User-defined outcomes of the Danish cardiovascular screening (DANCAVAS) trial: A post hoc analyses of a population-based, randomised controlled trial.

BACKGROUND: The Danish cardiovascular screening (DANCAVAS) trial, a nationwide trial designed to investigate the impact of cardiovascular screening in men, did not decrease all-cause mortality, an outcome decided by the investigators. However, the target group may have varied preferences. In this study, we aimed to evaluate whether men aged 65 to 74 years requested a CT-based cardiovascular screening examination and to assess its impact on outcomes determined by their preferences. METHODS AND FINDINGS: This is a post hoc study of the randomised DANCAVAS trial. All men 65 to 74 years of age residing in specific areas of Denmark were randomised (1:2) to invitation-to-screening (16,736 men, of which 10,471 underwent screening) or usual-care (29,790 men). The examination included among others a non-contrast CT scan (to assess the coronary artery calcium score and aortic aneurysms). Positive findings prompted preventive treatment with atorvastatin, aspirin, and surveillance/surgical evaluation. The usual-care group remained unaware of the trial and the assignments. The user-defined outcome was based on patient preferences and determined through a survey sent in January 2023 to a random sample of 9,095 men from the target group, with a 68.0% response rate (6,182 respondents). Safety outcomes included severe bleeding and mortality within 30 days after cardiovascular surgery. Analyses were performed on an intention-to-screen basis. Prevention of stroke and myocardial infarction was the primary motivation for participating in the screening examination. After a median follow-up of 6.4 years, 1,800 of 16,736 men (10.8%) in the invited-to-screening group and 3,420 of 29,790 (11.5%) in the usual-care group experienced an event (hazard ratio (HR), 0.93 (95% confidence interval (CI), 0.88 to 0.98; p = 0.010); number needed to invite at 6 years, 148 (95% CI, 80 to 986)). A total of 324 men (1.9%) in the invited-to-screening group and 491 (1.7%) in the usual-care group had an intracranial bleeding (HR, 1.17; 95% CI, 1.02 to 1.35; p = 0.029). Additionally, 994 (5.9%) in the invited-to-screening group and 1,722 (5.8%) in the usual-care group experienced severe gastrointestinal bleeding (HR, 1.02; 95% CI, 0.95 to 1.11; p = 0.583). No differences were found in mortality after cardiovascular surgery. The primary limitation of the study is that exclusive enrolment of men aged 65 to 74 renders the findings non-generalisable to women or men of other age groups. CONCLUSION: In this comprehensive population-based cardiovascular screening and intervention program, we observed a reduction in the user-defined outcome, stroke and myocardial infarction, but entail a small increased risk of intracranial bleeding. TRIAL REGISTRATION: ISRCTN Registry number, ISRCTN12157806 https://www.isrctn.com/ISRCTN12157806.

Screening of dermatology drugs for aberrant use-patterns: An application of epidemiologic estimates and measures of inequality in drug use.

AIMS: Dermatology treatments require adherence for safe and effective use. Real-world healthcare databases can reveal drug utilization patterns and uncover inappropriate or unexpected use. This study aimed to analyse dermatology drug utilization patterns using epidemiological and inequality measures, leveraging Danish nationwide registries. It also assessed the feasibility of this method for detecting aberrant drug use. METHODS: We formed a 2019 cohort of all patients treated for skin conditions through Danish healthcare registries. We calculated prevalence, incidence rates and treatment duration for dermatological drugs. Inequality in drug utilization was assessed using Lorenz curves, Gini coefficients and other measures. RESULTS: The study encompassed 1 021 255 patients using 94 dermatology drugs. Most usage aligned with 'expected clinical use', but we detected inequality, with some drugs having high Gini coefficients and disproportionate consumption by the top percentile of users. Notable findings included potential inappropriate antibiotic use, excessive topical corticosteroid use and unexpected drug use duration. CONCLUSIONS: In Denmark, dermatology drugs are used primarily as anticipated, with minimal unexpected patterns. Specific follow-up is required to draw conclusions about inappropriate use. This approach demonstrates broad applicability for screening aberrant drug utilization.

A case for screening real-world data for collateral drug benefits: Glucagon-like peptide 1 receptor agonists and bile acid diarrhea.

PURPOSE: Collateral drug benefits are hitherto unknown beneficial effects that might lead to repurposing of already marketed drugs. A randomized controlled trial has found liraglutide to be non-inferior to colesevelam in reducing bile acid diarrhea. We hypothesized that this collateral drug benefit of liraglutide could have been detected using observational data. METHODS: We performed a sequence symmetry analysis (SSA). In the SSA, we indexed individuals on the date of the first prescription of GLP1-RA and restricted the analysis to all individuals who had a first prescription of bile acid sequestrants between 365 days prior to until 365 days after the index date. Sequence ratios (SR), that is, the ratio between counts of persons initiating GLP1-RA first versus last, were calculated, and 95% confidence intervals were obtained. We adjusted for prescribing trends using null-effect SR adjustment. RESULTS: We included 158 individuals, with a median age of 58 years. The trend-adjusted SR was 0.96 (95% confidence interval 0.70-1.31). When stratifying on the type of GLP1-RA (liraglutide or semaglutide), we found results compatible with the previous trial (SRliraglutide 0.75, 0.51-1.10 and SRsemagltuide 1.23, 0.80-1.89). Since BAS also can be used as a cholesterol lowering drug, we repeated the main analysis while excluded statin users, resulting in a stronger association (SR 0.56, 0.33-0.96). CONCLUSION: Using the SSA methodology, we obtained estimates of a collateral drug benefit that were compatible with trial results. These results support the use of epidemiological analyses of observational data as instrument for detecting collateral drug benefits.

Application of the waiting time distribution in a nationwide screening of real-world dermatology drug utilization for aberrant use patterns.

BACKGROUND: Inappropriate use of medicines may have critical consequences from individual, public health, and economic perspectives. Discovering wrongful medicine use may require intentional surveillance or screening. OBJECTIVES: The objectives of this study were to: (i) apply and evaluate the waiting time distribution (WTD) method as a screening tool for identifying aberrant drug use and (ii) evaluate the nationwide use of Dermatology drugs in Denmark for signals of aberrant drug use. METHOD: Dermatology drug use data from the Danish nationwide healthcare registries from 2018 to 2020 were used to produce WTDs that were analyzed for drug use patterns. The method provides estimates of the prevalence and incidence and enables estimation of mean treatment duration, drug relapse, and unexpected drug prescribing. RESULTS: The study included 2 027 889 individual drug users and analyzed 6 141 449 prescriptions. The analysis included approximately 100 dermatology drugs and drug categories and produced 56 WTD drug curves. The WTD patterns and epidemiological estimates confirmed that most drugs are used as intended and revealed few unexpected patterns for further investigation. Three unexpected findings were identified concerning (i) short-term use that would entail suboptimal clinical efficiency for minoxidil, (ii) sub-optimal use of topical tacrolimus, and (iii) potential undesirable increase in short-course doxycycline treatments. CONCLUSION: In Denmark, dermatology drugs are predominantly used as expected, with few unexpected use patterns identified. Targeted specific follow-up on the identified signals is necessary for conclusions about inappropriate use. The findings suggest that the WTD method is applicable for screening for aberrant drug use.

Is the sequence ratio an unbiased estimate of the incidence rate ratio? A simulation study.

PURPOSE: We aimed to evaluate the conditions under which the sequence ratio (SR) obtained from a sequence symmetry analysis is an unbiased estimate of the true incidence rate ratio (IRR). METHODS: We simulated cohorts of 1 million individuals who could initiate an exposure drug and experience a very rare, rare, common, or frequent outcome of interest. The outcome rate among exposed individuals was modified by a true incidence rate ratio of 0.2, 0.5, 1.0, 2.0, and 5.0. We further evaluated scenarios where the outcome was fatal and led to immediate censoring or the outcome reduced the rate of initiation of the exposure drug. RESULTS: We found the SR to be close to unbiased for rare, common, and frequent events, except when the true IRR was 5.0 (mean SR 4.94 and 3.74 for common and frequent events). The SR was slightly biased when the outcome was very rare. When the outcome was potentially fatal, the SR was increasingly biased with an increasing probability of death. Likewise, when the outcome reduced the probability of future exposure, the SR was upwards biased. CONCLUSION: The SR is a biased estimate of the incidence rate ratio, when the true IRR is high, the outcome has a high mortality, or when the outcome reduces the probability of future exposure.

Identifying high-risk medications and error types in Danish patient safety database using disproportionality analysis.

BACKGROUND: Medication error (ME) surveillance in Danish healthcare relies on the mandatory national incident reporting system, the Danish Patient Safety Database (DPSD). Individual case reviews and descriptive statistics with frequency counts are the most often used approaches when analyzing MEs in incident reporting systems, including the DPSD. However, incident reporting systems often generate a large number of reports and may suffer from underreporting; consequently, additional approaches are needed to overcome these challenges. Disproportionality analysis (DPA) is a statistical tool used for signal detection of adverse drug reactions in pharmacovigilance reports, but the evidence for using DPA on ME analysis in safety reporting systems is limited. OBJECTIVES: We aimed to test the feasibility of DPA by analysing harmful MEs reported to DPSD 2014-2018. METHODS: We utilized proportional reporting ratios (PRR) to identify signals of diproportionality. RESULTS: We identified well-known high-risk medicines, including anticoagulants, opioids, insulins, antiepileptic, and antipsychotic drugs, and their association with several ME types and stages in a medication process. CONCLUSION: DPA might be suggested as an additional tool for screening MEs and identifying priority areas for further investigation in safety reporting systems.

Use of molnupiravir: A Danish nationwide drug utilization study.

PURPOSE: To describe utilization patterns, characteristics of users and prescribers of the new oral antiviral medication, molnupiravir, indicated for mild-to-moderate COVID-19. METHODS: Using nationwide registries, we identified all Danish adults who filled a prescription for molnupiravir from December 16th, 2021, to August 31st, 2022. We described weekly incidence rates and patient characteristics over time, prescriber characteristics as well as time between molnupiravir initiation and a positive SARs-CoV-2 test. Patient characteristics were compared to matched, untreated SARS-CoV-2 positive reference groups. RESULTS: By August 31st, 2022, 5847 individuals had filled a prescription for molnupiravir. The incidence rate gradually increased to 16 weekly prescriptions per 1000 RT-PCR SARS-CoV-2 positives. Users of molnupiravir were most often men (55% vs. 45% women). The majority (81%) had a positive RT-PCR SARS-CoV-2 test and few (2.9%) redeemed molnupiravir outside the recommended window of 5 days from the positive test result. Compared to matched, untreated SARS-CoV-2 positive reference groups, users of molnupiravir had a median age of 74 years versus 49 years, a higher proportion resided in a nursing home (12% vs. 1.5%) and had a higher number of comorbidities (median of 3 vs. 0); most commonly hypertension (38%), chronic lung disease (35%), diabetes (20%) and mood disorders (20%). General practitioners were the primary prescribers of molnupiravir (91%). CONCLUSIONS: Molnupiravir was mainly prescribed by general practitioners to RT-PCR SARS-CoV-2 positive individuals who had a potentially increased risk of severe COVID-19. Though some off-label prescribing occurred, our study indicates a high level of adherence to contemporary guidelines.

Lessons learned from a multi-data source research collaboration: The mirabegron post-authorization safety study program.

BACKGROUND: Many factors contribute to developing and conducting a successful multi-data source, non-interventional, post-authorization safety study (NI-PASS) for submission to multiple health authorities. Such studies are often large undertakings; evaluating and sharing lessons learned can provide useful insights to others considering similar studies. OBJECTIVES: We discuss challenges and key methodological and organizational factors that led to the delivery of a successful post-marketing requirement (PMR)/PASS program investigating the risk of cardiovascular and cancer events among users of mirabegron, an oral medication for the treatment of overactive bladder. RESULTS: We provide context and share learnings, including sections on research program collaboration, scientific transparency, organizational approach, mitigation of uncertainty around potential delays, validity of study outcomes, selection of data sources and optimizing patient numbers, choice of comparator groups and enhancing precision of estimates of associations, potential confounding and generalizability of study findings, and interpretation of results. CONCLUSIONS: This large PMR/PASS program was a long-term commitment from all parties and benefited from an effective coordinating center and extensive scientific interactions across research partners, scientific advisory board, study sponsor, and health authorities, and delivered useful learnings related to the design and organization of multi-data source NI-PASS.

Mortality and clinical outcomes following SARS-CoV-2 infection among individuals with haematological malignancies: A Danish population-based cohort study.

OBJECTIVES: We aimed to quantify the risk of death following a positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among individuals with haematological malignancies, stratified by virus variants and type of malignancy. METHODS: Using the Danish nationwide registries, we conducted a population-based cohort study among individuals who received a discharge diagnosis of haematological malignancies during the 5 years prior to testing positive for SARS-CoV-2 (February 2020-April 2023). All individuals were followed for 30 days after a positive test, and overall and time-stratified case fatality risks (CFR) were estimated. RESULTS: We identified 7154 individuals with a history of haematological malignancies who tested positive for SARS-CoV-2. Among these, we observed 223 deaths, yielding a CFR of 3.1%. The CFR was highest at the beginning of the pandemic (10%) and gradually declined to 1.9% during the period of Omicron BA1/BA2 predominance. The highest CFR was observed among individuals with acute leukaemia (CFR 6.2%, adjusted relative risk 1.95, 95% confidence interval 1.33-2.88) compared to individuals with lymphoma (CFR 3%). CONCLUSIONS: We observed a reduction in the CFR over time, which may be attributed to new treatments, COVID-19 vaccination and the emergence of less aggressive variants.

Identifying diabetogenic drugs using real world health care databases: A Danish and Australian symmetry analysis.

AIMS: Drug-induced diabetes is underreported in conventional drug safety monitoring and may contribute to the increasing incidence of type 2 diabetes. Therefore, we used routinely collected prescription data to screen all commonly used drugs for diabetogenic effects. METHODS: Leveraging the Danish nationwide health registries, we used a case-only symmetry analysis design to evaluate all possible associations between drug initiation and subsequent diabetes. The study was conducted among individuals aged ≥40 years with a first-ever prescription for any antidiabetic drug 1996-2018 (n = 348 996). Sequence ratios (SRs) and 95% confidence intervals (CIs) were obtained for all possible drug class-diabetes combinations. A lower bound of the 95% CI >1.00 was considered a signal. Signals generated in Denmark were replicated using the Services Australia, Pharmaceutical Benefits Scheme 10% data extract. RESULTS: Overall, 386 drug classes were investigated, of which 70 generated a signal. In total, 43 were classified as previously known based on the SIDER database or a literature review, for example, glucocorticoids (SR 1.67, 95% CI 1.62-1.72) and ß-blockers (SR 1.20, 95% CI 1.16-1.23). Of 27 new signals, three drug classes yielded a signal in both the Danish and Australian data source: digitalis glycosides (SR 2.15, 95% CI 2.04-2.27, and SR 1.76, 95% CI 1.50-2.08), macrolides (SR 1.20, 95% CI 1.16-1.24, and SR 1.11, 95% CI 1.06-1.16) and inhaled ß2-agonists combined with glucocorticoids (SR 1.35, 95% CI 1.28-1.42, and SR 1.14, 95% CI 1.06-1.22). CONCLUSION: We identified 70 drug-diabetes associations, of which 27 were classified as hitherto unknown. Further studies evaluating the hypotheses generated by this work are needed, particularly for the signal for digitalis glycosides.

Impact of low-dose quetiapine-use on glycosylated hemoglobin, triglyceride and cholesterol levels.

OBJECTIVE: Quetiapine use at standard doses has been associated with hyperglycemia and dyslipidemia. However, whether even frequently prescribed low-dose quetiapine results in significant metabolic disturbances remains unclear. Thus, this study aimed to investigate the association between off-label, low-dose quetiapine and changes in glycosylated hemoglobin (HbA1c) levels/lipid parameters. METHODS: We identified new users of low-dose quetiapine (≤50 mg tablets) in Denmark 2008-2018 with measurements of HbA1c, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), or fasting triglycerides (fTG) within 365 days before and after quetiapine initiation. Mixed-effects linear regression models were used to estimate coefficients (ß) with 95% confidence intervals (95%CIs) for change in cardiometabolic parameters after quetiapine initiation. Inverse probability weighting was used to mitigate selection bias. Higher doses of quetiapine (>50 mg) were included in sensitivity analyses. RESULTS: Among 106,711 eligible new low-dose quetiapine users (median age = 45 years, females = 55%), low-dose quetiapine initiation was associated with increased fTG (ß = 1.049[95%CI:1.027-1.072]) and decreased HDL-C (ß = 0.982[0.978-0.986]). Although HbA1c did not change significantly and TC and LDL-C even decreased considering all subjects, all three metabolic parameters increased significantly among individuals with normal pre-quetiapine initiation levels. The adverse metabolic effect of quetiapine on HbA1c, TC, LDL-C, and HDL-C was dose-dependent, which was not the case for fTG. CONCLUSIONS: Low-dose quetiapine was associated with a significant increase in fTG and decreases in HDL-C in all subjects, as well as with significant increases in HbA1c, TC, and LDL-C among those with normal baseline values. The risk of metabolic worsening with quetiapine was dose-dependent, except for fTG.

The association between diabetes and abdominal aortic aneurysms in men: results of two Danish screening studies, a systematic review, and a meta-analysis of population-based screening studies.

BACKGROUND: A paradoxical protective effect of diabetes on the development and progression of abdominal aortic aneurysms (AAA) has been known for years. This study aimed to investigate whether the protective role of diabetes on AAAs has evolved over the years. METHODS: A cross-sectional study, a systematic review and meta-analysis. This study was based on two large, population-based, randomised screening trials of men aged 65-74; VIVA (2008-2011) and DANCAVAS (2014-2018), including measurement of the abdominal aorta by ultrasound or CT, respectively. Analyses were performed using multiple logistic regressions to estimate the odds ratios (ORs) for AAAs in men with diabetes compared to those not having diabetes. Moreover, a systematic review and meta-analysis of population-based screening studies of AAAs to visualise a potential change of the association between diabetes and AAAs. Studies reporting only on women or Asian populations were excluded. RESULTS: In VIVA, the prevalence of AAA was 3.3%, crude OR for AAA in men with diabetes 1.04 (95% confidence interval, CI, 0.80-1.34), and adjusted OR 0.64 (CI 0.48-0.84). In DANCAVAS, the prevalence of AAA was 4.2%, crude OR 1.44 (CI 1.11-1.87), and adjusted OR 0.78 (CI 0.59-1.04). Twenty-three studies were identified for the meta-analysis (N = 224 766). The overall crude OR was 0.90 (CI 0.77-1.05) before 2000 and 1.16 (CI 1.03-1.30) after 1999. The overall adjusted OR was 0.63 (CI 0.59-0.69) before 2000 and 0.69 (CI 0.57-0.84) after 1999. CONCLUSION: Both the crude and adjusted OR showed a statistically non-significant trend towards an increased risk of AAA by the presence of diabetes. If this represents an actual trend, it could be due to a change in the diabetes population. TRIAL REGISTRATION: DANCAVAS: Current Controlled Trials: ISRCTN12157806. VIVA: ClinicalTrials.gov NCT00662480.

Harnessing patient complaints to systematically monitoring healthcare concerns through disproportionality analysis.

Staff observations are the most common source of data for driving improvements in care. However, the patient perspective should also be considered, and healthcare complaints offer concrete details that health organizations might otherwise overlook and that can highlight areas for learning and improvement in the healthcare system. However, because of the diverse nature of patient complaints, systematic analyses can be challenging. This study aimed to identify and prioritize areas for improvement using a data-driven approach to analysing patient complaints. The Danish version of the Healthcare Complaints Analysis Tool was used to categorize the content of complaint letters. All complaints managed by the national complaints authority, compensation claims to the Patient Compensation Association, and locally managed complaints that were filed directly at Odense University Hospital from 2017 to 2021 were included. Proportional reporting ratios (PRRs) were used to measure and display the top five signals of disproportionality and rank them by excess complaints at the hospital level and when divided into department types. The study included 6366 complaints containing 13 156 problems (on average, 2.1 problems mentioned per complaint letter). Surgical departments had the highest number of complaints (3818), followed by medical (1059), service (439), and emergency departments (239). Signal 1 of disproportionality, relating to quality problems during ward procedures, had the highest excess reporting of 1043 complaints at the hospital level and a PRR of 1.61 and was present in all department types. Signal 2, relating to safety problems during the examination and diagnosis stage, had an excess reporting of 699 problems and a PRR of 1.86 and was also present in all department types. Signal 3, relating to institutional problems during admission, had the highest PRR of 3.54 and was found in most department types. Signals 4 and 5, relating to environmental problems during ward procedures and care on the ward, respectively, had PRRs of 1.5 and 1.84 and were present in most department types. The study found that analysing patient complaints can identify potential areas for hospital improvement. The study identified recurring issues in multiple departments, including quality problems during ward procedures, safety problems during the examination, institutional problems during admission, and environmental problems on the ward. The study highlights disproportionality analysis of complaints as a valuable tool to monitor patient concerns systematically.

Oral anticoagulants in patients with atrial fibrillation at low stroke risk: a multicentre observational study.

AIMS: There is currently no consensus on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA2DS2-VASc point) should be treated with an oral anticoagulant. METHODS AND RESULTS: We conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland. In total, 59 076 patients diagnosed with AF at low stroke risk were included. We assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted (IPTW) Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was lower [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56-0.94], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84; 95% CI 0.54-1.30). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81; 95% CI 0.59-1.09), and the rate for ICH tended to be higher during VKA treatment (HR 1.37; 95% CI 0.88-2.14). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92; 95% CI 0.70-1.22), but the rate for ICH was lower during NOAC treatment (HR 0.63; 95% CI 0.42-0.94). CONCLUSION: These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a question that can be tested through a randomized controlled trial.

The effect of immunosuppressants on the prognosis of SARS-CoV-2 infection.

BACKGROUND: Immunosuppression may worsen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a nationwide cohort study of the effect of exposure to immunosuppressants on the prognosis of SARS-CoV-2 infection in Denmark. METHODS: We identified all SARS-CoV-2 test-positive patients from February 2020 to October 2020 and linked healthcare data from nationwide registers, including prescriptions for the exposure (immunosuppressant drugs). We estimated relative risks of hospital admission, intensive care unit (ICU) admission and death (each studied independently up to 30 days from testing) with a log-linear binomial regression adjusted for confounders using a propensity score-based matching weights model. RESULTS: A composite immunosuppressant exposure was associated with a significantly increased risk of death (adjusted relative risk 1.56 (95% CI 1.10-2.22)). The increased risk of death was mainly driven by exposure to systemic glucocorticoids (adjusted relative risk 2.38 (95% CI 1.72-3.30)), which were also associated with an increased risk of hospital admission (adjusted relative risk 1.34 (95% CI 1.10-1.62)), but not of ICU admission (adjusted relative risk 1.76 (95% CI 0.93-3.35)); these risks were greater for high cumulative doses of glucocorticoids than for moderate doses. Exposure to selective immunosuppressants, tumour necrosis factor inhibitors or interleukin inhibitors was not associated with an increased risk of hospitalisation, ICU admission or death, nor was exposure to calcineurin inhibitors, other immunosuppressants, hydroxychloroquine or chloroquine. CONCLUSIONS: Exposure to glucocorticoids was associated with increased risks of hospital admission and death. Further investigation is needed to determine the optimal management of coronavirus disease 2019 (COVID-19) in patients with pre-morbid glucocorticoid usage, specifically whether these patients require altered doses of glucocorticoids.

Epidural Analgesia and Recurrence after Colorectal Cancer Surgery: A Danish Retrospective Registry-based Cohort Study.

BACKGROUND: Surgery is the main curative treatment for colorectal cancer. Yet the immunologic and humoral response to surgery may facilitate progression of micro-metastases. It has been suggested that epidural analgesia preserves immune competency and prevents metastasis formation. Hence, the authors tested the hypothesis that epidural analgesia would result in less cancer recurrence after colorectal cancer surgery. METHODS: The Danish Colorectal Cancer Group Database and the Danish Anesthesia Database were used to identify patients operated for colorectal cancer between 2004 and 2018 with no residual tumor tissue left after surgery. The exposure group was defined by preoperative insertion of an epidural catheter for analgesia. The primary outcome was colorectal cancer recurrence, and the secondary outcome was mortality. Recurrences were identified using a validated algorithm based on data from Danish health registries. Follow-up was until death or September 7, 2018. The authors used propensity score matching to adjust for potential preoperative confounders. RESULTS: In the study population of 11,618 individuals, 3,496 (30.1%) had an epidural catheter inserted before surgery. The epidural analgesia group had higher proportions of total IV anesthesia, laparotomies, and rectal tumors, and epidural analgesia was most frequently used between 2009 and 2012. The propensity score-matched study cohort consisted of 2,980 individuals in each group with balanced baseline covariates. Median follow-up was 58 months (interquartile range, 29 to 86). Recurrence occurred in 567 (19.0%) individuals in the epidural analgesia group and 610 (20.5%) in the group without epidural analgesia. The authors found no association between epidural analgesia and recurrence (hazard ratio, 0.91; 95% CI, 0.82 to 1.02) or mortality (hazard ratio, 1.01; 95% CI, 0.92 to 1.10). CONCLUSIONS: In colorectal cancer surgery, epidural analgesia was not statistically significantly associated with less cancer recurrence.

Retinoids are not linked to risk of multiple sclerosis: A Danish nationwide cohort study.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system with an undetermined etiology. Retinoids may have immunomodulatory effects that favorably influence MS progression. We aimed to explore the yet unknown relationship between exposure to retinoids and the risk of acquiring MS. METHODS: We performed a nationwide cohort study in the Danish population in the period 1998-2016, comparing MS incidence in three groups: users of systemic retinoids; users of topical retinoids (negative control group); and users of non-retinoid acne drugs (control group). We used data from the Danish Multiple Sclerosis Registry (DMSR), the Danish National Prescription Registry and the Danish National Patient Registry. Linkage was obtained through the personal identification number (CPR number). We addressed confounding by three-way propensity score (PS)-matching weights. Additionally, to evaluate a cumulative dose-response effect for systemic retinoids on MS incidence, we conducted a case-control study, nested within the cohort. RESULTS: A total of 257,193 users of non-retinoid acne drugs, 130,560 users of topical retinoids, and 75,610 users of systemic retinoids were included. Systemic retinoid use was not associated with a reduced risk of MS compared to non-retinoid acne drug use in crude (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.61 to 1.05]) and weighted analyses (HR 0.89, 95% CI 0.67 to 1.20). There was no evidence of a cumulative dose-response association between systemic retinoids and MS incidence. CONCLUSIONS: Use of systemic retinoids was not associated with a reduced incidence of MS compared to use of non-retinoid acne drugs in this study.

Association between gabapentinoids and oedema treated with loop diuretics: A pooled sequence symmetry analysis from the USA and Denmark.

AIMS: To assess the gabapentinoid-oedema-loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark. METHODS: This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs. RESULTS: Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06-1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75-0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23-2.04). Pooled estimated incidence of the gabapentinoid-loop diuretic prescribing cascade was 8.14 (95% CI, 1.92-34.49) events per 1000 patient-years. CONCLUSION: We identified evidence of the gabapentinoid-oedema-loop diuretic prescribing cascade in 2 countries.

Trends in the use of oral anticoagulants, antiplatelets and statins in four European countries: a population-based study.

PURPOSE: To evaluate time trends in the prevalence of antithrombotic and statin use in four European countries. METHODS: Using population-based data from the United Kingdom, Denmark, Spain and Italy between 2010 and 2018, we calculated standardized annual prevalence proportions of antithrombotics and statin use, and changes in prevalence proportions (2018 vs. 2010). RESULTS: Prevalence proportion of statins increased from 24.8% to 24.6% (UK), 21.0% to 22.3% (Region of Southern Denmark [RSD]), 12.9% to 14.3% (Udine, Italy), and 20.3% to 23.2% (Spain). Prevalence proportions of antithrombotics declined in all four countries: 18.7% to 15.9% (UK; - 2.8% points), 18.9% to 18.1% (RSD; - 0.8% points), 17.7% to 16.6% (Udine; - 1.1% points) and 15.0% to 13.6% (Spain; - 1.4% points). These declines were driven by reductions in low-dose aspirin use: 15.3% to 8.9% (UK; - 6.4% points), 16.3% to 9.5% (RSD; - 6.8% points), 13.5% to 11.6% (Udine; - 1.9% points), and 10.2% to 8.8% (Spain; - 1.4% points). In the UK, low-dose aspirin use declined from 9.1% to 4.3% (- 4.8% points) for primary CVD prevention, and from 49.6% to 36.9% (- 12.7% points) for secondary prevention. Oral anticoagulant use gradually increased but did not fully account for the decrease in low-dose aspirin use. CONCLUSIONS: Antithrombotic use in the UK, RSD, Udine and Spain declined between 2010 and 2018, driven by a reduction in use of low-dose aspirin that is not completely explained by a gradual increase in OAC use. Use of statins remained constant in the UK, and increased gradually in the RSD, Udine and Spain.

Inhalation anaesthesia compared with total intravenous anaesthesia and postoperative complications in colorectal cancer surgery: an observational registry-based study†.

BACKGROUND: Postoperative complications are common after colorectal surgery, and possibly related to the type of anaesthesia. We aimed to determine associations between the type of anaesthesia and complications after colorectal cancer surgery using Danish registries. METHODS: Patients undergoing colorectal cancer surgery (2004-18) were identified in the Danish Colorectal Cancer Group Database. The cohort was enriched with the Danish Anaesthesia Database and Danish National Prescription Registry data linked by Danish Central Person Registration number. Patients were classified according to type of general anaesthesia: inhalation or TIVA. Confounders were adjusted by propensity score matching. The primary outcome was complications within 30 days postoperatively. Secondarily, we assessed specific medical and surgical complications. RESULTS: We identified 22 179 individuals undergoing colorectal cancer surgery with accompanying anaesthesia data. Propensity score matching yielded 8722 individuals per group. After propensity score matching, postoperative complications were seen in 1933 (22.2%) patients undergoing inhalation anaesthesia and in 2199 (25.2%) undergoing TIVA (odds ratio [OR]=0.84; 95% confidence interval [CI], 0.79-0.91). Although no difference was observed for medical complications, 1369 (15.7%) undergoing inhalation anaesthesia had surgical complications compared with 1708 (19.6%) undergoing TIVA (OR=0.76; 95% CI, 0.71-0.83). Rates of wound dehiscence, anastomotic leak, ileus, wound abscess, intra-abdominal abscess, and sepsis were statistically significantly lower in the inhalation anaesthesia group. CONCLUSION: In this propensity score-matched registry study, use of inhalation anaesthesia was associated with fewer postoperative complications after colorectal cancer surgery than use of TIVA. Inhalation anaesthesia was associated with fewer complications related to wound healing and surgical infections.