Validation of algorithms in studies based on routinely collected health data: general principles.

Clinicians, researchers, regulators, and other decision-makers increasingly rely on evidence from real-world data (RWD), including data routinely accumulating in health and administrative databases. RWD studies often rely on algorithms to operationalize variable definitions. An algorithm is a combination of codes or concepts used to identify persons with a specific health condition or characteristic. Establishing the validity of algorithms is a prerequisite for generating valid study findings that can ultimately inform evidence-based health care. This paper aims to systematize terminology, methods, and practical considerations relevant to the conduct of validation studies of RWD-based algorithms. We discuss measures of algorithm accuracy; gold/reference standard; study size; prioritizing accuracy measures; algorithm portability; and implication for interpretation. Information bias is common in epidemiologic studies, underscoring the importance of transparency in decisions regarding choice and prioritizing measures of algorithm validity. The validity of an algorithm should be judged in the context of a data source, and one size does not fit all. Prioritizing validity measures within a given data source depends on the role of a given variable in the analysis (eligibility criterion, exposure, outcome or covariate). Validation work should be part of routine maintenance of RWD sources.

Drug-Drug Interactions in the Treatment of Cancer-Associated Venous Thromboembolism with Direct Oral Anticoagulants.

Venous thromboembolism (VTE) is a frequent complication of cancer, and management of cancer-associated thrombosis (CAT) is challenging due to increased risks of bleeding and recurrent VTE. Recent trials have shown an acceptable efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of CAT compared to low-molecular weight heparin. Although DOACs provide an effective and convenient treatment option in CAT, the need to assess the risk of drug-drug interactions (DDI) with antineoplastic therapies poses a barrier to their use in clinical practice. With the aim of supporting the assessment of CAT patients for treatment with DOAC, this review provides a comprehensive overview of the compatibility of antineoplastic therapies with the individual DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban). Using several data sources, we characterized 100 widely used antineoplastic agents with regard to their effect on p-glycoprotein and cytochrome P450, both important in the transport and elimination of DOACs. This enabled us to evaluate 400 "DOAC-antineoplastic agent"-pairs regarding their likelihood to interact (unlikely, potential, or likely), ultimately leading to clinical recommendations on the appropriateness of concomitant use for each pair. A potential or likely DDI was identified for 12% of the evaluated pairs. For nearly all antineoplastic agents, at least one DOAC was considered compatible.

Prophylaxis of Venous Thromboembolism in Children: A Systematic Review.

Venous thromboembolism (VTE) in children is a rare but serious event. Current guidance on pharmacological thromboprophylaxis in children is mostly based on adult studies and expert opinions. The aim of this systematic review was to examine under which conditions children (age ≤ 18 years) would benefit from pharmacological thromboprophylaxis with low molecular weight heparin or unfractionated heparin. Eligible studies included children, who did not receive pharmacological thromboprophylaxis as comparator, and VTE events were radiologically verified. MEDLINE and Embase were searched up to October 3, 2021. Ten studies were included presenting data for 976 children receiving pharmacological thromboprophylaxis. We divided the studies into three categories based on the population studied: children in the intensive care unit (n = 2), children with fractures and/or undergoing surgery (n = 5), and children with systemic disease (n = 3). A lower incidence of VTE was found when pharmacological thromboprophylaxis was used compared with no prophylaxis in children in intensive care unit with central venous catheter and mechanical ventilation (7/27 vs. 13/24), children in the intensive care unit admitted after trauma with a very high risk of VTE based on several risk factors (0/21 vs. 13/96), and children with acute lymphoblastic leukemia treated with L-asparaginase concomitant with steroid and presence of central venous catheter (0/82 vs. 8/121). Pharmacological thromboprophylaxis was not associated with an increased bleeding risk. In conclusion, pharmacological thromboprophylaxis in children is sparsely investigated. Only children with several risk factors for VTE are likely to benefit from pharmacological thromboprophylaxis.

Venous Thromboembolism and Major Bleeding in Patients With Coronavirus Disease 2019 (COVID-19): A Nationwide, Population-Based Cohort Study.

BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and thromboprophylaxis should be balanced against risk of bleeding. This study examined risks of VTE and major bleeding in hospitalized and community-managed SARS-CoV-2 patients compared with control populations. METHODS: Using nationwide population-based registries, 30-day risks of VTE and major bleeding in SARS-CoV-2 positive patients were compared with those of SARS-CoV-2 test-negative patients and with an external cohort of influenza patients. Medical records of all COVID-19 patients at 6 departments of infectious diseases in Denmark were reviewed in detail. RESULTS: The overall 30-day risk of VTE was 0.4% (40/9460) among SARS-CoV-2 patients (16% hospitalized), 0.3% (649/226 510) among SARS-CoV-2 negative subjects (12% hospitalized), and 1.0% (158/16 281) among influenza patients (59% hospitalized). VTE risks were higher and comparable in hospitalized SARS-CoV-2 positive (1.5%), SARS-CoV-2 negative (1.8%), and influenza patients (1.5%). Diagnosis of major bleeding was registered in 0.5% (47/9460) of all SARS-CoV-2 positive individuals and in 2.3% of those hospitalized. Medical record review of 582 hospitalized SARS-CoV-2 patients observed VTE in 4% (19/450) and major bleeding in 0.4% (2/450) of ward patients, of whom 31% received thromboprophylaxis. Among intensive care patients (100% received thromboprophylaxis), risks were 7% (9/132) for VTE and 11% (15/132) for major bleeding. CONCLUSIONS: Among people with SARS-CoV-2 infection in a population-based setting, VTE risks were low to moderate and were not substantially increased compared with SARS-CoV-2 test-negative and influenza patients. Risk of severe bleeding was low for ward patients, but mirrored VTE risk in the intensive care setting.

Use of dipeptidyl peptidase-4 inhibitors and risk of splanchnic vein thrombosis: A Danish nationwide new-user active comparator cohort study.

Use of dipeptidyl peptidase-4 (DPP-4) inhibitors, on the basis of spontaneous adverse event reports, has recently been suspected of causing splanchnic vein thrombosis. Here, we report the results of a population-based new-user active comparator cohort study addressing this hypothesis, comparing DPP-4 inhibitor initiators (n = 75 042) with initiators of glucagon-like-peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose co-transporter-2 (SGLT2) inhibitors (n = 38 718). We estimated the hazard ratio (HR) associating DPP-4 inhibitor use with risk of splanchnic vein thrombosis using Cox regression. In a crude analysis, the incidence rate of splanchnic vein thrombosis was 0.22/1000 person-years among DPP-4 inhibitor initiators, compared to 0.17 among GLP-1RA/SGLT2 inhibitor initiators, corresponding to an unadjusted absolute incidence rate difference of 0.05 (95% confidence interval [CI] -0.04 to 0.14) and an HR of 1.29 (95% CI 0.78 to 2.15). Adjusting for potential confounders using stabilized inverse probability of treatment weighing, we obtained an absolute incidence rate difference of 0.03/1000 person-years (95% CI -0.07 to 0.14) and an HR of 1.18 (95% CI 0.62 to 2.26). No evidence of increased risk of splanchnic vein thrombosis was found in supplementary analyses, including an absence of any dose-response patterns. As such, we found no association between DPP-4 inhibitor use and splanchnic vein thrombosis risk.

Persistence and adherence to non-vitamin K antagonist oral anticoagulant treatment in patients with atrial fibrillation across five Western European countries.

AIMS: To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. METHODS AND RESULTS: We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. RESULTS: Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. CONCLUSION: Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.

Drug-drug interactions between vitamin K antagonists and statins: a systematic review.

PURPOSE: Concomitant use of vitamin K antagonists (VKA) and statins is frequent in cardiovascular patients. However, clinical guidelines on this drug combination are divergent. Therefore, we performed a systematic review to evaluate the effect of statin initiation on coagulation among VKA users. METHODS: Following the PRISMA guidelines, we applied two broad search strategies for the drug interaction between VKA and statins in both Embase and Pubmed; 8623 unique hits were obtained. In the final sample, eight studies were included. RESULTS: The most frequently used VKA in the studies was warfarin, while simvastatin was the most commonly initiated statin. All included studies showed a minor increase in the anticoagulant effect of VKA following statin initiation during VKA treatment. The reported increases in mean international normalized ratio (INR) ranged from 0.15-0.65. CONCLUSION: The anticoagulant effect of statin initiation in patients treated with VKA is likely to be of limited clinical relevance but should be evaluated individually.

Using the Case-Crossover Design to Assess Short-Term Risks of Bleeding and Arterial Thromboembolism After Switching Between Oral Anticoagulants in a Population-Based Cohort of Patients With Atrial Fibrillation.

Using nationwide Danish registries, we conducted a population-based case-crossover study evaluating the association between switching from a vitamin K antagonist (VKA) to a direct oral anticoagulant (DOAC), and vice versa, and 30-day risks of bleeding and arterial thromboembolism in patients with atrial fibrillation (AF). The case-crossover population was identified among oral anticoagulant users during 2011-2018 (n = 123,217) as patients with AF with 1) a case-defining outcome and 2) an anticoagulant switch during the 180 days preceding the outcome. Odds ratios were estimated using conditional logistic regression by comparing the occurrence of switching during the 30-day window immediately preceding the outcome to that in reference windows in the same individual 60-180 days before the outcome. The case-crossover populations for switching from VKA to DOAC and DOAC to VKA comprised 1,382 and 287 case patients, respectively. Switching from VKA to DOAC, but not from DOAC to VKA, was associated with an increased short-term risk of bleeding (odds ratio = 1.42; 95% confidence intervals: 1.13, 1.79, and 1.06; and 0.64, 1.75, respectively) and ischemic stroke (odds ratio = 1.74; 95% confidence intervals: 1.21, 2.51, and 0.92; and 0.46, 1.83, respectively). Our findings suggest that switching from VKA to DOAC is an intermittent risk factor of bleeding and ischemic stroke in patients with AF.

Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: A study in three European data sources.

PURPOSE: Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). METHODS: Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. RESULTS: Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code "unspecified jaundice" had high PPVs in Denmark. CONCLUSIONS: PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.

Use of direct oral anticoagulants in the first year after market entry of edoxaban: A Danish nationwide drug utilization study.

OBJECTIVES: To describe the early uptake of edoxaban; the fourth direct oral anticoagulant (DOAC) to enter the market. METHODS: Using the Danish nationwide health registries, we identified new users of edoxaban (n = 609) from June 6 (day of marketing) through June 2017. For comparison, we also identified new users of dabigatran (n = 2211), rivaroxaban (n = 19 227), and apixaban (n = 14 736). Users were described regarding indication of use, previous anticoagulant experience, comorbidity, and co-medication. RESULTS: The rate of edoxaban initiation increased to 2.0 per 100 000 person months in June 2017, compared with 6.3, 37.5, and 27.0 for dabigatran, rivaroxaban, and apixaban. Atrial fibrillation was the most common registered indication for edoxaban (67%) as well as the other DOACs (41-55%). Overall, users of edoxaban were comparable to users of other DOACs (median age 75 vs 72-76 years and 57% vs 53-59% males), except for a generally lower concomitant use of other drugs. Noticeably, 95% of edoxaban users had previously received anticoagulant treatment compared with 31% to 43% for new users of other DOACs, with 77% switching directly from another anticoagulant treatment to edoxaban (45% directly from VKA and 32% directly from DOACs). CONCLUSIONS: While the use of edoxaban is still limited compared with other DOACs, it is increasing. The majority of edoxaban users switch to edoxaban from other anticoagulant treatments. Continued monitoring of the utilization of DOACs, including effectiveness and safety, is considered essential to the safe and rational use of these drugs.

Empirical validation of the reverse parametric waiting time distribution and standard methods to estimate prescription durations for warfarin.

PURPOSE: In many prescription databases, the duration of treatment for the single prescription is not recorded. This study aimed to validate 2 different types of approaches for estimating prescription durations, using the oral anticoagulant warfarin as a case. METHODS: The approaches undergoing empirical validation covered assumptions of a fixed daily intake of either 0.5 or 1.0 defined daily dose (DDD), as well as estimates based on the reverse parametric waiting time distribution (rWTD), with different sets of covariates. We converted estimates of prescription duration to daily dose and compared them to prescribed daily dose as recorded in a clinical registry (using Bland-Altman plots). Methods were compared based on their average prediction error (logarithmic scale) and their limit of agreement ratio (ratio of mean error ± 1.96 SD after transformation to original scale). RESULTS: Estimates of daily doses were underestimated by 19% or overestimated by 62% when assumptions of 0.5 or 1.0 DDD were applied. The limit of agreement ratio was 6.721 for both assumptions. The rWTD-based approaches performed better when using the estimated mean value of the inter-arrival density, yielding on average negligible bias (relative difference of 0 to 2%) and with limit of agreement ratios decreasing upon additional covariate adjustment (from 6.857 with no adjustment to 4.036 with the fully adjusted model). CONCLUSIONS: Comparing the different methods, the rWTD algorithm performed best and led to unbiased estimates of prescribed doses and thus prescription durations and reduced misclassification on the individual level upon inclusion of covariates.

Methodological challenges when evaluating potential off-label prescribing of drugs using electronic health care databases: A case study of dabigatran etexilate in Europe.

PURPOSE: To report and discuss estimated prevalence of potential off-label use and associated methodological challenges using a case study of dabigatran. METHODS: Observational, cross-sectional study using 3 databases with different types of clinical information available: Cegedim Strategic Data Longitudinal Patient Database (CSD-LPD), France (cardiologist panel, n = 1706; general practitioner panel, n = 2813; primary care data); National Health Databases, Denmark (n = 28 619; hospital episodes and dispensed ambulatory medications); and Clinical Practice Research Datalink (CPRD), UK (linkable to Hospital Episode Statistics [HES], n = 2150; not linkable, n = 1285; primary care data plus hospital data for HES-linkable patients). STUDY PERIOD: August 2011 to August 2015. Two definitions were used to estimate potential off-label use: a broad definition of on-label prescribing using codes for disease indication (eg, atrial fibrillation [AF]), and a restrictive definition excluding patients with conditions for which dabigatran is not indicated (eg, valvular AF). RESULTS: Prevalence estimates under the broad definition ranged from 5.7% (CPRD-HES) to 34.0% (CSD-LPD) and, under the restrictive definition, from 17.4% (CPRD-HES) to 44.1% (CSD-LPD). For the majority of potential off-label users, no diagnosis potentially related to anticoagulant use was identified. Key methodological challenges were the limited availability of detailed clinical information, likely leading to overestimation of off-label use, and differences in the information available, which may explain the disparate prevalence estimates across data sources. CONCLUSIONS: Estimates of potential off-label use should be interpreted cautiously due to limitations in available information. In this context, CPRD HES-linkable estimates are likely to be the most accurate.

Clinical events preceding switching and discontinuation of oral anticoagulant treatment in patients with atrial fibrillation.

AIMS: Switching between oral anticoagulants and treatment discontinuation are common events related to therapy with non-vitamin K antagonist oral anticoagulants (NOACs). However, knowledge on the reasons leading to these treatment changes is scarce. The aim of this study was to identify clinical events preceding anticoagulant switching and NOAC discontinuation during oral anticoagulant therapy in patients with atrial fibrillation. METHODS AND RESULTS: We performed a nationwide register-based study including Danish atrial fibrillation patients initiating a NOAC between August 2011 and February 2016 (n = 50 623). We explored potential reasons leading to changes in anticoagulant treatment by identifying clinical events preceding switches from vitamin K antagonists (VKA) to NOAC, switches from NOAC to VKA, and discontinuations of NOACs. Among 23 531 anticoagulant users changing treatment, we identified 13 295 switches from VKA to NOAC, 5206 switches from NOAC to VKA, and 8995 discontinuations of NOACs. Approximately half of all treatment changes were preceded by a hospitalization. A relevant specific clinical event or procedure was identified prior to 18.3% of switches from VKA to NOAC, prior to 23.0% of switches from NOAC to VKA, and prior to 26.6% of discontinuations. Switches from VKA to NOAC were most often preceded by thromboembolic events (7.0%), whereas cardioversion was the most common specific event prior to a switch from NOAC to VKA (11.4%). Discontinuations were most often preceded by bleeding events (7.6%). CONCLUSION: For about one in five patients, treatment changes during anticoagulant therapy were preceded by a major clinical event. However, the majority of patients changed treatment for reasons not recorded in health registries.

Association of Antithrombotic Drug Use With Subdural Hematoma Risk.

IMPORTANCE: Incidence of subdural hematoma has been reported to be increasing. To what extent this is related to increasing use of antithrombotic drugs is unknown. OBJECTIVES: To estimate the association between use of antithrombotic drugs and subdural hematoma risk and determine trends in subdural hematoma incidence and antithrombotic drug use in the general population. DESIGN, SETTING, AND PARTICIPANTS: Case-control study of 10 010 patients aged 20 to 89 years with a first-ever subdural hematoma principal discharge diagnosis from 2000 to 2015 matched by age, sex, and calendar year to 400 380 individuals from the general population (controls). Subdural hematoma incidence and antithrombotic drug use was identified using population-based regional data (population: 484 346) and national data (population: 5.2 million) from Denmark. Conditional logistic regression models were used to estimate odds ratios (ORs) that were adjusted for comorbidity, education level, and income level. EXPOSURES: Use of low-dose aspirin, clopidogrel, a vitamin K antagonist (VKA), a direct oral anticoagulant, and combined antithrombotic drug treatment. MAIN OUTCOMES AND MEASURES: Association of subdural hematoma with antithrombotic drug use, subdural hematoma incidence rate, and annual prevalence of treatment with antithrombotic drugs. RESULTS: Among 10 010 patients with subdural hematoma (mean age, 69.2 years; 3462 women [34.6%]), 47.3% were taking antithrombotic medications. Current use of low-dose aspirin (cases: 26.7%, controls: 22.4%; adjusted OR, 1.24 [95% CI, 1.15-1.33]), clopidogrel (cases: 5.0%, controls: 2.2%; adjusted OR, 1.87 [95% CI, 1.57-2.24]), a direct oral anticoagulant (cases: 1.0%, controls: 0.6%; adjusted OR, 1.73 [95% CI, 1.31-2.28]), and a VKA (cases: 14.3%, controls: 4.9%; adjusted OR, 3.69 [95% CI, 3.38-4.03]) were associated with higher risk of subdural hematoma. The risk of subdural hematoma was highest when a VKA was used concurrently with an antiplatelet drug (low-dose aspirin and a VKA: 3.6% of cases and 1.1% of controls; adjusted OR, 4.00 [95% CI, 3.40-4.70]; clopidogrel and a VKA: 0.3% of cases and 0.04% of controls; adjusted OR, 7.93 [95% CI, 4.49-14.02]). The prevalence of antithrombotic drug use increased from 31.0 per 1000 individuals from the general population in 2000 to 76.9 per 1000 individuals in 2015 (P < .001 for trend). The overall subdural hematoma incidence rate increased from 10.9 per 100 000 person-years in 2000 to 19.0 per 100 000 person-years in 2015 (P < .001 for trend). The largest increase was among older patients (>75 years; n = 4441) who experienced an increase from 55.1 per 100 000 person-years to 99.7 per 100 000 person-years (P < .001 for trend). CONCLUSIONS AND RELEVANCE: In Denmark, antithrombotic drug use was associated with higher risk of subdural hematoma; and the highest odds of subdural hematoma was associated with combined use of a VKA and an antiplatelet drug. The increased incidence of subdural hematoma from 2000 to 2015 appears to be associated with the increased use of antithrombotic drugs, particularly use of a VKA among older patients.

Generic switching of warfarin and risk of excessive anticoagulation: a Danish nationwide cohort study.

PURPOSE: Generic switching of warfarin was recently repealed in Denmark, as adverse drug reaction (ADR) reports suggested risk of excessive anticoagulation following switches from branded to generic warfarin. We investigated this putative association in a formalized pharmacoepidemiological analysis. METHODS: We conducted a nationwide cohort study based on Danish healthcare registries, including data from the introduction of generic warfarin until the repeal (January 2011-April 2015). We followed Danish warfarin users over time and compared the rate of incident hospitalizations due to excessive anticoagulation (i.e. increased INR or any bleeding requiring hospitalization) in periods following a recent switch to generic warfarin to the rate in periods without a recent switch. RESULTS: We included 105,751 warfarin users, filling a total of 1,539,640 prescriptions for warfarin (2.5% for generic warfarin). This constituted 89.0% of all warfarin prescriptions in Denmark during the study period. We observed 19,362 switches to generic warfarin during the study period. The adjusted hazard ratio for excessive anticoagulation following a recent switch from branded to generic warfarin was 1.1 (95%CI, 0.8-1.4). The result was robust within subgroups and several sensitivity analyses. CONCLUSION: Switching from branded to generic warfarin is not associated with an increased risk of hospitalization with excessive anticoagulation. However, a minor excess risk of transient INR increase cannot be excluded. Pharmacoepidemiological studies provide an effective method for swift evaluation of hypotheses generated by ADR-reports.

Off-label prescribing of psychotropic drugs in a Danish child and adolescent psychiatric outpatient clinic.

This study aimed to describe the level of off-label treatment with psychotropic drugs at a child and adolescent psychiatric outpatient clinic in Denmark. We performed a cross-sectional study assessing records on patients treated with medicine at two outpatient clinics at the child and adolescent psychiatric ward, on 1 day in 2014. Prescriptions of drugs from ATC group N05-N06 were classified according to label status. Six hundred and fifteen drug prescriptions distributed on nine different drugs were prescribed to 503 children eligible for this study. Overall results showed that 170 of the 615 prescriptions were off-label, which corresponds to 27.6 %. Attention deficit hyperkinetic disorder (ADHD) drugs were prescribed 450 times (73.2 %) of which 11 prescriptions were off-label (2.4 %). Other psychotropic drugs comprised 165 (26.8 %) prescriptions and of these 159 (96.4 %) were off-label. With 106 prescriptions, melatonin was the most prescribed of these drugs; all prescriptions were off-label. The main reasons for classifying prescriptions as off-label were age and indication of treatment. This cross-sectional study reveals that medical treatment of children with other psychotropic drugs than ADHD drugs is usually off-label. ADHD drugs were, as the only drug group, primarily prescribed on-label. Although off-label prescription may be rational and even evidence based, the responsibility in case of, e.g. adverse drug reactions is a challenge, and clinical trials in children should be incited.

Infrequent transition to direct oral anticoagulants in patients with cancer.

INTRODUCTION: Pharmacokinetic drug-drug interactions (DDIs) are challenging aspects of direct oral anticoagulant (DOAC) therapy in patients with cancer. We evaluated the prevalence of potential DOAC/antineoplastic agent DDIs and the one-year cumulative incidence of switching from low-molecular-weight heparin (LMWH) to a DOAC in patients with cancer. METHODS: Patients with cancer and an indication of LMWH were included from Herlev and Gentofte Hospital, Denmark, in the 2014-2019 period. Follow-up was initiated when the first dose of LMWH was dispensed. Data were obtained from electronic medical records. One-year cumulative incidence of switching from LMWH to DOAC was estimated using the Aalen-Johansen estimator. Potential DDIs were evaluated using a report from the European Heart Rhythm Association (EHRA) and a review by Hellfritzsch et al. RESULTS. A total of 161 patients were included with a median age of 70.8 (interquartile range: 64.2-76.1) years. The one-year cumulative incidence of switching from LMWH to DOAC was 32% (95% confidence intervals: 21-43%) in patients eligible for DOACs. Using the EHRA report, a total of 24% of antineoplastic agents were not identified. This percentage decreased to 8% using data from Hellfritzsch et al. CONCLUSIONS. In patients with cancer, the one-year cumulative incidence of switching from LMWH to DOAC was less-t 35% in patients eligible for DOAC, revealing a potential for improved anticoagulant treatment. Furthermore, contemporary data elaborated on potential DDIs between DOACs/antineoplastic agents. FUNDING: "Helsefonden" (21-B-0350) and the "Karen Elise Jensens Fonden" (29-4-2021) funded the study. TRIAL REGISTRATION: Not relevant.

Comparison of international guideline recommendations for the diagnosis of pulmonary embolism.

Pulmonary embolism is one of the leading causes of death due to cardiovascular disease. Timely diagnosis is crucial, but challenging, as the clinical presentation of pulmonary embolism is unspecific and easily mistaken for other common medical emergencies. Clinical prediction rules and D-dimer measurement allow stratification of patients into groups of expected prevalence and are key elements in adequate selection of patients for diagnostic imaging; however, the strengths and weaknesses of the multiple proposed prediction rules, when to measure D-dimer, and which cutoff to apply might be elusive to a significant proportion of physicians. 13 international guidelines authored by medical societies or expert author groups provide recommendations on facets of the diagnostic investigations in suspected pulmonary embolism, some of which are hallmarked by pronounced heterogeneity. This Review summarises key recommendations of each guideline, considers the most recent evidence on the topic, compares guideline recommendations on each facet of the diagnosis of pulmonary embolism, and provides a synthesis on the most common recommendations.

Non-vitamin K antagonist oral anticoagulants, proton pump inhibitors and gastrointestinal bleeds.

OBJECTIVE: To evaluate if proton pump inhibitor (PPI) treatment reduces the risk of upper gastrointestinal bleeding (UGIB) in patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs). DESIGN: We used a common protocol, common data model approach to conduct a cohort study including patients with AF initiated on a NOAC in Stockholm, Denmark and the Netherlands from April 2011 until July 2018. The outcome of interest was a UGIB diagnosed in a secondary care inpatient setting. We used an inverse probability weighted (IPW) Poisson regression to calculate incidence rate ratios (IRRs), contrasting PPI use to no PPI use periods. RESULTS: In 164 290 NOAC users with AF, providing 272 570 years of follow-up and 39 938 years of PPI exposure, 806 patients suffered a UGIB. After IPW, PPI use was associated with lower UGIB rates (IRR: 0.75; 95% CI: 0.59 to 0.95). On an absolute scale, the protective effect was modest, and was found to be largest in high-risk patients, classified as age 75-84 years (number needed to treat for 1 year (NNTY): 787), age ≥85 years (NNTY: 667), HAS-BLED score ≥3 (NNTY: 378) or on concomitant antiplatelet therapy (NNTY: 373). CONCLUSION: Concomitant treatment with a PPI in NOAC-treated patients with AF is associated with a reduced risk of severe UGIB. This indicates that PPI cotreatment can be considered, in particular among the elderly patients, patients with a HAS-BLED score ≥3, and/or in patients on concomitant antiplatelet therapy.