Mapping Outcomes and Registries Used in Current Danish Pharmacoepidemiological Research.

Purpose: There is an increasing need for national and international pharmacoepidemiological studies based on high-quality real-world data of which the Danish registries are a valuable source. In lack of a complete overview of which data are used to assess real-world drug safety and effectiveness outcomes, we aimed to map the outcomes, data sources, and the reporting of outcome quality in recent pharmacoepidemiological studies. Methods: We conducted a systematic mapping review of pharmacoepidemiological studies based on Danish registries investigating drug safety and/or effectiveness, published in the period 2018-2019, identified in PubMed and Scopus. Extraction included: Anatomical Therapeutic Chemical level 2 code for drug exposures, outcomes, outcome data sources, and quality of outcomes. Results: Of the 210 included studies, 96% used outcomes categorized as Clinical, 4% utilized outcomes categorized as Society-related, 5% used outcomes categorized as Healthcare cost and utilization, and 3% of the studies applied outcomes categorized as Patient-reported in which the percentages are not mutually exclusive. Diagnosis (66%) and Mortality (38%) were the two most utilized subcategories among those categorized as Clinical outcomes. Danish Health Data Authority and Statistics Denmark registries were the most reported outcome data sources (90%). Ninety-six studies (46%) reported one or more quality parameters related to their outcomes of interest with accuracy/validity being the most reported parameter (22%). Conclusion: The Danish registries support a wide range of outcomes. Across therapeutic areas, most studies investigate traditional clinical outcomes of disease and mortality based on data from a small number of available registries. In contrast, clinical and biochemical databases, despite potentially offering outcomes with high responsiveness, and the high-quality social and healthcare cost registries were rarely used as outcome data sources.

Diabetic ketoacidosis in patients exposed to antipsychotics: a systematic literature review and analysis of Danish adverse drug event reports.

RATIONALE: Patients exposed to second-generation antipsychotics (SGAs) have approximately 10 times increased risk of diabetic ketoacidosis (DKA) compared with the general population. However, as DKA is a rare complication of type 2 diabetes mellitus, and susceptible patients exposed to antipsychotics may rapidly develop DKA independently of treatment duration and weight gain, this is rather suggestive of type 1 diabetes mellitus (T1DM) or latent autoimmune diabetes in adults. OBJECTIVES: We performed a systematic review of current studies regarding antipsychotic-associated DKA with type 1 etiology and analyzed Danish adverse drug event (ADE) reports (previously unpublished cases). METHODS: PubMed, Embase, and the Cochrane Library were searched for all relevant studies, and the Danish Medicines Agency retrieved ADE reports using the Danish ADE database (up to date as of June 28, 2016). Diagnosis of antipsychotic-associated DKA with type 1 etiology was either considered confirmed or possible depending on authors' conclusions in the studies and/or clinical aspects. In addition, clinico-demographic risk factors were extracted. RESULTS: A total of 655 records and 11 ADE reports were identified, and after screening for eligibility, we included 21 case reports/series and two ADE reports (n = 24). No relevant clinical studies were included. Although fatal cases were identified, these were excluded because of diagnostic uncertainties (n = 15). DKA occurred in 15 males (62.5 %) and nine females (37.5 %), with a mean age ± standard deviation of 34.8 ± 12.4 years. Median time to DKA was 5 months (interquartile range: 1.4-11 months). Associated antipsychotics were olanzapine (n = 9, 36 %), aripiprazole (n = 6, 24 %), risperidone (n = 6, 24 %), clozapine (n = 3, 12 %), and quetiapine (n = 1, 4 %). Nine patients (37.5 %) were confirmedly diagnosed with T1DM following DKA resolution, whereas 15 patients (62.5 %) had possible T1DM. In 22 patients (91.7 %), ongoing insulin treatment was required for glycemic control. CONCLUSIONS: Increased awareness of the potential risk of antipsychotic-associated DKA and subsequent T1DM diagnosis, with insulin requirements for glycemic control, is warranted. The underlying mechanisms are poorly understood but most probably multifactorial. Certainly, further studies are warranted. Clinicians must utilize appropriate monitoring in susceptible patients and consider the possibility of continuing antipsychotic treatment with appropriate diabetic care.

Eosinophilic myocarditis during treatment with olanzapine - report of two possible cases.

BACKGROUND: Drug-induced eosinophilic myocarditis is a life-threatening and frequently overlooked condition. The prevalence of myocarditis in clozapine-treated patients may be as high as 3 %. An association between olanzapine and myocarditis has not previously been described, but given the chemical similarity between olanzapine and clozapine, we hypothesized the existence of such an association. We searched the spontaneous adverse drug reports database of the Danish Health and Medicines Authority for olanzapine and myocarditis in the period from October 21, 1996 to - June 03, 2015. We identified two fatal cases of eosinophilic myocarditis associated with the use of olanzapine. CASE PRESENTATION: Case 1 was a 39-year-old Caucasian man with known substance abuse and schizophrenia. He was found dead in his home. Olanzapine was prescribed at day -54, and dose at time of death was 40 mg/day. Post-mortem toxicological examination demonstrated presence of olanzapine, morphine, venlafaxine and oxazepam. Syringes indicating substance abuse were found in his home. Case 2 was a 36-year-old Caucasian man diagnosed with schizophrenia was found dead unexpectedly. There was no history of substance abuse. Current treatment was olanzapine 20 mg/day +5 mg as PRN (prescribed for almost 4 years), aripiprazole 30 mg/day (prescribed for 6 months) and mirtazapine 30 mg/day (prescribed for 6 months). Both cases of eosinophilic myocarditis were confirmed by autopsy findings and both patients received olanzapine in doses exceeding the recommendations. CONCLUSION: Olanzapine may have contributed to and/or worsened the two reported fatal cases of myocarditis. Additional studies are required to establish a causal link between olanzapine and eosinophilic myocarditis.

Abuse Potential of Pregabalin: A Systematic Review.

BACKGROUND: Several case reports and epidemiological studies have raised concern about the abuse potential of pregabalin, the use of which has increased substantially over the last decade. Pregabalin is, in some cases, used for recreational purposes and it has incurred attention among drug abusers for causing euphoric and dissociative effects when taken in doses exceeding normal therapeutic dosages or used by alternative routes of administration, such as nasal insufflation or venous injection. The magnitude of the abuse potential and the mechanism behind it are not fully known. OBJECTIVE: The aim of this study was to present a systematic review of the data concerning the abuse potential of pregabalin. METHODS: We performed a systematic literature search and reviewed the preclinical, clinical and epidemiological data on the abuse potential of pregabalin. RESULTS: We included preclinical (n = 17), clinical (n = 19) and epidemiological (n = 13) studies addressing the abuse potential of pregabalin. We also reviewed case reports (n = 9) concerning abuse of pregabalin. The preclinical studies indicated that pregabalin possesses modulatory effects on the GABA and glutamate systems, leaving room for an abuse potential. Further, clinical studies reported euphoria as a frequent side effect in patients treated with pregabalin. The majority of case reports concerning abuse of pregabalin involved patients with a history of substance abuse and, similarly, epidemiological studies found evidence of abuse, especially among opiate abusers. CONCLUSIONS: Overall, the available literature suggests an important clinical abuse potential of pregabalin and prescribers should pay attention to signs of abuse, especially in patients with a history of substance abuse.

Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation.

BACKGROUND: The bleeding risk among patients with atrial fibrillation is higher early after initiating therapy with vitamin K antagonists (VKAs). Evidence is limited on how prior VKA experience affects bleeding risk when initiating novel oral anticoagulant therapy. We investigated this among patients with atrial fibrillation initiating dabigatran therapy. METHODS: By using nationwide Danish prescription and patient registries, we identified 11,315 first-time dabigatran users with atrial fibrillation. Warfarin controls were matched in a 2:1 ratio according to VKA experience status. The average follow-up time was 13 months. Across the 6 combinations of treatment (dabigatran 110 mg, dabigatran 150 mg, and warfarin) and VKA experience status (naive or experienced), VKA-naïve warfarin initiators had the highest rate of any bleeding event. Cox regressions adjusted for baseline characteristics showed reductions relative to this group ranging from 19% for VKA-experienced dabigatran 110 mg users (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66-1.00) to 41% for VKA-experienced dabigatran 150 mg users (HR, 0.59; 95% CI, 0.46-0.75). Among switchers to dabigatran from warfarin, when comparing with warfarin-persisting users, the rate of any bleeding was nonsignificantly decreased for switchers to dabigatran 150 mg (HR, 0.80; 95% CI, 0.62-1.03) but not for switchers to dabigatran 110 mg (HR, 1.12; 95% CI, 0.90-1.41). Results for major bleeding were similar. Crude rates of fatal, intracranial, and gastrointestinal bleeding were low. CONCLUSIONS: VKA-naïve warfarin initiators had the highest overall bleeding rate. We found no evidence of marked excess of overall bleeding events when comparing dabigatran with warfarin users, irrespective of prior VKA experience.

Myocardial ischemic events in 'real world' patients with atrial fibrillation treated with dabigatran or warfarin.

BACKGROUND: Dabigatran may provide less protection against myocardial infarction than vitamin K antagonists (VKAs) in patients with atrial fibrillation. This may be particularly evident among "switchers" to dabigatran from VKA, as a result of discontinuation effects. METHODS AND RESULTS: We identified in nationwide Danish registries a cohort of VKA-naïve "new starters" on dabigatran (110 mg twice daily [bid] and 150 mg bid dose regimes) or warfarin, and a cohort of prior VKA-experienced "switchers" to dabigatran or "continuers" on warfarin. Cohorts were followed for an average of 16.0 months. Adjusted Cox regression models were used to compare event rates. Relative to warfarin, there was a nonsignificant trend to lower myocardial infarction rates with dabigatran among VKA-naïve users (110 mg hazard ratio [HR] 0.71; 95% confidence interval [CI], 0.47-1.07; 150 mg HR 0.94; 95% CI, 0.62-1.41); however, there was a nonsignificant trend to increased myocardial infarction rates among prior VKA-experienced users (110 mg HR 1.45; 95% CI, 0.98-2.15; 150 mg HR 1.30; 95% CI 0.84-2.01). An increased myocardial infarction rate relative to warfarin among prior VKA-experienced users was clearly significant during the early follow-up period of <60 days (110 mg HR 3.01; 95% CI, 1.48-6.10; 150 mg HR 2.97; 95% CI, 1.31-6.73). Comparable results were obtained for a composite end point (myocardial infarction, unstable angina, or cardiac arrest) among both VKA-naïve and prior VKA-experienced users. CONCLUSIONS: In this large-scale nationwide cohort study, we found that switching to dabigatran increased the risk of myocardial infarction compared with continued warfarin usage in the early period after switching. Caution may be warranted, especially when switching prior VKA-experienced patients with atrial fibrillation to dabigatran.

Prescribing patterns and safety monitoring of duloxetine using the Danish Register of Medicinal Product Statistics as a source.

BACKGROUND: The safety and pattern of use of a medicinal product cannot be fully studied prior to its marketing. In Denmark, the Danish Health and Medicines Authority (DHMA) monitors marketed drugs. An available source is the Register of Medicinal Product Statistics (RMPS), which can possibly be used for these purposes. OBJECTIVE: To investigate utilisation and potential safety issues of relatively new antidepressants containing the active ingredient duloxetine (Cymbalta(®) and Xeristar(®)) by using dispensing data available in the RMPS. METHODS: A retrospective study using dispensing data was designed to estimate the size and composition of the user population and patterns of use of the antidepressants Cymbalta(®) and Xeristar(®) (active ingredient: duloxetine) in the period from 1 January 2005 to 31 December 2010. Data were retrieved from Epikur, a register subset of the RMPS. RESULTS: Both women and men in different age groups used duloxetine for depression. Some users switched to another antidepressant. Prescription of the drug for persons below the age of 18 years revealed a potential safety issue. Concomitant treatment with Cymbalta(®) or Xeristar(®) and fluvoxamine, isocarboxazid, Yentreve(®), or ciprofloxacin also revealed potential safety issues. CONCLUSIONS: The present study indicated that the RMPS is applicable in monitoring the pattern of use and potential safety issues related to duloxetine when it is prescribed for depression. Switching to other antidepressants could reflect some potential safety issues. Use of duloxetine for persons below the age of 18 years and its concomitant use with contraindicated drugs also indicated potential safety issues.

Efficacy and safety of dabigatran etexilate and warfarin in "real-world" patients with atrial fibrillation: a prospective nationwide cohort study.

OBJECTIVES: The aim of this study was to assess the efficacy and safety in an "everyday clinical practice" population of anticoagulant-naïve patients with atrial fibrillation (AF) treated with dabigatran etexilate after its post-approval availability in Denmark, compared with warfarin. BACKGROUND: Concerns have been raised about an excess of bleeding events or myocardial infarction (MI) among patients treated with the new oral direct thrombin inhibitor, dabigatran etexilate. METHODS: From the Danish Registry of Medicinal Product Statistics, we identified a dabigatran-treated group and a 1:2 propensity-matched warfarin-treated group of 4,978 and 8,936, respectively. Comparisons on efficacy and safety outcomes were made on the basis of Cox-proportional hazards models stratified on propensity-matched groups. RESULTS: Stroke and systemic embolism were not significantly different between warfarin- and dabigatran-treated patients. Adjusted mortality was significantly lower with both dabigatran doses (110 mg b.i.d., propensity-match group stratified hazard ratio [aHR]: 0.79, 95% confidence interval [CI]: 0.65 to 0.95; 150 mg b.i.d., aHR: 0.57, 95% CI: 0.40 to 0.80), when compared with warfarin. Pulmonary embolism was lower compared with warfarin for both doses of dabigatran. Less intracranial bleeding was seen with both dabigatran doses (110 mg b.i.d., aHR: 0.24, 95% CI: 0.08 to 0.56; 150 mg b.i.d., aHR: 0.08, 95% CI: 0.01 to 0.40). The incidence of MI was lower with both dabigatran doses (110 mg b.i.d., aHR: 0.30, 95% CI: 0.18 to 0.49; 150 mg b.i.d., aHR: 0.40, 95% CI: 0.21 to 0.70). Gastrointestinal bleeding was lower with dabigatran 110 mg b.i.d. (aHR: 0.60, 95% CI: 0.37 to 0.93) compared with warfarin but not dabigatran 150 mg b.i.d. The main findings were broadly consistent in a subgroup analysis of dabigatran users with ≥1-year follow-up (median follow-up 13.9 months [interquartile range: 12.6 to 15.3 months]). CONCLUSIONS: In this "everyday clinical practice" post-approval nationwide clinical cohort, there were similar stroke/systemic embolism and major bleeding rates with dabigatran (both doses) compared with warfarin. Mortality, intracranial bleeding, pulmonary embolism, and MI were lower with dabigatran, compared with warfarin. We found no evidence of an excess of bleeding events or MI among dabigatran-treated patients in this propensity-matched comparison against warfarin, even in the subgroup with ≥1-year follow-up.

[Prescription of topical immunomodulators]. / Ordination af topikale immunmodulatorer.

INTRODUCTION: As from 2005, the Danish Medicines Agency has recommended prescription of topical calcineurin inhibitors (TCI) to patients aged two years and older after attempting treatment with topical corticosteroids. MATERIAL AND METHODS: Via the Danish Register of Medical Product Statistics every TCI-user was identified (encrypted ID) from July 2002-2007: 18,780 tacrolimus- and 40,895 pimecrolimus users. Changes over time in first-line users are studied by 2 test and in age distributions by Mann-Whitney U-test. RESULTS: 1-year prevalence and incidence have decreased since 2005. In the period 2003-2007, 21% of all tacrolimus incident users and 36% of all pimecrolimus incident users were first-line users. In the period 2003-2007, 590 tacrolimus users and 4,913 pimecrolimus users were below the age of two years. These pimecrolimus users decreased in number from 1,440 in 2003 to 480 in 2007. In four out of five first-line pimecrolimus users below the age of two years, the first prescription was issued by a general practitioner. CONCLUSION: The decrease in the sale of TIM since 2005 coincided with the changed recommendations. On the basis of the available data, it is not possible to determine whether the percentage of first-line users are reasoned by the skin area is not suitable for corticosteroids. In 2007, the recommendation was not followed for a minor number of TIM users below the age of two years.

Acute exercise increases adipose tissue interstitial adiponectin concentration in healthy overweight and lean subjects.

OBJECTIVE: We studied how an acute bout of exercise influences expression and concentration of adiponectin and regulators of adiponectin in adipose tissue and plasma. DESIGN AND METHODS: Eight overweight and eight lean males were examined by large-pore microdialysis in s.c. abdominal adipose tissue (SCAAT) and had arterialized blood sampled. On one day subjects rested for 3 h, exercised for 1 h at 55% of maximal oxygen uptake and rested again for 2.5 h, and on another day subjects rested for 6.5 h. On the day including exercise SCAAT was biopsied before and after exercise. RESULTS: Exercise increased the SCAAT interstitial adiponectin concentration in both overweight and lean subjects and concentrations did not differ between groups. Plasma adiponectin did not increase during exercise and was similar in overweight and lean subjects. Adiponectin mRNA in SCAAT decreased during exercise and was similar in overweight and lean subjects. Surprisingly, the interstitial adiponectin concentration in SCAAT was only 20% of the plasma concentration. SCAAT interleukin-6 (IL-6) microdialyzate and plasma concentrations and SCAAT IL-6 mRNA increased during exercise in both groups. Tumor necrosis factor- (TNF-) plasma concentration did not change during exercise in any of the groups, but SCAAT TNF- mRNA increased after exercise in both groups. Furthermore, exercise decreased SCAAT leptin mRNA with no change in resistin mRNA. CONCLUSIONS: Acute exercise increases adipose tissue interstitial adiponectin concentration in both overweight and lean subjects with no major changes in plasma adiponectin concentration. The interstitial concentration of adiponectin in SCAAT is only 20% of that in plasma.

[The use of analgesics in Denmark, 2000-2004]. / Analgetikaforbruget i Danmark 2000-2004.

INTRODUCTION: The purpose of this survey was to map the sale of analgesics in the Danish primary care sector from 2000 to 2004. MATERIALS AND METHODS: Data on analgesics and NSAIDs were drawn from the Register of Medicinal Products Statistics. Sales in 2004 and changes from 2000 to 2004 are treated with descriptive statistics. Our focus was on analgesics bought on prescription. RESULTS: In 2004, approximately 580,000 persons bought an analgesic on prescription. Including NSAIDs it is a total of approximately 1.16 million people. Between 2000 and 2004, the number of users increased by 10%. STRONG OPIOIDS: The number of users was almost unchanged from 2000 to 2004. Most people bought ketobemidone and morphine, even though the number of these users decreased. In contrast, the number of oxycodone users increased greatly. Several-time users of oxycodone are often new users of strong opioids. Likewise, the number of users of transdermal fentanyl and buprenorphine patches increased. WEAK OPIOIDS: The number of users increased by approximately 31,000 (10%), due to a greater number of users of tramadol, while the number of users of other weak opioids decreased. Thirty percent of several-time users of tramadol had not previously bought other analgesics on prescription. NSAIDs: The number of users increased by approximately 95,000 (13%). After 2002, the number of coxib users decreased concurrently with an increased usage of other NSAIDs. After coxib treatment, 29% of several-time users did not shift to other analgesics bought on prescription. WEAK NON-OPIOIDS: The number of users increased by approximately 42,000 (15%). The majority were users of paracetamol. CONCLUSION: In 2004, every fifth Danish citizen bought analgesics on prescription. Between 2000 and 2004, the number increased. In particular, the number of users of NSAIDs was large. The number of users of strong opioids did not increase as did the number of users of the other groups of analgesics, but within that group there was a shift to more expensive drugs.

The outcome of bone mineral density measurements on patients referred from general practice.

The incidence of osteoporosis is increasing and the general practitioner is integral to identifying these patients. It is, therefore, of interest to characterize the referral pattern of patients scheduled for determination of bone density by means of dual-energy X-ray absorptiometry scanning. Altogether, 1551 scans from first-time referred women were analyzed with respect to normal bone mineral density (BMD), osteopenia, and osteoporosis as the outcome, and the results were compared with age and body mass index (BMI). Using multiple regression analysis, risk estimates for osteoporosis were calculated with respect to patient characteristics. Only 21% of the referred patients had osteoporosis and 34% had osteopenia. Of these, 24% had osteopenia and a Z-score below -1. Half of the referred patients were women less than 60 yr with a markedly low risk of osteoporosis. A BMI less than 20 kg/m(2) increased the predictive value considerably. A low BMI is a good indicator for referral of women less than 60 yr for measurements of bone density. Forty-five percent of the referred women from general practitioners had a normal BMD.