The impact of healthcare systems on the clinical diagnosis and disease-modifying treatment usage in relapse-onset multiple sclerosis: a real-world perspective in five registries across Europe.

Introduction: Prescribing guidance for disease-modifying treatment (DMT) in multiple sclerosis (MS) is centred on a clinical diagnosis of relapsing-remitting MS (RRMS). DMT prescription guidelines and monitoring vary across countries. Standardising the approach to diagnosis of disease course, for example, assigning RRMS or secondary progressive MS (SPMS) diagnoses, allows examination of the impact of health system characteristics on the stated clinical diagnosis and treatment access. Methods: We analysed registry data from six cohorts in five countries (Czech Republic, Denmark, Germany, Sweden and United Kingdom) on patients with an initial diagnosis of RRMS. We standardised our approach utilising a pre-existing algorithm (DecisionTree, DT) to determine patient diagnoses of RRMS or secondary progressive MS (SPMS). We identified five global drivers of DMT prescribing: Provision, Availability, Funding, Monitoring and Audit, data were analysed against these concepts using meta-analysis and univariate meta-regression. Results: In 64,235 patients, we found variations in DMT use between countries, with higher usage in RRMS and lower usage in SPMS, with correspondingly lower usage in the UK compared to other registers. Factors such as female gender (p = 0.041), increasing disability via Expanded Disability Status Scale (EDSS) score (p = 0.004), and the presence of monitoring (p = 0.029) in SPMS influenced the likelihood of receiving DMTs. Standardising the diagnosis revealed differences in reclassification rates from clinical RRMS to DT-SPMS, with Sweden having the lowest rate Sweden (Sweden 0.009, range: Denmark 0.103 - UK portal 0.311). Those with higher EDSS at index (p < 0.03) and female gender (p < 0.049) were more likely to be reclassified from RRMS to DT-SPMS. The study also explored the impact of diagnosis on DMT usage in clinical SPMS, finding that the prescribing environment and auditing practices affected access to treatment. Discussion: This highlights the importance of a healthcare system's approach to verifying the clinical label of MS course in facilitating appropriate prescribing, with some flexibility allowed in uncertain cases to ensure continued access to treatment.

Proportion and characteristics of secondary progressive multiple sclerosis in five European registries using objective classifiers.

Background: To assign a course of secondary progressive multiple sclerosis (MS) (SPMS) may be difficult and the proportion of persons with SPMS varies between reports. An objective method for disease course classification may give a better estimation of the relative proportions of relapsing-remitting MS (RRMS) and SPMS and may identify situations where SPMS is under reported. Materials and methods: Data were obtained for 61,900 MS patients from MS registries in the Czech Republic, Denmark, Germany, Sweden, and the United Kingdom (UK), including date of birth, sex, SP conversion year, visits with an Expanded Disability Status Scale (EDSS) score, MS onset and diagnosis date, relapses, and disease-modifying treatment (DMT) use. We included RRMS or SPMS patients with at least one visit between January 2017 and December 2019 if ≥ 18 years of age. We applied three objective methods: A set of SPMS clinical trial inclusion criteria ("EXPAND criteria") modified for a real-world evidence setting, a modified version of the MSBase algorithm, and a decision tree-based algorithm recently published. Results: The clinically assigned proportion of SPMS varied from 8.7% (Czechia) to 34.3% (UK). Objective classifiers estimated the proportion of SPMS from 15.1% (Germany by the EXPAND criteria) to 58.0% (UK by the decision tree method). Due to different requirements of number of EDSS scores, classifiers varied in the proportion they were able to classify; from 18% (UK by the MSBase algorithm) to 100% (the decision tree algorithm for all registries). Objectively classified SPMS patients were older, converted to SPMS later, had higher EDSS at index date and higher EDSS at conversion. More objectively classified SPMS were on DMTs compared to the clinically assigned. Conclusion: SPMS appears to be systematically underdiagnosed in MS registries. Reclassified patients were more commonly on DMTs.

How do patients with secondary progressive multiple sclerosis enrolled in the EXPAND randomized controlled trial compare with those seen in German clinical practice in the NeuroTransData multiple sclerosis registry?

Background: In EXPAND (NCT01665144), a phase 3 randomized clinical trial, siponimod reduced disability progression versus placebo in patients with secondary progressive multiple sclerosis (SPMS). Aim: To understand how a real-world population with SPMS relates to that in EXPAND, we conducted a retrospective, observational cohort study using the German NeuroTransData (NTD) multiple sclerosis (MS) registry. Methods: The NTD MS registry is run by a Germany-wide network of physicians. Two cross-sectional analyses were performed using the NTD MS registry. The first included patients with SPMS, as recorded in the registry, and compared their characteristics between 1 January 2018 and 31 December 2018 with patients in EXPAND. The second described the characteristics of patients in the registry at the time of diagnosis of SPMS between 1 January 2010 and 31 December 2018. Results: The first analysis included 773 patients: patients were older in the NTD MS registry than in EXPAND (mean age, 57.9 vs 48.0 years) and had a longer duration of SPMS (mean, 6.2 vs 3.8 years). In the NTD MS registry, median Expanded Disability Status Scale (EDSS) scores were comparable to EXPAND (6.0 versus 6.0), although fewer patients had relapses in the previous 24 months (16% vs 36% [siponimod] and 37% [placebo]). Data on gadolinium-enhancing lesions were only available for 5.8% of patients in the NTD MS registry. The second analysis included 916 patients: at the time of SPMS diagnosis, the mean age was 53.2 years and the median EDSS score was 5.0. Conclusion: The population in the NTD MS registry was older to that in EXPAND, but were similar in terms of disability. Differences likely reflect the inclusion criteria of EXPAND but also highlight that real-world populations encompass a wider range of patient characteristics.

Treatment patterns for retinal diseases in patients newly-treated with anti-VEGF agents: A retrospective analysis of claims data from the Japan Medical Data Center database.

PURPOSE: To describe treatment patterns in patients diagnosed with neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), or diabetic macular edema (DME), newly-treated with anti-vascular endothelial growth factor (anti-VEGF) agents as recorded in the Japanese Medical Data Center (JMDC) database. STUDY DESIGN: This non-interventional, descriptive, retrospective, observational cohort study included insured Japanese patients aged ≥ 21 and ≤ 75 years at index date (anti-VEGF treatment initiation). METHODS: Patients with minimum one claim in JMDC database with a diagnosis code for nAMD, RVO, or DME between October 2007-May 2015 and with minimum of one claim for anti-VEGF agents on or after the date of diagnosis were included. Frequency and proportion of claims submitted for anti-VEGF injections were assessed during 12 months post-index date. RESULTS: The median (interquartile range) number of claims for anti-VEGF injections during 12 months post-index date were 3 (1, 4) for nAMD (n = 255), 2 (1, 3) for RVO (n = 223) and 2 (1, 4) for DME (n = 125) patients. Frequencies of nAMD, RVO and DME patients with one or more claims for a retinal disease treatment other than an anti-VEGF agent were 4 (1.57%), 59 (26.46%) and 68 (54.40%) during the 12 months pre-index date and 21 (8.24%), 85 (38.12%) and 62 (49.60%) in the 12 months post-index date, respectively. CONCLUSIONS: The median number of anti-VEGF injections per patient was lower than those reported in clinical trials. Although various pre- and concomitant treatments were used in RVO and DME, anti-VEGF monotherapy was the first-line treatment in > 90% of nAMD patients.

SIERRA-AMD: A Retrospective, Real-World Evidence Study of Patients with Neovascular Age-Related Macular Degeneration in the United States.

PURPOSE: Characterize real-world baseline visual acuity (VA) and anti-vascular endothelial growth factor (VEGF) treatment patterns in neovascular age-related macular degeneration patients in 2012-2015. DESIGN: Retrospective, multicenter, noninterventional real-world evidence study. PARTICIPANTS: A total of 98 821 eyes from 79 885 patients receiving intravitreal anti-VEGF therapy. METHODS: Anonymized patient data routinely collected over 5 years were extracted from 58 United States centers to a central database using an electronic medical records system. MAIN OUTCOME MEASURES: Baseline VA, VA change from baseline, treatment frequencies, annual anti-VEGF injections, bilateral treatment frequencies, annual total clinic visits, and noninjection clinic visits. RESULTS: Baseline characteristics were comparable across years. Baseline VAs (Mean±standard deviation [SD] Early Treatment Diabetic Retinopathy Study [ETDRS] letters) were similar for 2012, 2013, and 2014 (53.6±23.3, 53.2±23.4, and 53.1±23.6, respectively), but was lower for 2015 (50.7±24.4). In eyes with 4-year follow-up, VA changes from baseline (ETDRS letters) were least squares means of +1.1 (95% confidence interval [CI], 1.0;1.3), -1.3 (95%CI, -1.5;-1.0), and -3.1 (95%CI, -3.5;-2.7), and -5.2 (95%CI, -6.0;-4.3) for years 1-4. Mean±SD number of injections was 7.5±1.9, 6.7±2.1, 6.6±2.3, and 6.4±2.3 for years 1-4. By year 4, 36.7% of eyes had ≤8-week dosing intervals (q8w) and 21.2% had ≥12-week dosing intervals. Eyes treated q8w increased 40% from Year 1 (32.4%) to Year 4 (45.3%). Baseline bilateral treatment frequency was 6.1%. Of the patients treated bilaterally, 32.0% received the first treatment in the better-seeing eye, and 68.0% received first treatment in an eye with vision the same as or worse than the fellow-eye. This trend was evident across all index years. CONCLUSIONS: This real-world study describes the treatment burden, initiation and monitoring patterns, and VA outcomes at a scale and timeframe that has not been previously reported. In this cohort, baseline VA was similar for the index years 2012-2014, but lower for 2015. In patients with 4-year follow-up, both VA and injection frequency declined, whereas the proportion of eyes treated more frequently than the recommended q8w interval increased. The reduction in dosing intervals may be a consequence of intensification of treatment due to year-on-year VA loss and disease progression.

Treat and Extend Treatment Interval Patterns with Anti-VEGF Therapy in nAMD Patients.

Treat and extend (T&E) is a standard treatment regimen for treating neovascular age-related macular degeneration (nAMD) with anti-vascular endothelial growth factors (anti-VEGFs), but the treatment intervals attained are not well documented. This retrospective, non-comparative, non-randomised study of eyes with nAMD classified treatment interval sequences in a T&E cohort in Australia using Electronic Medical Records (EMR) data. We analysed data from 632 treatment-naïve eyes from 555 patients injected with ranibizumab, aflibercept or unlicensed bevacizumab between January 2012 and June 2016 (mean baseline age 78.0). Eyes were categorised into non-overlapping clusters of interval sequences based on the first 12 months of follow-up. We identified 523 different treatment interval sequences. The largest cluster of 197 (31.5%) eyes attained an 8-week treatment interval before dropping to a shorter frequency, followed by 168 (26.8%) eyes that did not reach or attained a single 8-week interval at the end of the study period. A total of 65 (10.4%) and 83 (13.3%) eyes reached and sustained (≥2 consecutive injection intervals of the same length) an 8 and 12 weekly interval, respectively. This study demonstrates highly individualised treatment patterns in the first year of anti-VEGF therapy in Australia using T&E regimens, with the majority of patients requiring more frequent injections than once every 8 weeks.

Effectiveness of Continued Ranibizumab Therapy in Neovascular Age-Related Macular Degeneration versus Switch to Aflibercept: Real World Evidence.

PURPOSE: To assess the long-term comparative effectiveness of ranibizumab versus switching to aflibercept in neovascular age-related macular degeneration (nAMD). DESIGN: A 24-month, retrospective, comparative, nonrandomized, matched cohort study. PARTICIPANTS: Patients with nAMD initiated on ranibizumab who remained (nonswitchers) or who switched to aflibercept (switchers) captured from a United States electronic medical records database between July 1, 2011 and October 12, 2014. METHODS: Patient eyes were matched for baseline age, baseline visual acuity (VA), VA at month 3, and duration of follow-up. Matching ratio was 1:2 (switchers: nonswitchers) where possible and 1:1 otherwise. MAIN OUTCOME MEASURES: The primary outcome was VA change from baseline (first injection of ranibizumab) to month 24. Secondary end points were standardized area under the curve of VA change; patient eyes (%) gaining or losing ≥5, ≥10, or ≥15 letters, or with VA of >73 letters at month 24; number of injections and monitoring visits; and analysis of preswitch characteristics. RESULTS: A total of 454 switchers and 750 matched nonswitchers were included. The adjusted difference in mean VA change from baseline to month 24 for switchers to nonswitchers was 0.02 letters (95% confidence interval [CI], -1.63 to 1.68). The upper bound 95% CI (1.68) was below the predefined noninferiority margin of 5 letters. Switchers had a significantly higher annualized number of mean total visits compared with nonswitchers (10.0 vs. 9.0 for year 1; 8.7 vs. 7.4 for year 2), a higher number of injection visits (8.4 vs. 6.7 for year 1; 7.0 vs. 5.1 for year 2), but a lower number of monitoring-only visits (1.6 vs. 2.3 for year 1; 1.7 vs. 2.3 for year 2). During the preswitch period, switchers had a higher number of injection visits (7.6 vs. 6.5), fewer monitoring-only visits (1.5 vs. 2.2), and comparable total visits (9.1 vs. 8.7). Visual acuity change from baseline to switch was similar between switchers and nonswitchers (adjusted least squares mean difference, -1.36 letters; 95% CI, -2.76 to 0.05). CONCLUSIONS: Switching patients from ranibizumab to aflibercept resulted in no difference in VA change compared with those maintained on ranibizumab only. The lower retreatment rate in nonswitchers compared with switchers post switch does not support the view of a longer treatment efficacy.

The economic and humanistic burden of patients in receipt of current available therapies for nAMD.

AIM: To determine the economic and humanistic burden of neovascular age-related macular degeneration (nAMD) in a cohort of patients treated with anti-VEGF in Europe and the US. PATIENTS & METHODS: 79 respondents from the EU and 63 from the US with a self-reported diagnosis of nAMD and in current receipt of treatment, as reported in an international, general population survey, were compared with non-nAMD controls. RESULTS: Anti-VEGF-treated nAMD patients in the EU had a greater utilization of healthcare resources, poorer quality of life and greater overall activity impairment versus non-nAMD controls. In the US cohort, treated nAMD patients had significantly greater resource utilization for ophthalmologist visits only. CONCLUSION: The burden of care associated with nAMD on EU and US healthcare systems, and on patients who are in receipt of nAMD therapy, is significant and likely to be unsustainable.

Dispensing Patterns of Ranibizumab and Aflibercept for the Treatment of Neovascular Age-Related Macular Degeneration: A Retrospective Cohort Study in Australia.

INTRODUCTION: Anti-vascular endothelial growth factor therapy is the standard of care for neovascular age-related macular degeneration (nAMD). The dosage of two licensed agents, ranibizumab and aflibercept, was established through clinical trials; however, it is unclear if either agent is administered as recommended in routine clinical practice. Using pharmacy claims data, we investigated if the dispensing patterns of ranibizumab differ from those of aflibercept 6 and 12 months after treatment initiation. METHODS: Prescription data retrieved from the Australian IMS® AUS LRx database were used to identify nAMD patients with one or more claims for ranibizumab or aflibercept between December 1, 2012, and March 31, 2015, with follow-up of at least 6 months. The number of ranibizumab and aflibercept units dispensed was adjusted for baseline patient Medication-Based Disease Burden Index (MBDBI) scores. No difference in the number of ranibizumab versus aflibercept units dispensed was concluded if the 95% confidence interval (CI) limits of the adjusted mean difference between the study cohorts were 1.00 unit or less. RESULTS: Baseline patient MBDBI scores were similar for the ranibizumab (N = 1235) and aflibercept (N = 959) cohorts. The adjusted mean (standard deviation) number of units dispensed was 5.3 (1.3) versus 5.1 (1.4) at month 6 and 8.9 (2.2) versus 8.9 (2.3) at month 12. The 95% CI limits of the adjusted mean difference did not exceed 1.00 unit dispensed at either time point: 95% CI of 0.09 to 0.32 for an adjusted mean difference of 0.20 at month 6 and -0.23 to 0.30 for an adjusted mean difference of 0.04 at month 12. Mean (standard deviation) dispensing intervals were comparable for both cohorts: 35.3 (19.2) days versus 36.8 (20.0) days at month 6 (adjusted mean difference -1.59 days; 95% CI -2.51 to -0.67 days) and 41.2 (20.9) days versus 41.6 (20.4) days at month 12 (adjusted mean difference -0.40 days; 95% CI -1.70 to 0.91 days). CONCLUSIONS: Ranibizumab and aflibercept are dispensed in a similar manner by Australian pharmacies during the first year of treatment. FUNDING: Novartis Pharma AG.

Ranibizumab 0.5†mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study.

AIMS: To demonstrate non-inferiority of ranibizumab treat-and-extend (T&E) with/without laser to ranibizumab pro re nata (PRN) for best-corrected visual acuity (BCVA) in patients with diabetic macular oedema (DMO). METHODS: A 24-month single-masked study with patients randomised 1:1:1 to T&E+laser (n=121), T&E (n=128) or PRN (control; n=123). All patients received monthly injections until BCVA stabilisation. The investigator decided on re-treatment in the PRN and treatment-interval adaptations in the T&E groups based on loss of BCVA stability due to DMO activity. Likewise, laser treatment was at investigator's discretion. Collectively, these features reflect a real-life scenario. Endpoints included mean average change in BCVA from baseline to months 1-12 (primary), mean BCVA change from baseline to months 12 and 24, treatment exposure and safety profile. RESULTS: Both T&E regimens were non-inferior to PRN based on mean average BCVA change from baseline to months 1-12 (T&E+laser: +5.9 and T&E: +6.1 vs PRN: +6.2 letters; both p<0.0001). Mean BCVA change at month 24 was similar across groups (+8.3, +6.5 and +8.1 letters, respectively). The mean number of injections was 12.4 and 12.8 in the T&E+laser and T&E groups and 10.7 in the PRN group. The T&E regimens showed 46% reduction in the number of clinic visits. Over 70% of patients maintained their BCVA, with treatment intervals of ≥2 months over 24 months. Safety profile was consistent with that described in the product information. CONCLUSIONS: T&E is a feasible treatment option for patients with DMO, with a potential to reduce treatment burden. Slightly more injections were required versus PRN, likely due to the specifics of the T&E regimen applied here. TRIAL REGISTRATION NUMBER: NCT01171976.

Comparative efficacy and safety of approved treatments for macular oedema secondary to branch retinal vein occlusion: a network meta-analysis.

OBJECTIVE: To compare the efficacy and safety of approved treatments for macular oedema secondary to branch retinal vein occlusion (BRVO). DESIGN: Randomised controlled trials (RCTs) evaluating the efficacy and safety of approved treatments for macular oedema secondary to BRVO were identified from an updated systematic review. SETTING: A Bayesian network meta-analysis of RCTs of treatments for macular oedema secondary to BRVO. INTERVENTIONS: Ranibizumab 0.5 mg pro re nata, aflibercept 2 mg monthly (2q4), dexamethasone 0.7 mg implant, laser photocoagulation, ranibizumab+laser, or sham intervention. Bevacizumab and triamcinolone were excluded. OUTCOME MEASURES: Efficacy outcomes were mean change in best corrected visual acuity (Early Treatment Diabetic Retinopathy Study scale) and the percentage of patients gaining ≥ 15 letters. Safety outcome was the percentage of patients with increased intraocular pressure (IOP)/ocular hypertension (OH). RESULTS: 8 RCTs were identified for inclusion with 1743 adult patients. The probability of being the most efficacious treatment at month 6 or 12 based on letters gained was 54% for ranibizumab monotherapy, 30% for aflibercept, 16% for ranibizumab plus laser (adjunctive or prompt), and 0% for dexamethasone implant, laser or sham. The probability of being the most efficacious treatment for patients gaining ≥ 15 letters was 39% for aflibercept, 35% for ranibizumab monotherapy, 24% for ranibizumab plus laser, 2% for dexamethasone implant, and less than 1% for laser or sham. There was no statistical difference between ranibizumab monotherapy and aflibercept for letters gained (+1.4 letters for ranibizumab vs aflibercept with 95% credible interval (CrI) of -5.2 to +8.5 letters) or the OR for gaining ≥ 15 letters: 1.06 (95% CrI 0.16 to 8.94)). Dexamethasone implant was associated with significantly higher IOP/OH than antivascular endothelial growth factor agents (OR 13.1 (95% CrI 1.7 to 116.9)). CONCLUSIONS: There was no statistically significant difference between ranibizumab and aflibercept.

Efficacy of anti-VEGF and laser photocoagulation in the treatment of visual impairment due to diabetic macular edema: a systematic review and network meta-analysis.

OBJECTIVE: Compare the efficacy of ranibizumab, aflibercept, laser, and sham in the first-line treatment of diabetic macular edema (DME) to inform technology assessments such as those conducted by the UK National Institute for Health and Care Excellence (NICE). DATA SOURCES: MEDLINE, Embase, Cochrane Library, congress abstracts, ClinicalTrials.gov registry and Novartis data on file. INCLUSION CRITERIA: Studies reporting 6- or 12-month results of randomized controlled trials (RCTs) evaluating at least two of ranibizumab 0.5 mg pro re nata, aflibercept 2.0 mg bi-monthly, laser photocoagulation or sham. Study quality was assessed based on likelihood of bias in selection, attrition, detection and performance. OUTCOME MEASURE: Improvement in best-corrected visual acuity (BCVA) measured as the proportion of patients gaining ≥10 letters on the Early Treatment Diabetic Retinopathy Study scale. The outcome was chosen following acceptance by NICE of a Markov model with 10-letter health states in the assessment of ranibizumab for DME. META-ANALYSIS: Bayesian network meta-analyses with fixed and random effects adjusted for differences in baseline BCVA or central retinal thickness. RESULTS: The analysis included 1,978 patients from eight RCTs. The random effects model adjusting for baseline BCVA was the best model based on total residual. The efficacy of ranibizumab was numerically, but not statistically, superior to aflibercept (odds ratio [OR] 1.59; 95% credible interval [CrI], 0.61-5.37). Ranibizumab and aflibercept were statistically superior to laser monotherapy with ORs of 5.50 (2.73-13.16) and 3.45 (1.62-6.84) respectively. The probability that ranibizumab is the most efficacious treatment was 73% compared with 14% for aflibercept, 12% for ranibizumab plus laser, and 0% for laser. LIMITATIONS: Three of the eight RCTs included are not yet published. The models did not adjust for all potential effect modifiers. CONCLUSION: Ranibizumab was non-significantly superior to aflibercept and both anti-VEGF therapies had statistically superior efficacy to laser.

Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials.

PURPOSE: To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis. DESIGN: Three multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE. PARTICIPANTS: A total of 118 patients with Behçet's uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçet's uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçet's uveitis (ENDURE study) were enrolled. METHODS: After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study. MAIN OUTCOME MEASURES: Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes. RESULTS: After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies. CONCLUSIONS: The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM.

25-Hydroxyvitamin D is lower in deprived groups, but is not associated with carotid intima media thickness or plaques: results from pSoBid.

OBJECTIVE: The association of the circulating serum vitamin D metabolite 25-hydroxyvitamin D (25OHD) with atherosclerotic burden is unclear, with previous studies reporting disparate results. METHOD: Psychological, social and biological determinants of ill health (pSoBid) is a study of participants aged 35-64 years from Glasgow who live at extremes of the socioeconomic spectrum. Vitamin D deficiency was defined as 25OHD < 25nmol/L, as per convention. Cross-sectional associations between circulating 25OHD concentrations and a range of socioeconomic, lifestyle, and biochemistry factors, as well as carotid intima media thickness (cIMT) and plaque presence were assessed in 625 participants. RESULTS: Geometric mean levels of circulating 25OHD were higher among the least deprived (45.6 nmol/L, 1-SD range 24.4-85.5) versus most deprived (34.2 nmol/L, 1-SD range 16.9-69.2; p < 0.0001). In the least deprived group 15% were "deficient" in circulating 25OHD versus 30.8% in the most deprived (χ(2)p < 0.0001). Log 25OHD was 27% lower among smokers (p < 0.0001), 20% higher among the physically active versus inactive (p = 0.01), 2% lower per 1 kg/m(2) increase in body mass index (BMI) (p < 0.0001), and showed expected seasonal variation (χ(2)p < 0.0001). Log 25OHD was 13% lower in the most versus least deprived independent of the aforementioned lifestyle confounding factors (p = 0.03). One unit increase in log 25OHD was not associated with atherosclerotic burden in univariable models; cIMT (effect estimate 0.000 mm [95% CI -0.011, 0.012]); plaque presence (OR 0.88 [0.75, 1.03]), or in multivariable models. CONCLUSION: There is no strong association of 25OHD with cIMT or plaque presence, despite strong evidence 25OHD associates with lifestyle factors and socioeconomic deprivation.

Profile of microvolt T-wave alternans testing in 1003 patients hospitalized with heart failure.

AIMS: Observational studies in selected populations have suggested that microvolt T-wave alternans (MTWA) testing may identify patients with heart failure (HF) at risk of sudden cardiac death. The aims of this study were to investigate the utility of MTWA testing in an unselected population of patients with HF and to evaluate the clinical characteristics associated with the MTWA results. METHODS AND RESULTS: A total of 1003 patients hospitalized with decompensated HF were enrolled. MTWA testing was planned 1 month post-discharge; 648 patients returned for MTWA testing. Mean age was 70.8 ± 10.6 years and 58% were male. Of these patients who returned, 318 (49%) were ineligible for MTWA testing due to atrial fibrillation (AF), pacemaker dependency, or physical inability to undertake the test. Of the MTWA tests, 100 (30%) were positive, 78 (24%) were negative, and 152 (46%) were indeterminate; 112/152 indeterminate tests (74%) occurred because of failure to achieve target heart rate (HR) due to chronotropic incompetence or physical limitations. There were differences in patient characteristics according to MTWA result. Independent predictors of a negative result included younger age and higher left ventricular ejection fraction (LVEF). Independent predictors of a positive result included higher HR during MTWA testing and lower LVEF. Independent predictors of an indeterminate result included older age and history of previous/paroxysmal AF. CONCLUSIONS: Only half of patients with HF are eligible for MTWA testing and the most common result is an indeterminate test. Patients with positive and indeterminate tests have different clinical characteristics. MTWA treadmill testing is not widely applicable in typical HF patients and is unlikely to refine risk stratification for sudden death on a population level.

Early life socioeconomic adversity is associated in adult life with chronic inflammation, carotid atherosclerosis, poorer lung function and decreased cognitive performance: a cross-sectional, population-based study.

BACKGROUND: Socioeconomic gradients in health persist despite public health campaigns and improvements in healthcare. The Psychosocial and Biological Determinants of Ill-health (pSoBid) study was designed to uncover novel biomarkers of chronic disease that may help explain pathways between socioeconomic adversity and poorer physical and mental health. METHODS: We examined links between indicators of early life adversity, possible intermediary phenotypes, and markers of ill health in adult subjects (n = 666) recruited from affluent and deprived areas. Classical and novel risk factors for chronic disease (lung function and atherosclerosis) and for cognitive performance were assessed, and associations sought with early life variables including conditions in the parental home, family size and leg length. RESULTS: Associations were observed between father's occupation, childhood home status (owner-occupier; overcrowding) and biomarkers of chronic inflammation and endothelial activation in adults (C reactive protein, interleukin 6, intercellular adhesion molecule; P < 0.0001) but not number of siblings and leg length. Lung function (forced expiratory volume in 1 second) and cognition (Choice Reaction Time, the Stroop test, Auditory Verbal Learning Test) were likewise related to early life conditions (P < 0.001). In multivariate models inclusion of inflammatory variables reduced the impact and independence of early life conditions on lung function and measures of cognitive ability. Including variables of adult socioeconomic status attenuated the early life associations with disease biomarkers. CONCLUSIONS: Adverse levels of biomarkers of ill health in adults appear to be influenced by father's occupation and childhood home conditions. Chronic inflammation and endothelial activation may in part act as intermediary phenotypes in this complex relationship. Reducing the 'health divide' requires that these life course determinants are taken into account.

Validation of magnetic resonance myocardial perfusion imaging with fractional flow reserve for the detection of significant coronary heart disease.

BACKGROUND: Magnetic resonance myocardial perfusion imaging (MRMPI) has a number of advantages over the other noninvasive tests used to detect reversible myocardial ischemia. The majority of previous studies have generally used quantitative coronary angiography as the gold standard to assess the accuracy of MRMPI; however, only an approximate relationship exists between stenosis severity and functional significance. Pressure wire-derived fractional flow reserve (FFR) values <0.75 correlate closely with objective evidence of reversible ischemia. Accordingly, we have compared MRMPI with FFR. METHODS AND RESULTS: One hundred three patients referred for investigation of suspected angina underwent MRMPI with a 1.5-T scanner. The stress agent was intravenous adenosine (140 microg . kg(-1) . min(-1)), and the first-pass bolus contained 0.1 mmol/kg gadolinium. In the following week, coronary angiography with pressure wire studies was performed. FFR was recorded in all patent major epicardial coronary arteries, with a value <0.75 denoting significant stenosis. MRMPI scans, analyzed by 2 blinded observers, identified perfusion defects in 121 of 300 coronary artery segments (40%), of which 110 had an FFR <0.75. We also found that 168 of 179 normally perfused segments had an FFR > or = 0.75. The sensitivity and specificity of MRMPI for the detection of functionally significant coronary heart disease were 91% and 94%, respectively, with positive and negative predictive values of 91% and 94%. CONCLUSIONS: MRMPI can detect functionally significant coronary heart disease with excellent sensitivity, specificity, and positive and negative predictive values compared with FFR.

Differences in atherosclerosis according to area level socioeconomic deprivation: cross sectional, population based study.

OBJECTIVES: To examine the relation between area level social deprivation and ultrasound markers of atherosclerosis (common carotid intima-media thickness and plaque score), and to determine whether any differences can be explained by "classic" (currently recognised) or "emerging" (novel) cardiovascular risk factors. DESIGN: Cross sectional, population based study. SETTING: NHS Greater Glasgow Health Board area. PARTICIPANTS: 666 participants were selected on the basis of how their area ranked in the Scottish Index of Multiple Deprivation 2004. Approximately equal numbers of participants from the most deprived areas and the least deprived areas were included, as well as equal numbers of men and women and equal numbers of participants from each age group studied (35-44, 45-54, and 55-64 years). MAIN OUTCOME MEASURES: Carotid intima-media thickness and plaque score, as detected by ultrasound. RESULTS: The mean age and sex adjusted intima-media thickness was significantly higher in participants from the most deprived areas than in those from the least deprived areas (0.70 mm (standard deviation (SD) 0.16 mm) v 0.68 mm (SD 0.12 mm); P=0.015). On subgroup analysis, however, this difference was only apparent in the highest age tertile in men (56.3-66.5 years). The difference in unadjusted mean plaque score between participants from the most deprived and those from the least deprived areas was more striking than the difference in intima-media thickness (least deprived 1.0 (SD 1.5) v most deprived 1.7 (SD 2.0); P<0.0001). In addition, a significant difference in plaque score was apparent in the two highest age tertiles in men (46.8-56.2 years and 56.3-66.5 years; P=0.0073 and P<0.001) and the highest age tertile in women (56.3-66.5 years; P<0.001). The difference in intima-media thickness between most deprived and least deprived males remained significant after adjustment for classic risk factors, emerging risk factors, and individual level markers of socioeconomic status (P=0.010). Adjustment for classic risk factors and emerging cardiovascular risk factors, either alone or in combination, did not abolish the deprivation based difference in plaque presence (as a binary measure; adjusted odds ratio of 1.73, 95% confidence interval 1.07 to 2.82). However, adjustment for classic risk factors and individual level markers of early life socioeconomic status abolished the difference in plaque presence between the most deprived and the least deprived individuals (adjusted odds ratio 0.94, 95% CI 0.54 to 1.65; P=0.84). CONCLUSIONS: Deprivation is associated with increased carotid plaque score and intima-media thickness. The association of deprivation with atherosclerosis is multifactorial and not adequately explained by classic or emerging risk factors.

Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial.

BACKGROUND: There are few therapeutic options for the prevention of gastrointestinal mucosal damage caused by low-dose aspirin. We therefore investigated the efficacy of famotidine, a well-tolerated histamine H(2)-receptor antagonist, in the prevention of peptic ulcers and erosive oesophagitis in patients receiving low-dose aspirin for vascular protection. METHODS: Adult patients (aged >/=18 years) from the cardiovascular, cerebrovascular, and diabetes clinics at Crosshouse Hospital, Kilmarnock, UK, were eligible for enrolment in this phase III, randomised, double-blind, placebo-controlled trial if they were taking aspirin 75-325 mg per day with or without other cardioprotective drugs. Patients without ulcers or erosive oesophagitis on endoscopy at baseline were randomly assigned by computer-generated randomisation sequence to receive famotidine 20 mg twice daily (n=204) or placebo twice daily (n=200). Patients had a final endoscopic examination at 12 weeks. The primary endpoint was the development of new ulcers in the stomach or duodenum or erosive oesophagitis at 12 weeks after randomisation. Analysis was by intention to treat, including all randomised patients who received at least one dose of study drug (famotidine or placebo). This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN96975557. FINDINGS: All randomised patients received at least one dose and were included in the ITT population. 82 patients (famotidine, n=33; placebo, n=49) did not have the final endoscopic examination and were assumed to have had normal findings; the main reason for participant withdrawal was refusal to continue. At 12 weeks, comparing patients assigned to famotidine with patients assigned to placebo, gastric ulcers had developed in seven (3.4%) of 204 patients compared with 30 (15.0%) of 200 patients (odds ratio [OR] 0.20, 95% CI 0.09-0.47; p=0.0002); duodenal ulcers had developed in one (0.5%) patient compared with 17 (8.5%; OR 0.05, 0.01-0.40; p=0.0045); and erosive oesophagitis in nine (4.4%) compared with 38 (19.0%; OR 0.20, 0.09-0.42; p<0.0001), respectively. There were fewer adverse events in the famotidine group than in the placebo group (nine vs 15); four patients in the placebo group were admitted to hospital with upper gastrointestinal haemorrhage. The other most common adverse event was angina (famotidine, n=2; placebo, n=4). INTERPRETATION: Famotidine is effective in the prevention of gastric and duodenal ulcers, and erosive oesophagitis in patients taking low-dose aspirin. These findings widen the therapeutic options for the prevention of gastrointestinal damage in patients needing vascular protection. FUNDING: Merck Laboratories and Astellas Pharma.