Anne Broe

Use of proton-pump inhibitors among adults: a Danish nationwide drug utilization study

Background: The use of proton-pump inhibitors (PPIs) has increased over the last decade. The objective of this study was to provide detailed utilization data on PPI use over time, with special emphasis on duration of PPI use and concomitant use of ulcerogenic drugs. Methods: Using the nationwide Danish Prescription Registry, we identified all Danish adults filling a PPI between 2002 and 2014. Using descriptive statistics, we reported (i) the distribution of use between single PPI entities, (ii) the development in incidence and prevalence of use over time, (iii) measures of duration and intensity of treatment, and (iv) the prevalence of use of ulcerogenic drugs among users of PPIs. Results: We identified 1,617,614 adults using PPIs during the study period. The prevalence of PPI use increased fourfold during the study period to 7.4% of all Danish adults in 2014. PPI use showed strong age dependency, reaching more than 20% among those aged at least 80 years. The proportion of users maintaining treatment over time increased with increasing age, with less than10% of those aged 18–39 years using PPIs 2 years after their first prescription, compared with about 40% among those aged at least 80 years. The overall use of ulcerogenic drugs among PPI users increased moderately, from 35% of users of PPI in 2002 to 45% in 2014. Conclusions: The use of PPIs is extensive and increasing rapidly, especially among the elderly.

Increasing use of antibiotics in pregnancy during the period 2000–2010: prevalence, timing, category, and demographics

The aim of this study was to describe the use of antibiotics in a national population‐based cohort of pregnant Danish women between 2000 and 2010.

Use of antibiotics in children: a Danish nationwide drug utilization study.

Background: We aimed to describe the use of systemic antibiotics among children in Denmark. Methods: National data on drug use in Denmark were extracted from the Danish National Prescription Database. We used prescription data for all children in Denmark aged 0 to 11 years from January 1, 2000 to December 31, 2012. Results: We obtained data on 5,884,301 prescriptions for systemic antibiotics issued to 1,206,107 children. The most used single substances were phenoxymethylpenicillin (45%), amoxicillin (34%) and erythromycin (6%). The highest incidence rate of antibiotic treatment episodes was observed among children younger than 2 at 827 per 1000 children in 2012. Incidence rates were relatively stable throughout the study period. One-year prevalences in 2012 were 485, 363 and 190 per 1000 children among children aged 0–1, 2–4 and 5–11, respectively. A gradual shift from narrow-spectrum penicillin V to the broader-spectrum amoxicillin was found among children younger than 5. The use of macrolides decreased slightly, especially among those aged 0–1. Minor regional differences were noted, with somewhat higher use in the Capital Region. Skewness in use was most notable among those aged 0–1. There was little evidence of heavy users. Conclusion: Prescribing rate of antibiotics to children in Denmark remained stable at a high level from 2000 to 2012. An increase in the use of broad-spectrum beta-lactam penicillin was noted, but otherwise the prescribing pattern adhered well to National guidelines with respect to choice of antibiotics.

Initiation and persistence with dual antiplatelet therapy after acute myocardial infarction: a Danish nationwide population-based cohort study

Objectives The study investigated dual antiplatelet therapy (DAPT) patterns over time and patient characteristics associated with the various treatments in a myocardial infarction (MI) population. Design A registry-based observational cohort study was performed using antecedent data. Setting This study linked morbidity, mortality and medication data from Danish national registries. Participants All 28 449 patients admitted to a Danish hospital with a first-time MI and alive at discharge from 2009 through 2012 were included. Primary and secondary outcome measures Primary outcome was initiation of DAPT and secondary outcomes comprised persistence in DAPT treatment and switches between DAPT treatments. Results The overall proportion of patients prescribed DAPT increased from 68% (CL 95% 67–69%) to 73% (CL 95% 72–74%) from 2009 to 2012. For treatment of patients with and without percutaneous coronary intervention (PCI), the corresponding numbers were from 87% (CL 95% 86–88%) to 91% (CL 95% 90–92%) and from 49% (CL 95% 47–50%) to 52% (CL 95% 51–54%), respectively. Non-PCI patients had a higher cardiovascular risk compared with PCI patients. Among PCI patients, age>75 years, atrial fibrillation, diabetes and peripheral arterial disease were associated with a higher risk of treatment breaks for DAPT. Among patients without PCI, ticagrelor treatment was associated with an increased risk of treatment breaks during the first 12 months compared with clopidogrel treatment. Conclusions From 2009 to 2012, there was an increase in the proportion of patients with MI receiving DAPT, and a longer duration of DAPT. Still, a large proportion of patients without PCI are discharged either without DAPT or with a short DAPT duration. These findings may indicate the need for more careful attention to DAPT for patients with MI not undergoing PCI in Denmark.

Population Exposure to Phthalate-Containing Drugs

Phthalates are known endocrine disruptors. Not commonly recognized, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate‐containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed from medstat.dk. Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the ‘defined daily dose’ (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethyl phthalate (DEP) and dibutyl phthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate‐containing drugs in Denmark was common. We found 154 drug products containing five different phthalates. Two low‐molecular‐weight phthalates and three high‐molecular‐weight phthalates were identified, with a total sale of 59.4 and 112 DDD per 1000 inhabitants per day during the study period, respectively. The highest amount of DBP was found in multi‐enzymes (24.6–32.8 mg per DDD) and mesalazine (12.5–26.4 mg per DDD). Budesonide, lithium and bisacodyl also exceeded the DBP exposure limit of 0.01 mg/kg/day. Other drugs had high levels of DEP, although not exceeding the exposure limit. Sales of phthalate‐containing drugs in Denmark from 2004 to 2015 were substantial, and phthalate exposure from several products exceeded the regulatory exposure limit introduced in 2014.

Association between use of phthalate-containing medication and semen quality among men in couples referred for assisted reproduction

STUDY QUESTION Does phthalate exposure from prescription drugs affect semen quality? SUMMARY ANSWER Exposure to phthalate-containing drugs is associated with poor semen quality. WHAT IS KNOWN ALREADY Phthalates and their metabolites have been shown to disrupt the hormone signalling in animal studies. One study has shown associations between medicinal phthalate exposure and poor semen quality, suggesting similar effects in humans. STUDY DESIGN, SIZE, DURATION We included 18 515 males with poor semen quality (cases) and 31 063 males with normal semen quality (controls) registered in the Danish IVF Registry from 2006 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS Exposure to phthalate-containing drugs was assessed from the Danish Register of Medicinal Product Statistics. Outcome measures were obtained at the first contact with the fertility clinic, and categorized according to the International Classification of Diseases (ICD-10). The association between current use of phthalate-containing medications <90 days prior to semen sampling and reduced semen quality was analysed using unconditional logistic regression, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE In total, 57 cases and 72 controls redeemed at least one prescription for a drug containing ortho-phthalates in the 90 days before their first semen sample, yielding an adjusted odds ratio (OR) of 1.30 (95% CI: 0.91-1.85) for poor semen quality when compared to males exposed to phthalate-free generic drugs. Similarly, 81 cases and 78 controls exposed to a drug containing polymers had increased odds of poor semen quality (OR = 1.71, 95% CI: 1.24-2.35). Current exposure to polymer containing products from alimentary tract and metabolism drugs was associated with the highest OR of 2.80 (95% CI: 1.63-4.84). Comparing males exposed to drugs containing ortho-phthalates or polymers with males unexposed to prescription drugs, we found adjusted ORs of 1.32 (95% CI: 0.93-1.87) and 1.73 (95% CI: 1.26-2.36), respectively. We saw no clear relationship between degree of exposure and odds of poor semen quality. LIMITATIONS, REASONS FOR CAUTION The reliance on ICD-10 based register data restricted our ability to relate phthalate exposure to detailed semen parameters. Furthermore, due to imperfections in the registry, we could only include the first semen sample and could not follow semen quality over time. WIDER IMPLICATIONS OF THE FINDINGS Our results support the likely negative effect of phthalate exposure from medicinal drugs on semen quality. As exposures from medicinal products are readily avoidable, our findings may be of relevance to regulatory authorities. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by Odense University Hospital, Denmark (Grant number A1003). None of the authors declare conflict of interest.

Cumulative exposure to phthalates from phthalate-containing drug products: A Danish population-wide study

Up to 50‐fold higher levels of urinary phthalate metabolites have been observed in users of phthalate‐containing drug products compared with non‐users. This is of concern, as phthalates are suspected endocrine disrupters and have been associated with cancer development. This study aims to quantify annual cumulated phthalate exposure from drug products among users of phthalate‐containing oral medications in Denmark throughout the period of 2004–2016.

Patterns and predictors for prescription of psychotropics and mood‐stabilizing antiepileptics during pregnancy in Denmark 2000–2016

To analyse prescribing patterns during pregnancy for antipsychotics (APs), antidepressants (ADs) and mood‐stabilizing antiepileptics (AEDs) in Denmark from 2000 to 2016.

Use of Dicloxacillin and Risk of Pregnancy among Users of Oral Contraceptives

The antibiotic dicloxacillin has been shown to induce drug‐metabolizing CYP enzymes to a clinically relevant extent. In this study, we investigated whether the use of dicloxacillin confers an increased risk of unwanted pregnancy among oral contraceptive users. The study population comprised Danish women falling pregnant (1997–2015) during oral contraceptive use, defined as having filled a prescription for an oral contraceptive within 120 days both before and after the estimated date of conception. Data were analysed using a case‐crossover approach. For each woman, we assessed the use of dicloxacillin preceding the date of conception and during 10 previous control periods and estimated the odds ratio for such unintended pregnancies associated with the use of dicloxacillin. Among 364 women using dicloxacillin prior to conception, 40 (11%) were exposed to dicloxacillin at the time of conception, yielding an odds ratio (OR) associating use of dicloxacillin to unintended pregnancy of 1.18 (95% CI 0.84–1.65). Supplementary and sensitivity analyses generally returned similar estimates, except for a slightly increased risk among users of progestogen‐only oral contraceptives (OR 1.83, 95% CI 0.63–5.34). Analysis of other antibiotics as negative controls yielded results close to unity (ORs ranging from 0.83 to 1.13). In conclusion, our study found no evidence for an increased risk of oral contraceptive failure when using dicloxacillin. However, acknowledging study limitations, we suggest the use of supplementary barrier methods during treatment with dicloxacillin, until our findings are confirmed in further studies.

Use of beta-blockers and risk of serious upper gastrointestinal bleeding: a population-based case-control study:

Background: Some studies indicate a reduced risk of serious upper gastrointestinal bleeding (UGIB) for users of beta-blockers, but the association remains to be confirmed in larger studies and characterized with respect to differences among beta-blockers. We aimed to assess whether beta-blocker use decreases the risk of UGIB. Methods: We conducted a register-based, population-based case-control study in Denmark. We identified cases with a first validated discharge diagnosis of UGIB during the period 1995–2006. Controls were selected by risk-set sampling in a ratio of 10:1. We estimated crude and adjusted odds ratios (ORs) of the association between current beta-blocker use and the risk of UGIB by using conditional logistic regression and further stratified by selective and non-selective beta-blockers, respectively. Results: We identified 3571 UGIB cases and 35,582 controls. Use of beta-blockers was not found to be associated with a decreased risk of UGIB (adjusted OR 1.10; 95% CI: 1.00–1.21). The association remained neutral after stratification by selective and non-selective beta-blockers, and by single beta-blocker substances. Similarly, we found no association between current beta-blocker use and the risk of UGIB within different subgroups. Conclusions: We found no association between beta-blocker use and UGIB.