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Gabapentin and pregabalin have been associated with an increased risk of fragility fractures. Due to differences in pharmacokinetics, we aimed to assess the fracture-risk difference between the two medicines. We performed a Danish nationwide new user, high-dimensional propensity score-matched cohort study to assess the 90-day risk of fragility fractures among adults, from January 1996 to December 2018. We applied a high-dimensional propensity score to match new users of gabapentin with new users of pregabalin in a 1:1 intention-to-treat approach. Hazard ratios (HR), incidence rates (IR), and incidence rate difference (IRD) were obtained. We identified 388,236 eligible patients of which 294,223 and 98,869 initiated gabapentin and pregabalin, respectively. We included 48,272 matched pairs for further analysis. The mean age was 56 (IQR 44-69) years and the average follow-up was approximately 11,500 person-years (PY). The IR of fragility fragility fractures were 23.7 (95%CI 21.0-26.7), and 23.2 (95%CI 20.5-26.2) per 1,000 PY for gabapentin and pregabalin-exposed patients, respectively. This yielded a HR of 1.02 (95%CI 0.86-1.21) when using gabapentin as the intervention drug, and pregabalin as the reference drug. The IRD was estimated to 0.5 (95%CI -3.5-4.5) PY. In conclusion, short-term risk of fragility fractures among gabapentin-initiators was not different compared to those initiating pregabalin.

In March 2022, the Summary of Product Characteristics for the Lyrica brand of pregabalin was updated with warnings regarding malformation risks. This literature review and critical appraisal aims to explore whether these Summary of Product Characteristics updates are justified and provide clarity on the risk-benefit balance for pregabalin use in early pregnancy. A literature review was conducted in May 2022 to identify English language comparative studies of any design providing data about first trimester maternal pregabalin use and malformation risk. Five observational comparative cohort studies using data from 9 distinct datasets were located. Collectively these studies described at least 5300 unique pregabalin exposed pregnancies, with 4900 exposed in at least the first trimester. Three studies investigated overall major malformation risks, and 4 investigated specific malformation risks. The available evidence was found to be conflicting and generally of low quality, probably influenced by bias and data confounding, with no clear pattern of specific malformations observed. Findings from the largest study suggested absolute risks of major malformation of 4.8-5.6%, relative to a background risk of approximately 4%. Due to study methodology limitations, the available data were judged to only provide low quality evidence suggestive of a possible and unconfirmed small increased risk that cannot be solely attributed to foetal pregabalin exposure. This literature review and critical appraisal indicates that the Lyrica product literature updates are insufficiently substantiated and could result in confusion and misinformed clinical risk-benefit decision making.

Background: Serotonin syndrome is a potentially life-threatening syndrome with manifestations spanning from mild adverse effects to life-threatening toxicity. The syndrome is caused by overstimulation of serotonin receptors by serotonergic drugs. Since the use of serotonergic drugs is increasing, primarily due to the widespread use of selective serotonin reuptake inhibitors, cases of serotonin syndrome have likely seen a parallel increase. The true incidence of serotonin syndrome remains unknown due to its diffuse clinical presentation. Objectives: This review aims to provide a clinically focused overview of serotonin syndrome, covering its pathophysiology, epidemiology, clinical manifestations, diagnostic criteria, differential diagnosis, and treatment as well as classifying serotonergic drugs and their mechanism of action. The pharmacological context is emphasized, as it is crucial for detection and management of serotonin syndrome. Methods: Focused review based on a literature search using the PubMed database. Findings and conclusion: Serotonin syndrome can occur through therapeutic use or overdose of a single serotonergic drug, or as a drug interaction between two or more serotonergic drugs. Central clinical features consist of neuromuscular excitation, autonomic dysfunction and altered mental status, occurring in a patient undergoing new or altered serotonergic therapy. Early clinically recognition and treatment are crucial to prevent significant morbidity.

Purpose Taxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer. Methods We conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes. Results Among 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98–1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98). Conclusion Docetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Background: To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality.Methods: Our cohort included all premenopausal women aged 18-55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007-2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate or high), income (low, medium or high), and employment status (employed, unemployed or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs) and used Poisson regression to compute incidence rate ratios and 95% confidence intervals (95% CIs) of recurrence and death. We stratified on ER status/tamoxifen to evaluate interaction.Results: Our cohort included 2,616 women; 286 (CIP: 13%) experienced recurrence and 223 (CIP: 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased risks of recurrence (IRR: 1.45, 95% CI: 1.11-1.89) and mortality (IRR: 1.83, 95% CI: 1.32-2.52). Furthermore, we observed increased mortality in women with low education (IRR: 1.49, 95% CI: 0.95-2.33), low income (IRR: 1.37, 95% CI: 0.83-2.28), unemployment (IRR: 1.61, 95% CI: 0.83-3.13) or health-related work absenteeism (IRR: 1.80, 95% CI: 1.14-2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen.Conclusions: Low SEP in premenopausal women with non-metastatic breast cancer was associated with increased mortality, but not always recurrence. This suggests underdetection of recurrences in certain groups. Poor prognosis in women with low SEP, especially single women, may partly be explained by tamoxifen adherence. Citation Format: Cathrine Hjorth, Per Damkier, Bent Ejlertsen, Timothy L Lash, Henrik T Sørensen, Deirdre Cronin-Fenton. Socioeconomic position and prognosis in premenopausal breast cancer: A population-based cohort study in Denmark [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-22.

Purpose Breast cancer treatment is associated with adverse effects, which may delay return-to-work. Single nucleotide polymorphisms (SNPs) may influence the risk and severity of treatment toxicities, which in turn could delay return-to-work. We examined the association of 26 SNPs with return-to-work in premenopausal women with breast cancer. Methods Using Danish registries, we identified premenopausal women diagnosed with non-distant metastatic breast cancer during 2007‒2011, assigned adjuvant combination chemotherapy including cyclophosphamide and docetaxel. We genotyped 26 SNPs in 20 genes (ABCB1, ABCC2, ABCG2, CYP1A1, CYP1B1, CYP3A, CYP3A4, CYP3A5, GSTP1, SLCO1B1, SLCO1B3, ARHGEF10, EPHA4, EPHA5, EPHA6, EPHA8, ERCC1, ERCC2, FGD4 and TRPV1) using TaqMan assays. We computed the cumulative incidence of return-to-work (defined as 4 consecutive weeks of work) up to 10 years after surgery, treating death and retirement as competing events and fitted cause-specific Cox regression models to estimate crude hazard ratios (HRs) and 95% confidence intervals (CIs) of return-to-work. We also examined stable labor market attachment (defined as 12 consecutive weeks of work). Results We included 1,964 women. No associations were found for 25 SNPs. The cumulative incidence of return-to-work varied by CYP3A5 rs776746 genotype. From 6 months to 10 years after surgery, return-to-work increased from 25 to 94% in wildtypes (n = 1600), from 17 to 94% in heterozygotes (n = 249), and from 7 to 82% in homozygotes (n = 15). The HR showed delayed return-to-work in CYP3A5 rs776746 homozygotes throughout follow-up (0.48, 95% CI 0.26, 0.86), compared with wildtypes. Estimates were similar for stable labor market attachment. Conclusion Overall, the SNPs examined in the study did not influence return-to-work or stable labor market attachment after breast cancer in premenopausal women. Our findings did suggest that the outcomes were delayed in homozygote carriers of CYP3A5 rs776746, though the number of homozygotes was low.

In November 2013, the Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease was published, recommending statins for all individuals 50 years or older with an estimated glomerular filtration rate below 60 ml/min/1.73 m2 to lower the risk of major cardiovascular events. We quantified the prevalence of statin use among the target population before and after the guideline publication in a large Danish cohort of individuals with an estimated glomerular filtration rate below 60 ml/min/1.73 m2, to investigate the effect of the guideline, but found no difference in the prevalence of statin use prior to and after the guideline publication.

We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (−0.7–2.4), −5.9 (−11.8 to −0.03) and −1.1 (−2.5–0.4) h/L*10 −6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUC M3G/Dose)/(AUC morphine/Dose) and (AUC M6G/Dose)/(AUC morphine/Dose) ratio was reduced, −1.8 (−3.2 to −0.4) and −0.4 (−0.7 to −0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.

Background: The safety of fathers’ use of antidiabetic drugs in terms of child outcomes is an important clinical question. We aimed to assess the risk of adverse birth and early childhood outcomes after fathers’ use of antidiabetics prior to conception. Methods: A nationwide cohort study based on Danish health registries. The study comprised all live born singleton children in Denmark (1997 through 2018). Children were categorized according to fathers’ filled prescriptions for antidiabetic drugs three months prior to conception. Exposed cohorts: children born after paternal use of insulin or non-insulin anti-hyperglycemic agents. The unexposed constituted children born by fathers not treated with antidiabetics prior to conception. We examined adverse birth outcomes (preterm birth, small for gestational age (SGA)), and adverse childhood outcomes in the first year of life (major congenital malformations (MCMs), and infections diagnosed at a hospital). Results: A total of 1,318,684 children were included. In all, 5527 children were born after paternal use of insulin, 2121 after use of non-insulin anti-hyperglycemic agents, and 1,311,036 were unexposed. After fathers’ use of insulin we did not find increased risk of adverse outcomes. After fathers’ use of metformin, the adjusted OR of MCMs was 1.40 (95% CI 1.11–1.76). After fathers’ use of sulfonylureas, the adjusted OR of SGA was 1.80 (95% CI 1.11–2.93), and for child gastrointestinal infections the adjusted HR was 1.76 (95% CI 1.04–2.99). Conclusions: Fathers’ use of insulin was reassuring. Metformin and sulfonylureas were associated with selected adverse outcomes. Our findings suggest an additional 14 MCMs per 1000 fathers exposed to metformin prior to conception. As there is no meaningful supporting biological rationale, these findings should be confirmed in a different population prior to clinical consequences being drawn.

AimsThe Danish authorities implemented a differential rollout of the COVID-19 vaccines where individuals at high risk of COVID-19 were prioritized. We describe the temporal uptake of COVID-19 vaccines and changing characteristics of vaccine recipients in Denmark.MethodsUsing the Danish national health care registries, we identified all Danish residents ≥5 years of age who received at least one dose of a COVID-19 vaccine from December 27th, 2020, to January 29th, 2022. We charted the daily number of newly vaccinated individuals and the cumulative vaccine coverage over time, stratified by vaccine type, age groups, and vaccination priority groups. In addition, we described characteristics of vaccine recipients during 2-months-intervals and in vaccination priority groups.ResultsBy January 29th, 2022, 86%, 84% and 63% of Danish residents ≥5 years had received a first, second, and third dose, respectively, of a COVID-19 vaccine, most commonly the BNT162b2 vaccine (84% of vaccinated individuals). Vaccine uptake ranged from 48% in 5-11-year-olds up to 98% in 65-74-year-olds. Individuals vaccinated before June 2021 were older (median age 61-70 years vs. 10-35 years in later periods) and had more comorbidities such as hypertension (22-28% vs. 0.77-2.8% in later periods), chronic lung disease (9.4-15% vs. 3.7-4.6% in later periods), and diabetes (9.3-12% vs. 0.91-2.4% in later periods).ConclusionsThe uptake of the COVID-19 vaccines is high in Denmark. We document substantial changes over time in characteristics of vaccine recipients which should be considered when designing and interpreting studies on the effectiveness and safety of COVID-19 vaccines.

Julie Barberio,1 Thomas P Ahern,2 Richard F MacLehose,3 Lindsay J Collin,1 Deirdre P Cronin-Fenton,4 Per Damkier,5 Henrik Toft Sørensen,4 Timothy L Lash1 1Rollins School of Public Health, Emory University, Atlanta, GA, USA; 2The Robert Larner College of Medicine, University of Vermont, Burlington, VT, USA; 3University of Minnesota, Minneapolis, MN, USA; 4Aarhus University Hospital, Aarhus, Denmark; 5Odense University Hospital, Odense, DenmarkCorrespondence: Julie BarberioRollins School of Public Health, Emory University, Atlanta, GA, USAEmail julie.barberio@emory.eduPurpose: To compare the magnitude of bias due to unmeasured confounding estimated from various techniques in an applied example.Patients and Methods: We examined the association between dibutyl phthalate (DBP) and incident estrogen receptor (ER)-positive breast cancer in a Danish nationwide cohort (N=1,122,042). Cox regression analyses were adjusted for age and active drug compounds contributing to DBP exposure. We estimated the hazard ratios (HRs) that would have been observed had one of the DBP sources been unmeasured and calculated the strength of confounding by comparing to the fully adjusted HR. We performed a quantitative bias analysis (QBA) of the “unmeasured” confounder, using external information to specify the bias parameters. Upper bounds on the bias were estimated and E-values were calculated.Results: The adjusted HR for incident ER-positive breast cancer among women with high-level (≥ 10,000 cumulative milligrams) versus no DBP exposure was 2.12 (95% confidence interval 1.12 to 4.05). Removing each DBP source in isolation resulted in negligible change in the HR. The bias estimates from the QBA ranged from 1.00 to 1.01. The estimated maximum impact of unmeasured confounding ranged from 1.01 to 1.51. E-values ranged from 3.46 to 3.68.Conclusion: The impact of bias due to simulated unmeasured confounding was negligible, in part, because the unmeasured variable was not independent of controlled variables. When a suspected confounder cannot be measured in the study data, our exercise suggests that QBA is the most informative method for assessing the impact. E-values may best be reserved for situations where uncontrolled confounding emanates from an unknown confounder.Keywords: bias analysis, unmeasured confounding, the E-value

The association between lithium use and chronic kidney disease (CKD) needs further evaluation. We aimed to investigate this association using Danish nationwide healthcare registers and routinely collected plasma creatinine measurements from the Funen Laboratory Cohort. We conducted a case-control study nested within the population of Funen, 2001-2015. Incident cases of CKD (estimated glomerular filtration rate60 ml/min/1.73m

Background Return-to-work (RTW) after breast cancer may be challenging for breast cancer survivors, especially those who experience adverse effects. Neuropathies are common adverse effect of taxane-based chemotherapy. Single nucleotide polymorphisms (SNPs) in genes related to taxane metabolism and transport, neural function, and neural- or DNA-repair may influence the risk of taxane-induced adverse effects, potentially impacting patient recovery and RTW. We examined the association of such SNPs with RTW in premenopausal breast cancer survivors. Methods We used Denmark’s nationwide population-based health registries to ascertain data on premenopausal women aged 18‒55 years diagnosed with non‒distant metastatic breast cancer during 2007‒2011, who were candidates for adjuvant combination chemotherapy including cyclophosphamide and docetaxel. Only women employed at diagnosis were included. We collected archived tumor tissue from nationwide pathology departments and genotyped 26 SNPs in 20 genes using TaqMan assays. For each SNP, we categorized the women as wildtype, homozygote or heterozygote. Follow-up continued from the date of primary surgery to the first of RTW (defined as 4 consecutive weeks of work), recurrence, maternity leave/childbirth, other malignancy, retirement, death, emigration or 25th September 2017. We computed the cumulative incidence of RTW and used Cox regression models to calculate unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of RTW. Results We included 1,963 women. Women who were homozygotes for the phase 1 metabolizer CYP3A5 rs776746 (n=15) had lower cumulative incidence of RTW than wildtypes (n=1,600) and heterozygotes (n=249), 7%, 25% and 17% at six months, 57%, 87% and 88% at two years, and 82%, 94% and 94% at end of follow-up, respectively. Compared with wildtypes, CYP3A5 rs776746 homozygotes had delayed RTW throughout follow-up (HR 0-10 years: 0.48, 95% CI: 0.26, 0.86). No other SNPs were associated with RTW. Conclusions Among 26 SNPs, CYP3A5 rs776746 was associated with delayed RTW after breast cancer among premenopausal women. Our findings may help identify women at risk of a poor clinical course, who may benefit from enhanced supportive care during treatment and follow-up. Citation Format: Cathrine Hjorth, Per Damkier, Tore B. Stage, Søren Feddersen, Stephen Hamilton-Dutoit, Bent Ejlertsen, Timothy L. Lash, Henrik Bøggild, Henrik Sørensen, Deirdre Cronin-Fenton. The impact of single nucleotide polymorphisms on return-to-work after taxane-based chemotherapy in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-11.

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has—following publication of controversial and seemingly contradictory results—been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on “Fertility, pregnancy and lactation.” The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step—which has important clinical consequences—is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

Background Danish health registers are used widely to examine associations between specific risk factors and congenital malformations. Various overall prevalence rates of malformations have been reported in Denmark indicating differences in the underlying data sources or malformation definitions. We described trends in registration of malformations in Denmark 1997-2017 and identified potential caveats for the use of Danish health registries in epidemiological studies. We composed a Danish adaptation of EUROCATs definition of malformations. Methods Using nationwide Danish health registries, we identified all recorded pregnancies and followed livebirths for up to 5 years. We described the different data sources, ways to identify malformations, the overall rate of malformations over time, and identified the 10 most common major malformations. Results A total of 1,340,774 foetuses and infants from 1,313,281 pregnancies among 747,144 women from 1997 to 2017 were analysed. Using primary and secondary diagnoses from all available sources and restricting hip malformations to diagnoses after 6 weeks postpartum, we found that 65,411 (49/1000) foetuses or infants had at least one major malformation defined by our Danish translation of EUROCATs definition of malformations. The prevalence of major malformations increased over time from 39/1000 in 1997 to 53/1000 in 2017. The most common specific malformations were malformations of cardiac septa (Q21) and great arteries (Q25) with a peak of 10 and 6/1000 births in 2010 and 2009, respectively. Conclusion Malformations should be identified using primary and secondary diagnoses from the Birth register, the Patient register, and the Cause of Death register. To increase transparency and external validity, classification of major malformations should be based on the Danish adaptation of EUROCATs classification of malformations.

Lay Summary We report an association between balsalazide exposure during the development of fertilizing sperm and birth defects in offspring. Exposed offspring were approximately 8 times more likely to have a birth defect. There were no pre-existing reasons to suspect such a relationship, which should be confirmed in other data.

Background Human phthalate exposure is widespread through contact with myriad consumer products. Exposure is particularly high through medications formulated with phthalates. Phthalates disrupt normal endocrine signaling and are associated with reproductive outcomes and incidence of some cancers. We measured associations between gestational and childhood medication-associated phthalate exposures and the incidence of childhood cancers. Methods We identified all live births in Denmark between 1997 and 2017, including both children and birth mothers. Using drug ingredient data merged with the Danish National Prescription Registry, we measured phthalate exposure through filled prescriptions for mothers during pregnancy (gestational exposure) and for children from birth until age 19 years (childhood exposure). Incident childhood cancers were ascertained from the Danish Cancer Registry, and associations were estimated with Cox regression models. Results Among 1 278 685 children, there were 2027 childhood cancer cases diagnosed over 13.1 million person–years of follow-up. Childhood phthalate exposure was strongly associated with incidence of osteosarcoma (hazard ratio [HR] = 2.78, 95% confidence interval [CI] = 1.63 to 4.75). We also observed a positive association with incidence of lymphoma (HR = 2.07, 95% CI = 1.36 to 3.14), driven by associations with Hodgkin and non-Hodgkin lymphoma but not Burkitt lymphoma. Associations were apparent only for exposure to low-molecular phthalates, which have purportedly greater biological activity. Conclusions Childhood phthalate exposure was associated with incidence of osteosarcoma and lymphoma before age 19 years. Lingering questions include which specific phthalate(s) are responsible for these associations, by what mechanisms they occur, and to what extent childhood cancer cases could be avoided by reducing or eliminating the phthalate content of medications and other consumer products.

Increased transparency in study design and analysis is one proposed solution to the perceived reproducibility crisis facing science. Systematic review and meta-analysis—through which individual studies on a specific association are ascertained, assessed for quality and quantitatively combined—is a critical process for building consensus in medical research. However, the conventional publication model creates static evidence summaries that force the quality assessment criteria and analytical choices of a small number of authors onto all stakeholders, some of whom will have different views on the quality assessment and key features of the analysis. This leads to discordant inferences from meta-analysis results and delayed arrival at consensus. We propose a shift to interactive meta-analysis, through which stakeholders can take control of the evidence synthesis using their own quality criteria and preferred analytic approach—including the option to incorporate prior information on the association in question—to reveal how their summary estimate differs from that reported by the original analysts. We demonstrate this concept using a web-based meta-analysis of the association between genetic variation in a key tamoxifen-metabolising enzyme and breast cancer recurrence in tamoxifen-treated women. We argue that interactive meta-analyses would speed consensus-building to the degree that they reveal invariance of inferences to different study selection and analysis criteria. On the other hand, when inferences are found to differ substantially as a function of these choices, the disparities highlight where future research resources should be invested to resolve lingering sources of disagreement.

Background: In clinical oncology, systemic 5-fluorouracil (5-FU) and its oral pro-drugs are used to treat a broad group of solid tumours. Patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency are at elevated risk of toxicity if treated with standard doses of 5-FU. DPYD genotyping and measurements of plasma uracil concentration (DPD phenotyping) can be applied as tests for DPD deficiency. In April 2020, the European Medicines Agency recommended pre-treatment DPD testing to reduce the risk of 5-FU-related toxicity. Objectives: The objective of this study is to present the current evidence for DPD testing in routine oncological practice. Methods: Two systematic literature searches were performed following the PRISMA guidelines. We identified studies examining the possible benefit of DPYD genotyping or DPD phenotyping on the toxicity risk. Findings: Nine and 12 studies met the criteria for using DPYD genotyping and DPD phenotyping, respectively. Conclusions: The evidence supporting either DPYD genotyping or DPD phenotyping as pre-treatment tests to reduce 5-FU toxicity is poor. Further evidence is still needed to fully understand and guide clinicians to dose by DPD activity.

The antibiotics dicloxacillin and flucloxacillin induce cytochrome P450-dependent metabolism of warfarin. We explored the influence of these drug–drug interactions on the clinical effectiveness of warfarin therapy due to atrial fibrillation or heart valve replacement. Using the population-based Danish registers, we performed a propensity-score matched cohort study including around 50,000 episodes of dicloxacillin/flucloxacillin matched to phenoxymethylpenicillin and to no antibiotic, respectively. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) by comparing 21-day (days 7–28) risks of ischemic stroke/systemic embolism (SE) following initiation of each exposure. When compared with phenoxymethylpenicillin, dicloxacillin/flucloxacillin was associated with an HR of ischemic stroke/SE of 2.09 (95% CI 1.51–2.90; strongest for dicloxacillin (HR 2.17; 95% CI 1.56–3.02)). Use of an untreated comparator strengthened the association (HR 2.84; 95% CI 1.97–4.09). Dicloxacillin should be used with caution in patients receiving warfarin. This may also apply to flucloxacillin; however, more data on the risks associated with flucloxacillin exposure during warfarin therapy are needed.

Kasper Bruun Kristensen,1 Lars Christian Lund,1 Peter Bjødstrup Jensen,1 Anne Broe,1 Emelie Rotbain,2 Per Damkier,1,3,4 Anton Pottegård,1 Jacob Harbo Andersen,1 Mikkel Højlund,1,5 Morten Olesen,1 Lotte Rasmussen,1 Morten Rix Hansen,1,3,4 Martin Thomsen Ernst,1 Rikke Wesselhoeft,1,6 Daniel Pilsgaard Henriksen,3 Mette Reilev,1 Mette Bliddal,1,7 Jesper Hallas1 1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark; 2Department of Hematology, Odense University Hospital, Odense, Denmark; 3Department of Clinical Pharmacology, Odense University Hospital, Odense, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark; 6Child and Adolescent Psychiatry Odense, Mental Health Services in the Region of Southern Denmark, Odense, Denmark; 7Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Jesper Hallas, Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 19, 2, Odense, 5000, Denmark, Tel +4565503010, Email jhallas@health.sdu.dkPurpose: To develop the Nordic Multimorbidity Index (NMI), a multimorbidity measure specifically suited to the Nordic health and administrative registry data based on current diagnosis, treatment, and coding practices.Methods: The NMI was developed to predict 5-year mortality in a population-based cohort of randomly sampled Danish residents aged ≥ 40 years (n = 425,087) followed from 2013 to 2018. Included predictors were selected from hospital diagnoses and filled drug prescriptions based on a combination of subject matter knowledge and a data-driven approach using backwards elimination. The performance of the NMI was assessed in a temporal validation cohort of Danish residents followed from 2007 to 2012 and in six cohorts of new users of selected drugs. The discriminative performance of the NMI, Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) was assessed using the c-statistic from logistic regression models with 5-year mortality as dependent variable and the multimorbidity index score, age, and sex as independent variables.Results: The NMI included 50 predictors. In the temporal validation cohort, the c-statistic of the NMI (0.887, 95% CI 0.883– 0.890) exceeded that of the CCI (0.871, 95% CI 0.868– 0.874) and ECI (0.866, 95% CI 0.863– 0.870). In all new user cohorts, the NMI outperformed the other indices with c-statistics ranging from 0.781 (95% CI 0.779– 0.784) to 0.838 (95% CI 0.834– 0.842).Conclusion: The NMI predicted 5-year mortality in a general Danish population and six cohorts of new users of selected drugs and was superior to the CCI and ECI. The NMI could be preferred over these indices to quantify the level of multimorbidity for, eg, descriptive purposes or confounding control. The NMI should be validated in other patient populations and other Nordic countries.Keywords: multimorbidity, comorbidity, pharmacoepidemiology, prognosis, risk score

Background Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence. Methods In this population-based case-control study, we included women diagnosed with stage I–III breast cancer between 1985 and 2001, aged 35–69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER−/TAM−). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence. Results HIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER−/TAM− stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER−/TAM− OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER−/TAM− stratum. Conclusion In this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER− breast cancer.

The aim of the study was to investigate if there is a clinically relevant drug interaction between metformin and codeine. Volunteers were randomized to receive on four separate occasions: (A) orally administered metformin (1 g), (B) intravenously administered metformin (0.5 g), (C) five doses of tablet codeine 25 mg; the last dose was administered together with oral metformin (1 g), and (D) five doses of tablet codeine 25 mg; the last dose was administered together with metformin (0.5 g) intravenously. Blood samples were drawn for 24 h after administration of metformin, and for 6 h after administration of codeine and analyzed using liquid chromatography and tandem mass spectrometry. Healthy volunteers genotyped as CYP2D6 normal metabolizers (*1/*1) without known reduced function variants in the OCT1 gene (rs12208357, rs34130495, rs34059508, and rs72552763) were invited. The median absorption fraction of metformin was 0.31 and was not influenced by codeine intake. The median time to maximum concentration ((Formula presented.)) after oral intake of metformin was 2 h without, and 3 h with codeine (p = 0.06). The geometric mean ratios of the areas under the plasma concentration time-curve (AUCs) for morphine and its metabolites M3G and M6G for oral intake of metformin-to-no metformin were 1.21, 1.31, and 1.27, respectively, and for i.v. metformin-to-no metformin 1.28, 1.34, and 1.30, respectively. Concomitant oral and i.v. metformin increased the plasma levels of morphine, M3G and M6G. These small pharmacokinetic changes may well contribute to an increased risk of early discontinuation of metformin. Hence, a clinically relevant drug-drug interaction between metformin and codeine seems plausible.

Background To investigate how socioeconomic position (SEP) influences the effectiveness of cancer-directed treatment in premenopausal breast cancer patients in terms of breast cancer recurrence and mortality. Methods We conducted a cohort study nested in the ProBeCaRe (Predictors of Breast Cancer Recurrence) cohort (n = 5959). We identified all premenopausal women aged 18–55 years diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy in Denmark during 2007–2011. Population-based administrative registries provided data on SEP: marital status (married including registered partnership or single including divorced or widowed), cohabitation (cohabiting or living alone), education (low, intermediate, or high), income (low, medium, or high), and employment status (employed, unemployed, or health-related absenteeism). For each SEP measure, we computed incidence rates, cumulative incidence proportions (CIPs), and used Poisson regression to compute incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of recurrence and death. We stratified on estrogen receptor (ER) status/tamoxifen to evaluate interaction. Results Our study cohort included 2616 women; 286 (CIP 13%) experienced recurrence and 223 (CIP 11%) died during follow-up (median 6.6 and 7.2 years, respectively). Single women had both increased 5-year risks of recurrence (IRR 1.45, 95% CI 1.11–1.89) and mortality (IRR 1.83, 95% CI 1.32–2.52). Furthermore, we observed increased 5-year mortality in women with low education (IRR 1.49, 95% CI 0.95–2.33), low income (IRR 1.37, 95% CI 0.83–2.28), unemployment (IRR 1.61, 95% CI 0.83–3.13), or health-related work absenteeism (IRR 1.80, 95% CI 1.14–2.82), but smaller or no increased risk of recurrence. These findings were especially evident among women with ER+ tumors prescribed tamoxifen. Overall analyses (follow-up max. 10 years) provided similar results. Conclusions Low SEP in premenopausal women with non-metastatic breast cancer was associated with increased mortality, but not always recurrence. This suggests underdetection of recurrences in certain groups. Poor prognosis in women with low SEP, especially single women, may partly be explained by tamoxifen adherence.

A substantial proportion of atrial fibrillation patients initiating direct oral anticoagulants (DOAC) are vitamin K antagonists (VKA)-experienced, for example switchers from VKA to DOAC. With this study, we aimed to summarize available evidence on the effectiveness and safety of DOAC vs VKA in real-life VKA-experienced atrial fibrillation patients. We searched EMBASE, MEDLINE and Cochrane Library systematically for English-language studies indexed any time before October 2018. We included studies of VKA-experienced atrial fibrillation patients initiating DOAC therapy, with continued VKA therapy as comparator. Outcomes included arterial thromboembolism and bleeding. When appropriate, meta-analysis was performed by calculating pooled, weighted and adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Eight cohort studies comparing VKA-experienced DOAC (dabigatran or rivaroxaban) users with continued VKA users were included. When comparing DOAC to VKA, an increased risk of ischaemic stroke and myocardial infarction was found for dabigatran (pooled aHR of 1.61 [95% CI 1.19-2.19, I 2 = 65%] and 1.29 [95% CI 1.10-1.52, I 2 = 0%], respectively), but not for rivaroxaban. The use of dabigatran in VKA-experienced users was associated with an increased risk of gastrointestinal bleeding (pooled aHR 1.63 [95% CI 1.36-1.94, I 2 = 30%]), but a decreased risk of intracranial bleeding (pooled aHR 0.45 [95% CI 0.32-0.64, I 2 = 0%]). In conclusion, the use of dabigatran in prior VKA users in clinical practice was associated with a slightly increased risk of arterial thromboembolism and gastrointestinal bleeding, but a decreased risk of intracranial bleeding. Importantly, observational studies of real-life VKA-experienced oral anticoagulant users may be confounded by the reason for switching.

BACKGROUND: The average postponement of the outcome (gain in time to event) has been proposed as a measure to convey the effect of preventive medications. Among its advantages over number needed to treat and relative risk reduction is a better intuitive understanding among lay persons. OBJECTIVES: To develop a novel approach for modeling outcome postponement achieved within a trial’s duration, based on published trial data and to present a formalized meta-analysis of modeled outcome postponement for all-cause mortality in statin trials. METHODS: The outcome postponement was modeled on the basis of the hazard ratio or relative risk, the mortality rate in the placebo group and the trial’s duration. Outcome postponement was subjected to a meta-analysis. We also estimated the average outcome postponement as the area between Kaplan–Meier curves. Statin trials were identified through a systematic review. RESULTS: The median modeled outcome postponement was 10.0 days (interquartile range, 2.9–19.5 days). Meta-analysis of 16 trials provided a summary estimate of outcome postponement for all-cause mortality of 12.6 days, with a 95% postponement interval (PI) of 7.1–18.0. For primary, secondary, and mixed prevention trials, respectively, outcome postponements were 10.2 days (PI, 4.0–16.3), 17.4 days (PI, 6.0–28.8), and 8.5 days (PI, 1.9–15.0). CONCLUSIONS: The modeled outcome postponement is amenable to meta-analysis and may be a useful approach for presenting the benefits of preventive interventions. Statin treatment results in a small increase of average survival within the duration of a trial. SYSTEMATIC REVIEW REGISTRATION: The systematic review was registered in PROSPERO [CRD42016037507]. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-019-05024-4) contains supplementary material, which is available to authorized users.

This cohort study used data from Danish registers to assess whether recipients of mRNA COVID-19 vaccines had a higher risk of appendicitis after receiving the shot compared with individuals who did not receive the vaccine.

Some patients may have partial or complete deficiency of dihydropyrimidin dehydrogenase (DPD) and be more likely to experience severe toxicity with 5-fluorouracil. Since the spring of 2020, the Danish Medicines Agency has recommended genotype or phenotype testing before treatment with a fluoropyrimidine, but the most appropriate test strategy is debated. In this review, we present polymorphisms in the genes coding for DPD and summarise the evidence for DPD-enzyme deficiency testing and pharmacokinetic guided dosing.