Risk Assessment of Acute Myocardial Infarction and Stroke Associated with Long-Acting Muscarinic Antagonists, Alone or in Combination, versus Long-Acting beta2-Agonists.

Background: The long-acting muscarinic antagonist (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). A post-authorization safety study was initiated to assess potential cardiovascular risks associated with LAMAs versus long-acting beta2-agonists. Purpose: To estimate incidence rates and adjusted incidence rate ratios (IRRs) for acute myocardial infarction (AMI), stroke, and major adverse cardiac events (MACE) in new users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA compared with initiators of LABA. Patients and Methods: This population-based cohort study included patients with COPD aged ≥40 years initiating COPD medications in the UK Clinical Practice Research Datalink (CPRD) Aurum database from 2012 to 2019. Poisson regression models were used to estimate the IRR for AMI, stroke, and MACE in users of COPD medications versus LABA, adjusting for clinically relevant covariables. Results: The study included 11,121 new users of aclidinium, 4804 of aclidinium/formoterol, 56,198 of tiotropium, 23,856 of other LAMA, 17,450 of LAMA/LABA, 70,289 of LABA/ICS, and 13,716 of LABA. During periods of continuous medication use after initiation (current use), crude incidence rates per 1000 person-years for AMI ranged from 8.7 (aclidinium/formoterol) to 12.4 (LAMA/LABA), for stroke ranged from 4.8 (aclidinium/formoterol) to 7.2 (LAMA/LABA), and for MACE ranged from 13.5 (aclidinium/formoterol) to 19.3 (LAMA/LABA). Using LABA as reference, adjusted IRRs [95% confidence intervals] were close to 1 for all study drugs for AMI (lowest for aclidinium/formoterol, 0.95 [0.60-1.52], and highest for LAMA/LABA, 1.23 [0.91-1.67]), stroke (lowest for aclidinium/formoterol, 0.64 [0.39-1.06], and highest for tiotropium, 1.02 [0.81-1.27] for tiotropium) and for MACE (lowest for aclidinium, 0.93 [0.75-1.16], and highest for LAMA/LABA, 1.24 [0.97-1.59]). Conclusion: Risks of AMI, stroke, and MACE in current users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, LAMA/LABA, or LABA/ICS were similar to the risks among current users of LABA.

GOLD assessment of COPD severity in the Clinical Practice Research Datalink (CPRD).

PURPOSE: To evaluate availability of spirometry and symptom data in the Clinical Practice Research Datalink (United Kingdom) to assess COPD severity using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016 definition and comparing it with an algorithm used in other studies. METHODS: This was a descriptive, noninterventional, secondary database cohort study of patients with COPD aged 40 years or older, who initiated treatment with specific COPD medications. Patients were classified according to COPD severity (1) in GOLD 2016 "ABCD" categories based on symptoms (Medical Research Council dyspnea grade, COPD Assessment Test, breathlessness), percent predicted FEV1, and exacerbation history and (2) as mild, moderate, severe, or very severe based on treatment and exacerbation history. RESULTS: The study included 63 900 patients with COPD aged 40 years or older that were new users of 1 or more COPD medication of interest. Percent predicted FEV1 was available for 80.9% of patients; symptoms for 75.6% of patients. Classification into GOLD 2016 ABCD categories was possible for 75.6% of the patients. The GOLD 2016 ABCD definition classified more patients under the high-risk categories (22.1%, A; 18.8%, B; 21.3%, C; 37.9%, D) than did the adapted algorithm (7.9%, mild; 48.6%, moderate; 42.1%, severe; 1.4%, very severe). CONCLUSION: Using our adaptation of the GOLD 2016 COPD severity classification, the information in the Clinical Practice Research Datalink allowed us to ascertain COPD severity in approximately 75% of patients with COPD. Algorithms that include medication use tend to misclassify patients with the extreme COPD severity categories.

Cost-Utility of Group Acceptance and Commitment Therapy for Fibromyalgia Versus Recommended Drugs: An Economic Analysis Alongside a 6-Month Randomized Controlled Trial Conducted in Spain (EFFIGACT Study).

The aim of this study was to analyze the cost utility of a group-based form of acceptance and commitment therapy (GACT) in patients with fibromyalgia (FM) compared with patients receiving recommended pharmacological treatment (RPT) or on a waiting list (WL). The data were derived from a previously published study, a randomized controlled trial that focused on clinical outcomes. Health economic outcomes included health-related quality of life and health care use at baseline and at 6-month follow-up using the EuroQoL and the Client Service Receipt Inventory, respectively. Analyses included quality-adjusted life years, direct and indirect cost differences, and incremental cost effectiveness ratios. A total of 156 FM patients were randomized (51 GACT, 52 RPT, 53 WL). GACT was related to significantly less direct costs over the 6-month study period compared with both control arms (GACT €824.2 ± 1,062.7 vs RPT €1,730.7 ± 1,656.8 vs WL €2,462.7 ± 2,822.0). Lower direct costs for GACT compared with RPT were due to lower costs from primary care visits and FM-related medications. The incremental cost effectiveness ratios were dominant in the completers' analysis and remained robust in the sensitivity analyses. In conclusion, acceptance and commitment therapy appears to be a cost-effective treatment compared with RPT in patients with FM. PERSPECTIVE: Decision-makers have to prioritize their budget on the treatment option that is the most cost effective for the management of a specific patient group. From government as well as health care perspectives, this study shows that a GACT is more cost effective than pharmacological treatment in management of FM.

Dimensionality, reliability, and validity of the revised fibromyalgia impact questionnaire in two Spanish samples.

OBJECTIVE: The present study attempted to fill a research gap by performing the first dimensionality analysis of the Revised Fibromyalgia Impact Questionnaire (FIQR) using exploratory and confirmatory techniques. A second objective was to report on the reliability and construct validity of the FIQR in Spanish patients. METHODS: FIQR data from a sample of adult fibromyalgia patients (n = 113) were analyzed using principal components analysis (PCA). Subsequently, a set of confirmatory factor analyses (CFAs) was conducted in another sample (n = 179) to analyze the goodness of fit of various factor models. FIQR reliability was assessed by computing Cronbach's alpha and coefficient H. Construct validity was evaluated by comparing the FIQR scores of participants categorized by employment status. RESULTS: According to the PCA, the FIQR structure might be described as having 1 global factor of functional impairment. Although subsequent CFAs confirmed that 1 factor accounted for the greatest proportion of common variance in the FIQR items, a confirmatory bifactor analysis indicated that the items were multidimensional because of their simultaneous significant loading on specific factors. The Cronbach's alpha values of the FIQR domains were very good (>0.80) and the H estimate for the FIQR total score was excellent (0.93). Overall, the FIQR domains were able to distinguish between patients differing in employment status (working outside the home versus on sick leave). CONCLUSION: Our results indicate that the Spanish version of the FIQR has a complex factor structure, has excellent reliability, and shows good construct validity.

Psychometric properties of the IDS-SR30 for the assessment of depressive symptoms in Spanish population.

BACKGROUND: Due to the high prevalence of depression, it is clinically relevant to improve the early identification and assessment of depressive episodes. The main objective of the present study was to examine the psychometric properties of the IDS-SR30 (Self-rated Inventory of Depressive Symptomatology) in a large Spanish sample of depressive patients. METHODS: This prospective, naturalistic, multicenter, nationwide epidemiological study conducted in Spain included 1595 adult patients (65.3% females) with a DSM-IV Major Depressive Disorder (MDD. IDS-SR30 and the Hamilton Depression Rating Scale (HDRS, 21 items)were administered to the sample. Data was collected during 2 routine visits. The second assessment was carried out after 10 ± 2 weeks after first assessment. RESULTS: The IDS-SR30 showed good internal consistency (α = 0.94) and high item total correlations (≥ 0.50) were found in 70% of the items. The convergent validity was 0.85. Results of the principal component analysis (PCA) and confirmatory factor analyses (CFA) showed that a three factor model (labelled mood/cognition, anxiety/somatic and sleep) is adequate for the current sample. CONCLUSIONS: The Spanish version of the IDS-SR30 seems a reliable, valid and useful tool for measuring depression symptomatology in Spanish population.

Clinical and economic consequences of medication non-adherence in the treatment of patients with a manic/mixed episode of bipolar disorder: results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) study.

The aim of the present study was to investigate clinical and economic consequences of medication non-adherence during 21-month follow-up in the treatment of bipolar disorder following a manic or mixed episode. Data were taken from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM), which was a prospective, observational study on patient outcomes with a manic/mixed episode in Europe. Physician-rated adherence was dichotomized as adherence/non-adherence at each assessment. Cox proportional hazards models were employed to investigate the impact of non-adherence on remission, recovery, relapse, recurrence, hospitalization and suicide attempts. Costs of medication and resource use in adherent and non-adherent patients during follow-up were estimated with multivariate analyses. Of the 1341 patients analysed, 23.6% were rated non-adherent over 21 months. Non-adherence was significantly associated with decreased likelihood of achieving remission and recovery as well as increased risk of relapse and recurrence as well as hospitalization and suicide attempts. In addition, costs incurred by non-adherent patients during this period were significantly higher than those of adherent patients (£10231 vs £7379, p<0.05). This disparity mainly resulted from differences in inpatient costs (£4796 vs £2150, p<0.05). In conclusion, non-adherence in bipolar patients was associated with poorer long term clinical outcomes that have economic implications for health-care providers.

Methodological quality in pharmacogenetic studies with binary assessment of treatment response: a review.

OBJECTIVE: To evaluate the reporting of critical design issues and methods of statistical analysis in pharmacogenetic studies published in the medical literature. STUDY DESIGN AND SETTINGS: Systematic review of 65 original pharmacogenetic studies published in the literature over the last 15 years. RESULTS: The sample size determination and the planned sample size were lacking in 63 papers. The study design characterization was lacking in 43 papers. The number of patients analyzed ranged from 36 to 1400 (median=161 and interquartile range of 119-250). The Pearson's χ2 test and the Fisher's test were the most common forms of analysis. Multiple statistical testing was relevant to 59 papers, but only 11 addressed the issue of multiplicity (Bonferroni correction). Sources of multiplicity were multiple association assessment (45 papers), analysis of both genotype and allelic frequencies (44), and multiple analysis methods (unadjusted and adjusted). Hardy-Weinberg equilibrium was tested in 12 of 45 papers performing allelic analysis and was fully reported in four of them. The results of association analyses were commonly reported as P values but rarely as estimates of an association measure (odds ratio or relative risk) and its accuracy. CONCLUSIONS: These results show that there is considerable room for improvement in the current standards of design, analysis, and reporting of pharmacogenetic research.

The 12-item World Health Organization Disability Assessment Schedule II (WHO-DAS II): a nonparametric item response analysis.

BACKGROUND: Previous studies have analyzed the psychometric properties of the World Health Organization Disability Assessment Schedule II (WHO-DAS II) using classical omnibus measures of scale quality. These analyses are sample dependent and do not model item responses as a function of the underlying trait level. The main objective of this study was to examine the effectiveness of the WHO-DAS II items and their options in discriminating between changes in the underlying disability level by means of item response analyses. We also explored differential item functioning (DIF) in men and women. METHODS: The participants were 3615 adult general practice patients from 17 regions of Spain, with a first diagnosed major depressive episode. The 12-item WHO-DAS II was administered by the general practitioners during the consultation. We used a non-parametric item response method (Kernel-Smoothing) implemented with the TestGraf software to examine the effectiveness of each item (item characteristic curves) and their options (option characteristic curves) in discriminating between changes in the underliying disability level. We examined composite DIF to know whether women had a higher probability than men of endorsing each item. RESULTS: Item response analyses indicated that the twelve items forming the WHO-DAS II perform very well. All items were determined to provide good discrimination across varying standardized levels of the trait. The items also had option characteristic curves that showed good discrimination, given that each increasing option became more likely than the previous as a function of increasing trait level. No gender-related DIF was found on any of the items. CONCLUSIONS: All WHO-DAS II items were very good at assessing overall disability. Our results supported the appropriateness of the weights assigned to response option categories and showed an absence of gender differences in item functioning.

Utility of the twelve-item World Health Organization Disability Assessment Schedule II (WHO-DAS II) for discriminating depression "caseness" and severity in Spanish primary care patients.

PURPOSE: The 12-item WHO-DAS II was developed to assess the activity limitations and participation restrictions experienced by individuals irrespective of medical diagnosis. In this paper we examine the known-groups' validity of the instrument by evaluating its ability to discriminate between patients with/without major depression, patients with depression with/without medical comorbidity, and patients with depression with different depression severity. METHOD: The participants were 3,615 PC patients from 17 regions of Spain, with a first-time diagnosis of major depressive episode according to the general practitioner. The 12-item WHO-DAS II, the PHQ-9, and a chronic medical conditions checklist were administered during the consultation. RESULTS: The statistical analyses indicated that the 12-item WHO-DAS II was able to discriminate between patients with/without depression and between those with different depression severity. The ROC analysis revealed that with a cutoff score >or=50, the instrument correctly classified 70.4% of the sample (area under the ROC curve = .76; sensitivity = 71.4%; specificity = 67.6%). CONCLUSIONS: Overall, our results support the discriminant validity of the 12-item WHO-DAS II for major depression, being quite recommendable its use in epidemiological research.