KRAS G12C mutated advanced non-small cell lung cancer (NSCLC): Characteristics, treatment patterns and overall survival from a Danish nationwide observational register study.

OBJECTIVES: We aimed to characterize the advanced NSCLC population in terms of KRAS G12C prevalence, patient characteristics, and survival outcomes after the introduction of immunotherapies. MATERIALS AND METHODS: We identified adult patients diagnosed with advanced NSCLC between January 1, 2018 and June 30, 2021 using the Danish health registries. Patients were grouped by mutational status (any KRAS mutation, KRAS G12C, and KRAS/EGFR/ALK wildtype [Triple WT]). We analyzed KRAS G12C prevalence, patient and tumor characteristics, treatment history, time-to-next-treatment (TTNT), and overall survival (OS). RESULTS: We identified 7,440 patients of whom 40% (n = 2,969) were KRAS tested prior to the first line of therapy (LOT1). Among the KRAS tested, 11% (n = 328) harbored KRAS G12C. More KRAS G12C patients were women (67%), smokers (86%), had a high (≥50%) level of PD-L1 expression (54%), and more frequently received anti-PD-L1 treatment than any other group. From the date of the mutational test result, OS (7.1-7.3 months) was similar between the groups. OS from LOT1 (14.0 months) and LOT2 (10.8 months), and TTNT from LOT1 (6.9 months) and LOT2 (6.3 months) was numerically longer for the KRAS G12C mutated group compared to any other group. However, from LOT1 and LOT2, the OS and TTNT were comparable when stratifying the groups by PD-L1 expression level. Regardless of the mutational group, OS was markedly longer for patients with high PD-L1 expression. CONCLUSION: In patients diagnosed with advanced NSCLC after the implementation of anti-PD-1/L1 therapies, the survival in KRAS G12C mutated patients is comparable to patients with any KRAS mutation, Triple WT, and all NSCLC patients.

Trends in use of attention deficit hyperactivity disorder medication among children and adolescents in Scandinavia in 2010-2020.

The objective of the study was to compare the use of attention deficit hyperactivity disorder (ADHD) medication among children and adolescents in Scandinavia 2010-2020. Using aggregated prescription data for individuals aged 5-19 years, we calculated annual prevalence proportions of ADHD medication (users/1000 inhabitants) for each country, overall and stratified by age and sex. Overall, use of ADHD medication increased during 2010-2020 in all countries. The increase was pronounced in Sweden reaching 35 users/1000 inhabitants in 2020 (119% increase), whereas it reached 22/1000 in Denmark and Norway (equivalent to a 38% and 16% increase, respectively). Methylphenidate was the most frequently used drug and Sweden had the highest use reaching 25/1000 in 2020 compared to 16/1000 and 18/1000 in Denmark and Norway, respectively. Lisdexamfetamine use increased steadily and was also highest in Sweden (13/1000 in 2020). In 2020, atomoxetine use was higher in Sweden (4.6/1000) and Denmark (4.5/1000) compared to Norway (2.2/1000). From 2015, use of guanfacine increased in Sweden reaching 4.4/1000 in 2020 but remained low in Denmark (0.4/1000) and Norway (0.7/1000). Use of dexamphetamine was low (ranging from 0.47 to 0.75/1000 in 2020) in the three countries. ADHD medication use was highest in Sweden across all age groups. In all countries, the prevalence was higher in males compared to females. In conclusion, use of ADHD medication among children and adolescents in Scandinavia is increasing. The prevalence of use is higher in Sweden for all drug groups compared to Norway and Denmark.

Opioid prescriber responsibility: A Danish drug utilization study.

AIMS: We describe the distribution of prescribers responsible for opioid initiation and maintenance (general practice, hospital prescribers and other prescribers) in Denmark. METHODS: We leveraged data on opioid fills from a 20% sample of all Danes alive during 2000-2021. RESULTS: Overall, general practitioners were responsible for most treatment initiation (74% during 2000-2021) and maintenance treatment (92%). However, while hospital prescribers initiated ≈20% of treatments during 2001-2012, this increased to 35% in 2021. Similarly, hospital prescriber's share of maintenance treatment increased from 5.9% during 2000-2012 to 13% in 2021. This change was particularly pronounced for morphine initiation (48% hospital prescribers in 2021 up from 38% during 2000-2010) and oxycodone initiation (78% up from 41%). Regarding choice of opioids, codeine use dropped markedly, in particular among hospital prescribers. Tramadol was consistently the most common first choice opioid in general practice (33% in 2021), whereas its use among hospital prescribers decreased (54% during 2000-2015 to 15% in 2021). Conversely, the proportion of treatment initiation by hospital prescribers composed of morphine and oxycodone increased to 38% and 42% in 2021, respectively. CONCLUSIONS: General practice prescribes most opioids; however, hospital prescribers are increasingly responsible for opioid prescribing, in particular initiation of morphine and oxycodone.

Short-term mortality following tramadol poisonings in Denmark.

Tramadol is a commonly used opioid with a potential of addiction and abuse. Using Danish nationwide registers, we aimed to (1) characterise opioid poisonings; (2) assess the 30-day mortality following morphine, oxycodone, and mixed poisonings compared to tramadol poisonings; and (3) assess the development in tramadol poisonings during a 12-year period. Poisonings were identified from 2006 to 2017. A Cox proportional hazards regression model was used to estimate adjusted hazard ratios (aHRs) along with 95% confidence intervals (CIs) for 30-day mortality following morphine, oxycodone or mixed poisonings compared to tramadol poisonings. We identified 7718 opioid poisonings among 6365 patients. The patients with a tramadol poisoning were younger and had less comorbidities than the patients with a morphine, oxycodone or mixed poisoning. Within 30 days, a total of 205 patients died. The 30-day mortality risk was higher following morphine (aHR 3.2, 95% CI 2.0-5.1), oxycodone (aHR 2.1, 95% CI 1.2-3.6) and mixed poisonings (aHR 1.6, 95% CI 1.0-2.7) compared to tramadol poisonings. The annual number of tramadol poisonings increased from 233 in 2006 to 501 in 2013 and declined to 348 in 2017. In conclusion, despite a lower mortality risk compared to other opioid poisonings, physicians should consider the poisoning and abuse risks when prescribing tramadol.

Exposure to Tramadol During Early Pregnancy and Risk of Spontaneous Abortion or Major Congenital Malformations.

OBJECTIVE: To investigate whether exposure to tramadol during early pregnancy is associated with an increased risk of spontaneous abortion or major congenital malformations. METHODS: The study is a nationwide cohort study including all registered pregnancies in Denmark between January 1, 1997, and December 31, 2016. The Danish National Prescription Register was used to identify maternal exposure to tramadol. Pregnancies with maternal exposure to tramadol were matched with pregnancies without maternal exposure to tramadol in a ratio of up to 1:4 using propensity scoring. The primary outcomes were spontaneous abortion and major congenital malformations. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) of spontaneous abortion, and log binominal models were used to estimate the relative risk ratios (RRs) of major congenital malformations. RESULTS: A total of 36,467 (tramadol exposure n=7,310) and 18,907 (tramadol exposure n=3,796) pregnancies were included in the analyses of spontaneous abortion and major congenital malformations, respectively. Spontaneous abortion occurred in 893 (12.2%) pregnancies with maternal exposure to tramadol and in 3,471 (11.9%) pregnancies without maternal exposure to tramadol (HR 1.06, 95% CI 0.99-1.14). A major congenital malformation occurred in the offspring of 151 (4.0%) pregnancies with maternal exposure to tramadol, compared with 579 (3.8%) in pregnancies without maternal exposure to tramadol (RR 1.04, 95% CI 0.87-1.24). CONCLUSION: Exposure to tramadol during early pregnancy does not appear to be associated with an increased risk of spontaneous abortion or major congenital malformations.

Ciprofloxacin exposure and adverse pregnancy outcomes: A Danish nationwide cohort study.

OBJECTIVE: To examine the association between maternal exposure to ciprofloxacin and the risk of miscarriage and major malformations. DESIGN: A nationwide register-based cohort study. SETTING: Data were obtained from the Medical Birth Registry, the National Hospital Registry, the Danish National Prescription Registry and Statistics Denmark. POPULATION: Data were collected in the period between 1997 and 2016 and included all registered pregnancies that ended in an elective termination, miscarriage, stillbirth or a live birth. Exposure was defined as redeeming one or more prescriptions of ciprofloxacin. METHODS: Miscarriage was defined as a diagnosis given before 22 weeks without any medical intervention. Major malformations were classified according to EUROCAT 1.4. We matched ciprofloxacin-exposed pregnancies to unexposed pregnancies on the propensity score in a ratio 1:4. To estimate the hazard ratio (HR) of miscarriage a Cox proportional hazard regression model was used. A log binomial model was used to estimate the relative risk ratio (RR) of major malformations. MAIN OUTCOME MEASURES: HR of miscarriage and the RR of major malformations. RESULTS: A total of 1 650 649 pregnancies were identified. Of these, 10 250 (2050 ciprofloxacin-exposed) and 6100 (1220 ciprofloxacin-exposed) were included in the miscarriage and major malformation analysis, respectively. The HR of miscarriage was 0.99 (95% confidence interval [CI] 0.84-1.17). For major malformation, the RR was 1.01 (95% CI 0.72-1.40). For the organ-specific major malformations and the sensitivity analyses, no significant increased risks were identified. CONCLUSION: We demonstrated no association between miscarriage and maternal ciprofloxacin exposure within the first 22 weeks of pregnancy, or between major malformations and maternal exposure during the first trimester. TWEETABLE ABSTRACT: No association between maternal ciprofloxacin exposure and adverse pregnancy outcomes.

Drug-related challenges following primary total hip and knee arthroplasty.

We aimed to characterize the in-hospital analgesic use among total hip or knee arthroplasty (THA or TKA) patients, and to identify possible drug-related challenges. We identified 15 263 patients operated with a THA or TKA between 1 January 2012 and 30 April 2016. The prevalence of analgesic users and patients with potential clinically relevant drug-drug interactions (DDIs), along with the prevalence of readmission among patients with vs. without a DDI, were calculated. A DDI was defined as the combination of (A) a diuretic, an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, and an non-steroidal anti-inflammatory Drug (NSAID); (B) warfarin and an NSAID; and (C) a benzodiazepine or a benzodiazepine-related drug and an opioid. The prevalence of analgesics administered in THA and TKA patients was 99.3% and 99.1% for paracetamol and 93.8% and 98.8% for opioids, respectively. The prevalence of patients who received interaction A, B or C was 8.4%, 2.5% and 40.7%, respectively. Patients with vs. without a DDI had a higher prevalence of 30-day readmission. In conclusion, most THA and TKA patients were administered paracetamol or opioids. The prevalence of 30-day readmission was higher in patients with than in patients without a potential clinically relevant DDI.

Use of tramadol and other analgesics following media attention and risk minimization actions from regulators: a Danish nationwide drug utilization study.

PURPOSE: To describe the use of tramadol and other analgesics in Denmark focusing on the impact of media attention (June and December 2017) and regulatory actions (September 2017 and January 2018) on the use of tramadol. METHODS: Using nationwide registries, we identified all adults who filled a prescription for tramadol and other analgesics from 2014 to 2019. We described incidence rates, prevalence proportions, and total use of tramadol and other analgesics over time. We also described switching between analgesics, treatment duration, skewness in drug use, and doctor-shopping. RESULTS: From early 2017 until the end of 2019, total tramadol use decreased markedly while the use of morphine and oxycodone decreased slightly. The quarterly prevalence of tramadol use decreased from 32/1000 individuals in 2014 to 18/1000 at the end of 2019, dropping mainly at the time of media attention. Concomitantly, the quarterly prevalence increased for oxycodone (from 5.1 to 8.2) and morphine (from 8.5 to 9.8), mainly due to more short-term and sporadic users, and decreased for codeine (14 to 9.6). From 2014 to mid-2017, the incidence of tramadol use was stable (around 2.2/1000 person-months) but dropped in June 2017 to 1.7/1000, coinciding with the media attention. The incidence of tramadol use continued to decrease (to 1.1/1000 at the end of 2019). CONCLUSION: We identified a decline in tramadol use coinciding with the media attention in 2017 and continuing during regulatory actions. There was generally no evidence of unintended effects on the utilization of opioids related to the media attention and regulatory actions.

Sex and age differences among tramadol users in three Nordic countries.

INTRODUCTION: The aim of this study was to examine the prevalence and characteristics of tramadol users in Denmark, Norway and Sweden. METHODS: Data from the national prescription databases comprising the entire population of Denmark, Norway and Sweden between 2007 and 2015 were used to assess prescription medicine use and sold amount (in defined daily doses (DDDs)) of tramadol, other opioids and non-steroidal anti-inflammatory drugs. RESULTS: From 2007 to 2015 the prevalence of tramadol users increased in Denmark from 45 to 52 per 1,000 residents, and in Norway from 20 to 41 per 1,000 residents. In Sweden, the prevalence decreased from 36 to 17 per 1,000 residents. In comparison, the prevalence of other opioid users decreased in Denmark and Norway, but increased in Sweden. During the study period, there were more female than male tramadol users in all three countries, and the prevalence of tramadol users tended to increase with age. The average tramadol DDD per treated patient remained fairly constant in Norway, while it increased in Denmark and Sweden. In Denmark and Norway, women received a higher DDD than men. The amount of sold tramadol and other opioids combined per 1,000 residents was highest in Denmark. CONCLUSIONS: From 2007 to 2015, the prescription patterns of tramadol and other opioids differed between the three countries. Tramadol was generally used more frequently by women. Women received higher DDD then men in Norway and Denmark, but not in Sweden. The prevalence of tramadol users tended to increase with age in all countries. FUNDING: none. TRIAL REGISTRATION: not relevant.

Analgesics use and withdrawal in people with dementia - a register-based Danish study and a systematic review.

INTRODUCTION: Pain assessment in people with dementia is difficult, and withdrawal of analgesics may allow for assessment of treatment efficacy whilst decreasing pill burden, adverse events and interactions. We aimed to describe the use of analgesics among elderly in Denmark and to compile the evidence for withdrawal of analgesics among people with dementia. METHODS: With respect to analgesics use, we employed data from national registries on the analgesic prescription use (opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen) in 2017 among elderly people with and without dementia. Trial evidence was produced by performing a systematic search in MEDLINE, Embase and Cinahl for trials evaluating withdrawal of analgesics in people with dementia. RESULTS: Opioids were prescribed more frequently (p = 0.026) and NSAIDs less frequently (p = 0.026) to people with dementia. With respect to trial evidence, we identified two studies: An observational cross-over study (n = 3) reporting acetaminophen withdrawal leading to increases in pain frequency and duration, and a cluster-randomised clinical trial (n = 352) reporting changes in mobilization-observation-behaviour-intensity-dementia-2 (MOBID-2) pain score during a four-week withdrawal period (acetaminophen, opioids and/or pregabaline) from a mean ± standard deviation of 2.3 ± 2.1 to 2.9 ± 2.6 compared with 3.5 ± 2.6 to 3.5 ± 2.5 in the control group. CONCLUSIONS: In Denmark, use of opioids is higher in elderly with dementia compared to elderly without dementia. The evidence suggests that withdrawal of analgesics may aggravate pain but increases in pain scores may be of little clinical relevance in most people. Clinical trials investigating analgesics withdrawal are warranted.