebo (P > 0.05). Patients receiving 12 and 16 weeks of sofosbuvir + ribavirin (FUSION) had similar utility scores (P > 0.05). In FISSION, patients receiving sofosbuvir + ribavirin had significantly better utilities compared to patients receiving interferon + ribavirin (P < 0.001). Patients receiving sofosbuvir + ribavirin + interferon (NEUTRINO) had a decrease in utilities during treatment (SF-6D: from 0.72 to 0.62, EQ-5D: 0.79 to 0.65; P < 0.0001) similar to that observed in patients receiving pegylated interferon + ribavirin for 24 weeks in FISSION (0.72 to 0.62 and 0.77 to 0.65, respectively, P < 0.0001). After 12 weeks post-treatment, patients with SVR (FUSION) had improvement in SF-6D (+0.026 from baseline, P = 0.013) and EQ-5D (+0.043, P = 0.013). In multivariate analyses, baseline depression, anxiety, fatigue, insomnia and treatment-related anaemia were the most consistent predictors of utilities. CONCLUSIONS: Patients' health utilities are minimally impacted by sofosbuvir + ribavirin treatment, as compared to interferon-based, therapy regardless of treatment duration. Clinical trials' numbers: NCT01542788 (POSITRON), NCT01497366 (FISSION), NCT01604850 (FUSION), NCT01641640 (NEUTRINO).

Cost of skeletal-related events in European patients with solid tumours and bone metastases: data from a prospective multinational observational study.

OBJECTIVES: Patients with bone metastases often experience skeletal-related events (SREs: radiation or surgery to bone, pathologic fracture, and spinal cord compression). This study examined health resource utilization and costs associated with SREs. METHODS: Data presented are from the European cohort (Germany, Italy, Spain, and the UK) of patients with solid tumours enrolled in a multi-national, prospective, observational study in patients with solid tumours or multiple myeloma. Patients with Eastern Cooperative Oncology Group score 0-2 and life expectancy ≥6 months, who experienced an SRE up to 97 days before enrolment, were eligible. Health resource utilization associated with SREs (including number/length of inpatient stays, numbers of procedures and outpatient visits) were collected through chart review for up to 97 days before enrolment and prospectively during follow-up. Country-specific cost calculations were performed. RESULTS: In total, 478 eligible patients contributed 893 SREs to this analysis. Radiation to bone occurred most frequently (66% of total). Spinal cord compression (7%) and surgery to bone (10%) were the least common events, but most likely to require inpatient stays. The most costly SREs were also spinal cord compression (mean per SRE across countries, €4884-€12,082) and surgery to bone (€3348-€9407). Inpatient stays were the main cost drivers. LIMITATIONS: Health resource utilization used to calculate the costs associated with SREs may have been under-estimated as a result of exclusion of patients with low performance status or life expectancy; unavailable information and exclusion of resource consumption associated with pain. Thus, the estimate of associated costs is likely to be conservative. CONCLUSIONS: SREs result in considerable health resource utilization, imposing a substantial financial burden driven by inpatient stays. Treatments that prevent/delay SREs may help ease this burden, thereby providing cost savings across European healthcare systems.

Efficacy of telaprevir and boceprevir in treatment-naïve and treatment-experienced genotype 1 chronic hepatitis C patients: an indirect comparison using Bayesian network meta-analysis.

BACKGROUND AND AIMS: To indirectly compare the efficacy of telaprevir (TVR) and boceprevir (BOC) combined with peginterferon/ribavirin α-2a/2b (PR) in achieving sustained viral response (SVR) in treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C virus (HCV) infection. METHODS: A systematic literature review was conducted to identify randomized controlled trials reporting the efficacy of PR-based treatment in genotype 1 chronic HCV patients. A Bayesian network meta-analysis was performed on the endpoint of SVR, assuming fixed study effects. For treatment-experienced patients, only previous relapsers and partial responders were included, as no results in prior null responders were available for boceprevir. RESULTS: Eleven publications were included. In treatment-naïve patients, the odds ratios (OR) (posterior median [95% credible interval]) for telaprevir (12 weeks + response guided treatment [RGT] 24/48 weeks PR) and boceprevir (24 weeks + RGT 28/48 weeks PR) versus PR were respectively 3.80 (2.78-5.22) and 2.99 (2.23-4.01). The OR for telaprevir versus boceprevir was 1.42 (0.89-2.25), with a probability for telaprevir being more effective (P[OR > 1]) of 0.93. In treatment-experienced patients, the OR of telaprevir (12 weeks + 48 weeks PR) and boceprevir (32 weeks + RGT 36/48 weeks PR) versus PR were respectively 13.11 (7.30-24.43) and 5.36 (2.90-10.30). The OR for telaprevir versus boceprevir was 2.45 (1.02-5.80), with telaprevir having a probability of 0.98 of being more effective. LIMITATIONS: The main limitation of this study is the low number of trials included in the analysis, especially for the treatment-experienced patient population, which only allowed random-effect models to be explored. We tried to identify potential biases due to study heterogeneity. CONCLUSIONS: In the absence of direct comparative head-to-head studies between telaprevir and boceprevir for the treatment of chronic HCV genotype 1 patients, an indirect comparison based on Bayesian network meta-analysis suggests better efficacy for telaprevir than boceprevir in both treatment-naïve and treatment-experienced patients.

A retrospective database study comparing treatment outcomes and cost associated with choice of fixed-dose inhaled corticosteroid/long-acting beta-agonists for asthma maintenance treatment in Germany.

AIMS: This retrospective, observational cohort study aimed to compare treatment outcomes and healthcare costs in the year after initiation of maintenance treatment with budesonide/formoterol or salmeterol/fluticasone in a German healthcare setting. METHODS: Data on German asthma patients initiating treatment with budesonide/formoterol or salmeterol/fluticasone between June 2001 and June 2005 were obtained from the IMS Disease Analyzer database. The primary outcome was the probability of treatment success, defined according to short-acting beta(2)-agonist prescriptions and switches or addition of controller medications, during the postindex year. A secondary definition of treatment success included hospitalisations and oral corticosteroid (OCS) prescriptions. Secondary outcomes included severe asthma exacerbations, defined as >or=1 OCS prescription, asthma-related hospitalisation and/or referral. The effect of treatment on costs was estimated using generalised linear models, adjusting for patient and physician characteristics. RESULTS: There were no significant differences between the budesonide/formoterol (n = 1456) and salmeterol/fluticasone (n = 982) groups in disease severity markers in the pre-index year. Patients on budesonide/formoterol had a 44% greater probability of treatment success [odds ratio (OR): 1.44; p = 0.0003] according to the primary definition and a 26% greater probability (OR: 1.26; p = 0.0119) according to the secondary definition, fewer severe exacerbations (-33.4%; p = 0.0123) and fewer OCS prescriptions (-31.5%; p = 0.0082) compared with salmeterol/fluticasone, after controlling for baseline characteristics. Adjusting for covariates, budesonide/formoterol had a significant inverse relationship on asthma-related costs compared with salmeterol/fluticasone (-13.4%; p < 0.001). Total cost (asthma- and non-asthma-related costs) was 12.6% lower for budesonide/formoterol (p < 0.0001). CONCLUSION: This study suggests that for patients with chronic asthma in Germany, budesonide/formoterol rather than salmeterol/fluticasone had a higher likelihood of treatment success, and that budesonide/formoterol is the less costly option. Although the cohorts appeared to be well matched at baseline, the results should be interpreted with caution given the observational nature of the study.

L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disease with an autosomal recessive mode of inheritance. It was first reported in 1980. Patients with this disease have mutations in both alleles of the L2HDGH gene. The clinical presentation of individuals with L-2-HGA is somewhat variable, but affected individuals typically suffer from progressive neurodegeneration. Analysis of urinary organic acids reveals an increased signal of 2-hydroxyglutaric acid, mainly as the L-enantiomer. L-2-HGA is known to occur in individuals of various ethnic backgrounds, but up to now mutation analysis has been mainly focused on patients of Turkish and Portuguese origin. This led us to confirm the diagnosis on the DNA level and undertake the corresponding mutation analysis in individuals of diverse ethnicity previously diagnosed with L-2-HGA on the basis of urinary metabolites and clinical/neuroimaging data. In 24 individuals from 17 families with diverse ethnic and geographic origins, 13 different mutations were found, 10 of which have not been reported previously. At least eight of the patients were compound heterozygotes. The identification of two mutations (c.751C > T and c.905C > T in exon 7) in patients with different origins supports the view that they occurred independently in different families. In contrast, the mutation c.788C > T was detected in all six Venezuelan patients originating from the same Caribbean island of Margarita, but not in other patients, thus rendering a founder effect likely. None of the mutations was found in the control population, indicating that they are most probably causative. Mutation analysis may improve the quality of diagnosis and prenatal diagnosis of L-2-HGA.

Droperidol for acute psychosis.

BACKGROUND: People suffering from acute psychotic illnesses, especially those associated with agitated or violent behaviour, may require urgent pharmacological tranquillisation or sedation. Droperidol, a butyrophenone neuroleptic, has been used for this purpose in several countries. OBJECTIVES: To estimate the effects of droperidol compared to other treatments for controlling disturbed behaviour and reducing psychotic symptoms for people with suspected acute psychotic illnesses. SEARCH STRATEGY: We updated previous searches by searching the Cochrane Schizophrenia Group Register (September 2003). References of all identified studies were searched for further trial citations and authors of trials were contacted. Twenty-one other databases were also searched as part of a broader project and this composite database was searched for this review. This was supplemented by hand searching reference lists and contacting both the pharmacological industry and relevant authors. SELECTION CRITERIA: The review included randomised controlled trials comparing droperidol to any other treatment for people with suspected acute psychotic illnesses, including schizophrenia, schizoaffective disorder, mixed affective disorders, the manic phase of bipolar disorder or a brief psychotic episode. DATA COLLECTION AND ANALYSIS: Relevant studies were selected for inclusion, their quality was assessed and data extracted. Data were excluded when more than 50% of participants were lost to follow up. For binary outcomes, standard estimates of risk ratio (RR) and the corresponding 95% confidence intervals (CI) were calculated. Where possible, weighted number needed to treat or harm statistics (NNT, NNH), and the corresponding 95% confidence intervals (CI), were calculated. MAIN RESULTS: We identified only two relevant trials. One additional study focused on outcomes at 30 days rather than at a few hours. One small (n = 41) randomised trial compared intravenous (iv) droperidol (10 mg) with iv placebo and found that people allocated to droperidol were significantly less likely to need additional injections of another drug, haloperidol, in the first few minutes (n = 41, RR 0.37 CI 0.2 to 0.7, NNT 2 CI 1 to 10) compared to those given placebo. By 90 minutes this difference was still evident but not statistically significant (RR 0.46 CI 0.2 to 1.2). When 5 mg intramuscular (im) droperidol was compared with 5 mg im haloperidol, those given droperidol were also less likely to need additional injections by 30 minutes, than those given haloperidol, but this result was not statistically significant (n = 27, RR 0.45 CI 0.2 to 1.01). One person out of the 16 given haloperidol experienced a mild dystonic reaction (muscle spasms or abnormal contractions), while none of the 11 people allocated to droperidol were reported to have experienced adverse effects. REVIEWERS' CONCLUSIONS: This is an important, and surprisingly under-researched, area. To date, use of droperidol for emergency situations has been justified by experience rather than evidence from well conducted and reported randomised trials, but, as world reserves diminish, droperidol will no longer be a treatment option.

Droperidol for acute psychosis.

BACKGROUND: People with acute psychotic illnesses, especially when associated with agitated or violent behaviour, may require urgent pharmacological tranquillisation or sedation. Droperidol, a butyrophenone neuroleptic, is used for this purpose in several countries. OBJECTIVES: To estimate the effects of droperidol when compared to other treatments for controlling disturbed behaviour and reducing psychotic symptoms for people with suspected acute psychotic illnesses. SEARCH STRATEGY: The Cochrane Controlled Trials Register (Issue 2, 2000), The Cochrane Schizophrenia Group's Register (May 2000), EMBASE (1980-2000), MEDLINE (1966-2000), PASCAL (1973-2000) and PsycLIT (1970-2000) were methodically searched. Twenty-one other databases were also searched as part of a broader project and this composite database was searched for this review. This was supplemented by hand searching reference lists, contacting industry and relevant authors. SELECTION CRITERIA: Randomised clinical trials comparing droperidol to any treatment, for people with suspected acute psychotic illnesses, such as schizophrenia, schizoaffective disorder, mixed affective disorders, manic phase of bipolar disorder or brief psychotic episode. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality assessed and data extracted. Data were excluded where more than 50% of participants were lost to follow up. For binary outcomes, standard estimations of risk ratio (RR) and their 95% confidence intervals (CI) were calculated. Where possible, weighted number needed to treat or harm statistics (NNT, NNH), and their 95% confidence intervals (CI), were also calculated. MAIN RESULTS: Only two clearly relevant randomised trials with usable data were identified. One additional study was included but focused on outcomes at 30 days rather than a few hours. One small (n=41) randomised trial compared droperidol (10mg IV) with placebo IV and found that people allocated to droperidol were significantly less likely to need additional haloperidol injections in the first few minutes (n=41, RR 0.37 CI 0.2 to 0.7, NNT 2 CI 1 to 10) than those given placebo. By 90 minutes this difference was still evident but not statistically significant (RR 0.46 CI 0.2 to 1.2). When 5mg IM droperidol was compared to 5mg IM haloperidol people given droperidol were again less likely to need additional injections by 30 minutes, than those given haloperidol, but this result did not quite reach conventional levels of statistical significance (n=27, RR 0.45 CI 0.2 to 1.01). One person out of 16 given haloperidol experienced a mild dystonic reaction, and none of the 11 people allocated to droperidol were reported to have experienced adverse effects. REVIEWER'S CONCLUSIONS: This is an important and surprisingly under-researched area. Use of droperidol for the emergency situation is currently justified on experience rather than evidence from well conducted and reported randomised trials.

Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition. Mutations in the CTSC gene that encodes cathepsin C have been described in families affected with Papillon--Lefèvre syndrome. Cathepsin C is the least understood of the lysosomal cysteine proteases; it has been reported to participate in both intracellular and extracellular cleavage of proteins and activation of serine proteases in immune and inflammatory cells. We report here eight new mutations in Papillon-Lefèvre syndrome families: four deletions and four point mutations, including a missense mutation in the propeptide chain that could help elucidate structure-function relationships in this protein. We also found that the 458C > T mutation, first reported in two families by Hart et al (2000c), was a neutral polymorphism in our families, as suggested by Allende et al (Cathepsin C gene: first compound heterozygous patient with Papillon--Lefèvre syndrome and novel symptomless mutation. Hum Mutat 17:152-153, 2001).

Clinical and genetic studies of 3 large, consanguineous, Algerian families with Mal de Meleda.

BACKGROUND: Mal de Meleda (MIM 248300), also referred to as keratosis palmoplantaris transgrediens of Siemens, is a rare autosomal recessive skin disorder with a prevalence in the general population of 1 in 100,000. The main clinical characteristics are transgressive palmoplantar keratoderma, hyperhidrosis, and perioral erythema, but there are also associated features such as brachydactyly, nail abnormalities, and lichenoid plaques. OBSERVATIONS: We studied the clinical and genetic characteristics of 3 large, consanguineous, Algerian families, including 14 affected individuals. Homozygosity mapping of the third family confirmed localization of the responsible gene to 8qter in all 3 families. CONCLUSIONS: Although some differences in phenotypic expression among subjects were noted, genetic analysis of the 3 families who shared a common ethnic background indicated that a single gene is responsible for mal de Meleda in this population.

Two new loci for autosomal recessive ichthyosis on chromosomes 3p21 and 19p12-q12 and evidence for further genetic heterogeneity.

Autosomal recessive ichthyosis (ARI) includes a heterogeneous group of disorders of keratinization characterized by desquamation over the whole body. Two forms largely limited to the skin have been defined: lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). A first gene for LI, transglutaminase TGM1, has been identified on chromosome 14, and a second one has been localized on chromosome 2. In a genomewide scan of nine large consanguineous families, using homozygosity mapping, two new loci for ARI were found, one for a lamellar form in a 6-cM interval on chromosome 19 and a second for an erythrodermic form in a 7.7-cM interval on chromosome 3. Linkage to one of the four loci could be demonstrated in more than half of 51 consanguineous families, most of them from the Mediterranean basin. All four loci could be excluded in the others, implying further genetic heterogeneity in this disorder. Multipoint linkage analysis gave maximal LOD scores of 11.25 at locus D19S566 and 8.53 at locus D3S3564.

A new citrated formulation of nalidixic acid (Mictral U.K.) for the treatment of acute cystitis.

A 3-day course of a new citrated formulation of nalidixic acid (Mictral) was assessed in fifty-four women presenting with acute uncomplicated cystitis. Over 96% of women with a significant Gram-negative bacteriuria were cured of the infection following a course of treatment. Only two relapses occurred in this group during the follow-up period. Relief of symptoms occurred in nearly 90% of infected patients and generally by the second day of treatment. Although the incidence of side-effects was about 20% they were not considered serious.