Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

BACKGROUND: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. OBJECTIVES: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. RESULTS: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. CONCLUSIONS: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS.

Characteristics of New Users of Aclidinium Bromide, Aclidinium/Formoterol, and Other COPD Medications in the United Kingdom, Denmark, and Germany.

BACKGROUND AND OBJECTIVES: Aclidinium bromide was approved in the European Union for the treatment of chronic obstructive pulmonary disease (COPD) in adult patients in 2012 and in a fixed-dose combination with formoterol in 2014. We characterised new users of aclidinium, aclidinium/formoterol and other COPD medications and evaluated off-label prescribing of these medications in three European populations. METHODS: We described demographic characteristics, comorbidities, comedications, COPD severity and off-label prescribing of new users of aclidinium, aclidinium/formoterol and other COPD medications in patients with COPD aged ≥ 40 years in the Clinical Practice Research Datalink (CPRD, UK), Danish National Health Databases, and German Pharmacoepidemiological Research Database (GePaRD) between 2015 and 2017. RESULTS: We included 17,668 new users of aclidinium (CPRD, 4871; Denmark, 2836; GePaRD, 9961) and 14,808 new users of aclidinium/formoterol (CPRD, 2153; Denmark, 2586; GePaRD, 10,069). Study patients were of similar age, except in GePaRD, where users of long-acting beta2-agonists (LABA)/inhaled corticosteroids were younger. Patients had multiple comorbidities and used multiple comedications-most frequently hypertension (50-79%) and short-acting beta2-agonists (26-84%). Aclidinium users in CPRD and long-acting anticholinergics/LABA users in Denmark and GePaRD had the highest frequency of severe/very severe COPD. Off-label prescribing of aclidinium (5.0% [CPRD]-8.9% [Denmark]) and aclidinium/formoterol (2.6% [GePaRD]-3.2% [CPRD]) was low, and the main reason was asthma without a COPD diagnosis. CONCLUSIONS: Aclidinium and aclidinium/formoterol were mostly prescribed according to label, with preference given to older patients with more severe COPD and to patients with a high prevalence of comorbidities and comedication use.

Cardiovascular Risk in Users of Mirabegron Compared with Users of Antimuscarinic Treatments for Overactive Bladder: Findings from a Non-Interventional, Multinational, Cohort Study.

INTRODUCTION: During clinical trials, mirabegron, a ß3-adrenoreceptor agonist, was associated with increased vital signs vs placebo in patients with overactive bladder. OBJECTIVE: The purpose of this study was to compare incidence rates of adverse cardiovascular (CV) outcomes following mirabegron or antimuscarinic use. METHODS: We conducted an observational post-marketing safety study utilising real-world data. The study population was identified within five sources: Danish and Swedish National Registers, Clinical Practice Research Datalink (UK), Optum (USA) and Humana (USA). Episodes of time when patients were new users of mirabegron or antimuscarinics (October 2012-December 2018) were sourced from prescriptions and matched on propensity scores. Occurrences of major adverse cardiovascular events (MACE), acute myocardial infarction (AMI), stroke, CV mortality and all-cause mortality were identified. Outcome incidence rates and hazard ratios from Cox models were estimated. RESULTS: Overall, 152,026 mirabegron and 152,026 antimuscarinic episodes were matched. The population consisted of 63.1% women and 72.6% were ≥ 65 years old. There were no appreciable differences in the incidence rates of MACE, AMI or stroke between users of mirabegron and antimuscarinics. Incidence rates of CV mortality (hazard ratio 0.83, 95% confidence interval 0.73-0.95) and all-cause mortality (hazard ratio 0.80, 95% confidence interval 0.76-0.84) were no higher with mirabegron vs antimuscarinics. Results restricted to episodes at high risk for CV events or stratified by age (< 65 years, ≥ 65 years) or prior overactive bladder medication use were consistent with overall findings. CONCLUSIONS: This large, multinational study found no higher risk of MACE, AMI, stroke, CV mortality or all-cause mortality among users of mirabegron relative to users of antimuscarinics.

During clinical trials, mirabegron, which is a treatment for overactive bladder, was associated with small increases in heart rate and blood pressure. This study was conducted to compare the frequency of cardiac events following the use of mirabegron or antimuscarinics, a group of treatments also used to treat overactive bladder. We obtained the data for this study from four countries: Denmark, Sweden, the UK and the USA. We identified people who were new users of mirabegron or antimuscarinics from 2012 to 2018 using prescription or dispensing records. Occurrences of major cardiac events, heart attack, stroke, death due to cardiac events and death from any cause were evaluated. Overall, we identified 152,026 times when mirabegron or antimuscarinics were each used as new treatments. Most of the people in the study were women (63.1%) and at least 65 years old (72.6%). There were no notable differences between the treatment groups with regard to how often major cardiac events, heart attack or stroke occurred. Further, death due to cardiac events and death from any cause were no higher with mirabegron compared with antimuscarinics. We obtained similar results when the data were assessed for patients who were at high risk for cardiac events or split by age (less than 65 years or at least 65 years) or a history of overactive bladder medication use. In conclusion, this large study involving data from several countries found no higher risk of major cardiac events, heart attack, stroke or death among people prescribed mirabegron compared with antimuscarinics.

A study of cancer occurrence in users of mirabegron and antimuscarinic treatments for overactive bladder.

OBJECTIVE: This post-authorization safety study (EU PAS Register Number: EUPAS16088) was designed to compare the incidence of cancer outcomes in patients treated with mirabegron versus antimuscarinic medications. METHODS: Cohorts of mirabegron initiators during 2012-2018 were propensity-score matched to antimuscarinic medication initiators within real-world data sources (Danish National Registers, Swedish National Registers, Clinical Practice Research Datalink [UK], Optum [US], and Humana [US]). Incident cancer cases were identified during follow-up from direct linkage to cancer registers or validated through medical record review or through physician questionnaires. Comparisons of sex-specific composite cancer outcomes (cancer of the lung/bronchus, colon/rectum, melanoma of skin, urinary bladder, non-Hodgkin lymphoma, kidney/renal pelvis, pancreas, prostate in men and breast and uterus in women) were made overall and for person-time in the first year and after the first year following start of treatment, for all ages and for the subgroup ≥65 years. RESULTS: Among the 80,637 mirabegron initiators matched to 169,885 antimuscarinic medication initiators, 68% were at least 65 years of age and 66% were women. Over 5000 incident cancer cases were observed overall. Incidence rates were higher for men than women for composite and individual cancer outcomes. The pooled fixed effects hazard ratios for composite cancer outcomes (all ages) were 1.05 (95% confidence interval [CI]: 0.98-1.14) for women and 1.06 (95% CI: 0.98-1.14) for men. Results were similar in persons ≥65 years. CONCLUSIONS: The results suggest no association between mirabegron use and risk of cancer, compared with antimuscarinic medications, in either men or women. Registration: EU PAS Register Number: EUPAS16088.

Patterns of use of antimuscarinic drugs to treat overactive bladder in Denmark, Sweden, and the United Kingdom.

PURPOSE: To describe the use of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark, Sweden, and the United Kingdom (UK). METHODS: We identified new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, and trospium aged 18 years or older from the Danish National Registers (2004-2012), the Swedish National Registers (2006-2012), and UK Clinical Practice Research Datalink (2004-2012). Users were followed until disenrollment, cancer diagnosis, death, or study end. Treatment episodes, identified by linking consecutive prescriptions, were described with respect to duration, drug switch, and drug add-on. RESULTS: Mean age of OAB drug users was 66 years in Denmark (n = 72,917) and Sweden (n = 130,944), and 62 years in the UK (n = 119,912); 60% of Danish and Swedish patients and 70% of UK patients were female. In Denmark, of 224,680 treatment episodes, 39% were with solifenacin, and 35% with tolterodine; 2% were with oxybutynin. In Sweden, of 240,141 therapy episodes, 37% were with tolterodine and 35% with solifenacin; 5% were with oxybutynin. In the UK, of 245,800 treatment episodes, 28% were with oxybutynin, 27% with solifenacin, and 26% with tolterodine. In the three countries, 49%-52% of treatment episodes comprised one prescription and over 80% of episodes ended because of no refill; less than 20% ended because of a switch to another antimuscarinic. During the study years, we observed a change in OAB treatment preference from tolterodine to solifenacin. CONCLUSIONS: In these cohorts, persistence with antimuscarinic drugs was low. By 2012, the preferred drug was solifenacin; oxybutynin use was marginal in Nordic countries compared with the UK.

Comparison of cardiovascular events among treatments for overactive bladder: a Danish nationwide cohort study.

PURPOSE: The purpose of this study is to explore the cardiovascular safety of antimuscarinic drugs to treat overactive bladder (OAB) in Denmark. METHODS: This was a cohort study using data recorded in Danish registries from patients newly exposed to darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium in 2004-2012. We estimated crude and standardized incidence rates (IRs) for acute myocardial infarction (AMI); stroke; cardiovascular mortality; major adverse cardiac events (MACE, a combined endpoint of the previous three outcomes); and all-cause death for the individual and combined drugs. We also estimated crude, standardized, and propensity score-stratified incidence rate ratios (IRRs) comparing individual antimuscarinic drugs to tolterodine as the reference. RESULTS: Among 72,917 new users of OAB drugs (mean age, 66 years; 60% women), the standardized IR (95% confidence interval) per 1000 person-years for current use of any OAB drug was 2.7 (2.5-2.9) for AMI, 1.3 (1.2-1.5) for stroke, 7.8 (7.5-8.1) for MACE, 4.8 (4.5-5.0) for cardiovascular mortality, and 15.2 (14.8-15.6) for all-cause mortality. Propensity score-stratified IRRs for current use (reference, tolterodine) were close to the null for all drugs and endpoints. CONCLUSIONS: We did not identify differences in the risk of cardiovascular events or mortality among users of individual antimuscarinic OAB drugs.

Off-hours admission and quality of hip fracture care: a nationwide cohort study of performance measures and 30-day mortality.

OBJECTIVE: Higher risks of adverse outcomes have been reported for patients admitted acutely during off-hours. However, in relation to hip fracture, the evidence is inconsistent. We examined whether time of admission influenced compliance with performance measures, surgical delay and 30-day mortality in patients with hip fracture. DESIGN: Cohort study. SETTING: Data from The Danish Multidisciplinary Hip Fracture Registry linked with data from Danish National Registries. PARTICIPANTS: Danish patients undergoing hip fracture surgery, aged >65 years, admitted 1 March 2010 to 30 November 2013 (N = 25 305). EXPOSURE: Off-hours: weekday evenings and nights, and weekends. MAIN OUTCOME MEASURES: Meeting specific performance measures, surgical delay and mortality. RESULTS: No differences were found in patient characteristics or in meeting performance measures (RRs from 0.99 [95% CI: 0.98-1.01] to 1.01 [95% CI: 0.99-1.02]. When comparing admission on weekdays (evenings and nights vs. days), off-hours admission was associated with a lower risk of surgical delay (adjusted OR 0.75 [95% CI: 0.66-0.85]) while no differences in 30-day mortality was found (adjusted OR 0.91 [95% CI: 0.80-1.04]. When comparing admission during weekends with admission during weekdays, off-hours admission was associated with a higher risk of surgical delay (adjusted OR 1.19 [95% CI: 1.05-1.37]) and a higher 30-day mortality risk (adjusted OR 1.13 [95% CI: 1.04-1.23]. The risk of surgical delay appeared not to explain the excess 30-day mortality. CONCLUSIONS: Patients admitted off-hours and on-hours received similar quality of care. The risk of surgical delay and 30 days mortality was higher among patients admitted during weekends; explanations need to be clarified.

Off-hours admission and acute stroke care quality: a nationwide study of performance measures and case-fatality.

BACKGROUND AND PURPOSE: Studies have reported higher risks of death and other adverse outcomes in acute stroke patients admitted off-hours; however, little is known about the underlying mechanisms. According to time of admission, our aim was to examine compliance with performance measures for acute stroke care processes, including the effect of a systematic quality improvement program, and to examine 30 days case-fatality. METHODS: A population-based historical cohort study, including patients admitted to Danish hospitals with a first ever acute stroke (January 1, 2003, to December 31, 2011; N=64 975). Off-hours were weekends and evening and nighttime shifts on weekdays. Compliance with performance measures was compared using general linear modeling, and odds ratios for 30 days case-fatality were obtained using multivariable logistic regression. RESULTS: Patients admitted off-hours had a lower chance of compliance with 8 out of 10 performance measures; however, these differences diminished over time. Unadjusted odds ratio for 30 days case-fatality, for patients admitted off-hours compared with patients admitted on-hours, was 1.15 (95% confidence interval, 1.09-1.21). Adjusting for patient characteristics (in particular, stroke severity) decreased the odds ratio to 1.03 (95% confidence interval, 0.97-1.10). Additional adjustment for hospital characteristics and compliance with performance measures had no effect on the odds ratio. CONCLUSION: Patients admitted off-hours received a poorer quality of care. However, the admission time-related differences in care were substantially reduced over time, and the differences in 30 days case-fatality appeared primarily to be explained by differences in stroke severity.