Evaluating a Cox marginal structural model to assess the comparative effectiveness of inhaled corticosteroids versus no inhaled corticosteroid treatment in chronic obstructive pulmonary disease.

PURPOSE: To evaluate the potential of a Cox marginal structural model (MSM) to estimate the time-varying causal inference of a known clinical trial association where the effectiveness of inhaled corticosteroid- (ICS-) versus non-ICS-containing treatments has been compared in patients with chronic obstructive pulmonary disease (COPD). METHODS: This retrospective study from 2006-2016 used linked data from Clinical Practice Research Datalink-GOLD, Hospital Episode Statistics, and Office for National Statistics mortality. A Cox MSM, incorporating a new-user design, was deemed capable of replicating a clinical trial-like pathway. Repeated outcomes for exacerbation events and stabilized weights were used to include time-varying and fixed covariate exposures. RESULTS: Of 45,958 patients, 55% were male; 52% had moderate COPD. ICS-treated patients had a higher incidence of comorbid asthma than non-ICS-treated patients. Adjusted hazard risk ratios for any exacerbation event: ICS and/or long-acting ß2-agonist (LABA) versus long-acting muscarinic antagonist (LAMA), 1.07 (95% confidence interval 1.04-1.10); ICS/LABA versus LABA and/or LAMA, 1.05 (1.00-1.10); ICS and/or LABA and/or LAMA versus LAMA, 1.04 (1.01-1.06); ICS and/or LABA and/or LAMA versus LABA and/or LAMA 1.02 (0.97-1.07). CONCLUSIONS: The Cox MSM was not able to fully demonstrate results consistent with the previously established benefits of ICS-containing treatments seen in clinical trials. Future studies should continue to investigate causal inference methods and their capability to estimate the long-term outcomes of treatment in COPD.

Anticholinergic Burden and Associated Healthcare Resource Utilization in Older Adults with Overactive Bladder.

BACKGROUND: Bladder anticholinergics are the most widely used drugs to treat overactive bladder (OAB) but can contribute to cumulative anticholinergic burden, which may be associated with adverse outcomes. OBJECTIVE: This study aimed to evaluate the association between cumulative anticholinergic burden and healthcare resource utilization (HRU) and costs in older adults with OAB. MATERIALS AND METHODS: This was a retrospective, observational study that used data from the UK Clinical Practice Research Datalink (CPRD) GOLD database. Participants were aged ≥ 65 years with ≥ 3 years of continuous enrolment before and ≥ 2 years after the index date (date of OAB diagnosis or first prescription for any OAB drug between 1 April 2007 and 31 December 2015). The primary endpoint was the association between cumulative anticholinergic burden (assessed using the Anticholinergic Cognitive Burden [ACB] scale during the 3-year pre-index period) and HRU (GP consultations, specialist referrals, urological tests, hospital admissions) over the 2-year post-index period. RESULTS: Data from 23,561 adults were included in the analysis. Mean (SD) ACB scores in the pre- and post-index periods were 1.0 (1.1) and 2.4 (1.7), respectively; urological drugs contributed most (58.8%) to the latter. For the primary endpoint, higher pre-index ACB scores were associated with higher post-index HRU and costs. Mean (SD) ACB scores in the post-index period were 1.2 (1.3) and 2.5 (1.7) in those treated with mirabegron (beta-3 agonist) or bladder anticholinergics, respectively. LIMITATIONS: The generalizability of the results outside the UK is unclear. CONCLUSIONS: In older adults with OAB, higher anticholinergic burden before initiating OAB drugs is associated with higher HRU and costs. When making treatment decisions in older adults, consideration should be given to assessing the existing anticholinergic burden and using OAB treatments that do not add to this burden.

Editor's Choice - A Study of the Cost-effectiveness of Fenestrated/branched EVAR Compared with Open Surgery for Patients with Complex Aortic Aneurysms at 2 Years.

OBJECTIVES: The aim was to assess the cost-effectiveness of fenestrated and branched stent grafts (f/b EVAR) compared with open surgical repair (OSR) in thoraco-abdominal or complex abdominal aortic aneurysms (TAAA/AAA) at 2 years. METHODS: Two matched cohorts of patients with TAAA or complex AAA were compared after a follow-up of two years. Patients included in the WINDOW French multicentre prospective registry were treated by f/b EVAR, and OSR patients were extracted from the French national hospital discharge database. All cause mortality was assessed along with readmissions and hospital costs. The association between treatment and 2 year mortality was assessed by uni/multivariate Cox regression analyses using pre- and post-operative characteristics. Incremental cost-effectiveness ratios (ICER) were estimated for para/juxtarenal AAA, and infra- and supra-diaphragmatic TAAA. RESULTS: A total of 268 high risk patients were treated by f/b EVAR and 1678 average or low risk patients were treated with OSR during the same period. Mortality did not significantly differ between the groups (14.9% vs. 11.8%, p = .150) and multivariate Cox regressions did not find an association between 2 year mortality and treatment. Similar proportions of patients were readmitted at least once (69.7% with f/b EVAR vs. 64.2% with OSR, p = .096) but f/b EVAR patients had more readmissions on average (2.2 vs. 1.7, p = .001). Two year hospital costs were higher in the f/b EVAR group (€46,039 vs. €22,779, p < .001). At 2 years, f/b EVAR was dominated (more expensive and less effective), except in the supra-diaphragmatic TAAA subgroup with an ICER of €42,195,800 per death averted. CONCLUSIONS: f/b EVAR in high risk patients offers similar 2 year mortality to OSR performed in lower risk patients but at a higher cost. The cost is mainly driven by the cost of the stent graft, which is not compensated for by lower healthcare resource consumption. Further studies are necessary to evaluate the cost-effectiveness in low risk f/b EVAR patients who may experience fewer complications.

Clobazam and clonazepam use in epilepsy: Results from a UK database incident user cohort study.

OBJECTIVE: To compare patient characteristics and treatment patterns among clobazam (CLB) and clonazepam (CZP)-treated patients with epilepsy in a longitudinal primary care database. METHODS: In this pharmacoepidemiological study, real-life usage data from the Clinical Practice Research Database (CPRD) were evaluated. The CPRD collects data from approximately 690 primary care practices throughout the UK. Data included were from patients with ≥1 incident CLB or CZP prescription from 1995 to 2011 and were present in the database for ≥182 days prior to the index date (date patient was first prescribed CLB or CZP within the study period). RESULTS: Of 21,099 patients who met inclusion criteria, 18.4% were receiving CLB and 81.6% were receiving CZP. More patients used CLB for epilepsy than CZP (76.1% vs 8.7%). CLB-treated adults (≤18years) were younger than those treated with CZP (41.0 vs 48.2 years; p<0.001), while CLB-treated children (≤18 years) were older than those treated with CZP (8.8 vs 7.3 years, p<0.001). The median CLB dosage did not change from baseline to last follow-up, while median CZP dosage increased 25% in adults and 50% in children. Median treatment duration, as well as retention rate up to 10 years, was similar between CLB and CZP in each age group. CONCLUSIONS: Among adult and pediatric patients in the UK, CLB is more often prescribed for epilepsy than CZP. The median CLB dosage used by both adults and children remained stable over the 16-year study period, while the median CZP dosage increased in both adults and children.

Cost-effectiveness of computed tomography coronary angiography versus conventional invasive coronary angiography.

OBJECTIVES: To determine the costs and cost-effectiveness of a diagnostic strategy including computed tomography coronary angiography (CTCA) in comparison with invasive conventional coronary angiography (CA) for the detection of significant coronary artery disease from the point of view of the healthcare provider. METHODS: The average cost per CTCA was determined via a micro-costing method in four French hospitals, and the cost of CA was taken from the 2011 French National Cost Study that collects data at the patient level from a sample of 51 public or not-for-profit hospitals. RESULTS: The average cost of CTCA was estimated to be 180 (95 % CI 162-206) based on the use of a 64-slice CT scanner active for 10 h per day. The average cost of CA was estimated to be 1,378 (95 % CI 1,126-1,670). The incremental cost-effectiveness ratio of CA for all patients over a strategy including CTCA triage in the intermediate risk group, no imaging test in the low risk group, and CA in the high risk group, was estimated to be 6,380 (95 % CI 4,714-8,965) for each additional correctly classified patient. This strategy correctly classifies 95.3 % (95 % CI 94.4-96.2) of all patients in the population studied. CONCLUSIONS: A strategy of CTCA triage in the intermediate-risk group, no imaging test in the low-risk group, and CA in the high-risk group, has good diagnostic accuracy and could significantly cut costs. Medium-term and long-term outcomes need to be evaluated in patients with coronary stenosis potentially misclassified by CTCA due to false negative examinations.

Comparison of two data collection processes in clinical studies: electronic and paper case report forms.

BACKGROUND: Electronic Case Report Forms (eCRFs) are increasingly chosen by investigators and sponsors of clinical research instead of the traditional pen-and-paper data collection (pCRFs). Previous studies suggested that eCRFs avoided mistakes, shortened the duration of clinical studies and reduced data collection costs. METHODS: Our objectives were to describe and contrast both objective and subjective efficiency of pCRF and eCRF use in clinical studies. A total of 27 studies (11 eCRF, 16 pCRF) sponsored by the Paris hospital consortium, conducted and completed between 2001 and 2011 were included. Questionnaires were emailed to investigators of those studies, as well as clinical research associates and data managers working in Paris hospitals, soliciting their level of satisfaction and preferences for eCRFs and pCRFs. Mean costs and timeframes were compared using bootstrap methods, linear and logistic regression. RESULTS: The total cost per patient was 374€ ±351 with eCRFs vs. 1,135€ ±1,234 with pCRFs. Time between the opening of the first center and the database lock was 31.7 months Q1 = 24.6; Q3 = 42.8 using eCRFs, vs. 39.8 months Q1 = 31.7; Q3 = 52.2 with pCRFs (p = 0.11). Electronic CRFs were globally preferred by all (31/72 vs. 15/72 for paper) for easier monitoring and improved data quality. CONCLUSIONS: This study found that eCRFs and pCRFs are used in studies with different patient numbers, center numbers and risk. The first ones are more advantageous in large, low-risk studies and gain support from a majority of stakeholders.

Discontinuation of hormone therapy in the French GAZEL cohort 1990-2006.

OBJECTIVE: To analyze changes in hormone therapy (HT) use after the publication of the Women's Health Initiative (WHI) results, in a country (France) where HT is different from that assessed in the WHI. DESIGN: Longitudinal study. SETTING: Women in the GAZEL cohort of employees of the French national power company. PARTICIPANT(S): One thousand six hundred five postmenopausal women ever-users of HT. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Discontinuation of HT. RESULT(S): Rates of discontinuation were higher after 2002: 65% of users who began HT in 1998 were still using it after 5 years. In contrast, >90% of those who began before 1994 were still using it after 5 years. Discontinuation was associated with women's social and medical characteristics and with factors related to side effects and expectations concerning HT. After adjustment for these factors, women were twice as likely to stop HT after publication of the WHI. CONCLUSION(S): Even in France, publication of the WHI has led to a decline in HT use.

Long-term outcome of parenthood project during in vitro fertilization and after discontinuation of unsuccessful in vitro fertilization.

OBJECTIVE: To explore the long-term outcome of patients who began IVF treatment by considering not only treatment outcome in the center but also the parenthood project outcome after discontinuation of unsuccessful IVF. DESIGN: Retrospective cohort follow-up study. SETTING: Two French IVF centers. PATIENT(S): Seven hundred twenty-four patients who began IVF treatment in 1998. INTERVENTION(S): Postal and phone contacts with unsuccessful IVF patients. MAIN OUTCOME MEASURE(S): Long-term outcome of parenthood project. RESULT(S): Of the 724 patients, a minimum of 53% and a maximum of 81% finally succeeded in their parenthood project during or after IVF treatment (depending on the hypotheses that the 204 patients not contacted either failed or succeeded in their parenthood project). An intermediate hypothesis gave an estimation of 66% of patients finally succeeding in having a child (40% during IVF treatment in the center and 26% after). Achievement of the parenthood project after IVF discontinuation was due mainly to adoption of a child (46%) or a birth following a spontaneous pregnancy (42%). CONCLUSION(S): Unsuccessful patients should not lose hope, because nearly half may subsequently succeed in having a child.

Association between premenopausal progestogen use and postmenopausal hormonal therapy in the GAZEL cohort.

OBJECTIVES: The aim of this work was to verify the existence of and characterise the relationship between premenopausal progestogen use, subsequent use of estrogen-progestogen therapy (EPT) and risk factors for breast cancer, and to describe and analyse premenopausal progestogen use among women participating in a longitudinal study. METHODS: Data came from self-administered questionnaires mailed to 2254 pre- or peri-menopausal women aged 45 years or older participating in the French GAZEL cohort and followed for 10 years. Bivariate and multivariate analyses first examined the association between progestogen use and women's and physicians' characteristics. A generalised linear model was then used to analyse the association between progestogen use and EPT use, while taking into account factors associated with progestogen use. RESULTS: Thirty-six percent of the women had used progestogens before menopause: 56% of them 19-norpregnane derivatives, and 13% 17alpha hydroxyprogesterone derivatives. They were more likely to report breast pain, a family history of breast cancer and mood changes, to be thin, to consult a gynaecologist rather than a general practitioner, to consult a female physician, and to consult often. Of the 1756 women who had reached menopause, EPT users were more likely to have used progestogens premenopausally (adjusted RR: 1.2; 95% CI: 1.1-1.3). CONCLUSIONS: Physician characteristics play an important role in the use of progestogens before menopause. Our results also suggest that women using progestogens may have a higher risk of breast cancer, that is, that progestogen use may be a confounding rather than causal factor. The analyses concerning the relationship between EPT use and breast cancer risk must take progestogen use before menopause into account, as they do other confounding factors, such as age at menarche, parity, and use of oral contraceptives.