Use of antibiotics for urinary tract infections up to and after care home admission in Denmark: a nationwide study.

PURPOSE: Older people have the highest use of antibiotics for acute and chronic urinary tract infection (UTI), despite diagnostic uncertainty and the growing problem of antibiotic resistance. We aim to describe use-patterns of UTI antibiotics two years prior to and following care home admission in Denmark. METHODS: This was a register-based nationwide drug-utilization study. In a cohort comprising all Danish residents admitted into a care home from 2015 to 2021, we described the use of UTI antibiotics, and examined differences between regions and individual care homes in rates of UTI antibiotic use. Further, we described trends in UTI-related contacts with hospitals in the two years prior to and following care home admission. RESULTS: The cohort comprised 101,297 residents (61% female; median age 84 years). UTI antibiotic use doubled from 7 to 14 treatments/100 residents/month two months prior to care home admission and remained at 10 treatments/100 residents/month the following two years. Prescription of pivmecillinam (55%) was most common. Primary care practitioners prescribed the majority (92%) of UTI antibiotics. UTI-related hospital contacts peaked at two months prior to care home admission, with 6 admissions/100 residents/month, subsequently dropping to 2 admission/100 residents/month. We found considerable variation in UTI antibiotic use, with 10% of care homes responsible for 20% of treatments in 2021. CONCLUSION: Use of UTI antibiotics increased prior to and remained at a stable high level following care home admission in Denmark. Despite variation in use across regions and individual care homes, an overall decrease was seen throughout the years 2016-2021.

Statin use before and after the KDIGO Lipids in chronic kidney disease guideline: A population-based interrupted time series analysis.

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.

High-dose non-sedating antihistamines are used insufficiently in chronic urticaria patients treated with omalizumab.

BACKGROUND: The lifetime prevalence of chronic urticaria (CU) is 0.5%-1%. In some patients with CU, symptomatic control is not achieved with non-sedating second-generation H1 antihistamines (nsAH1) alone, even with quadrupled standard doses as recommended in international guidelines. In these cases, biological treatment with omalizumab can be added. Since omalizumab is expensive compared to antihistamines, lack of adherence to guidelines for high dose nsAH1 (up to four-fold standard dose per day) may be associated with substantial unnecessary costs. The aim was to measure the use nsAH1 before and during omalizumab use for the first time in an omalizumab treated CU population. METHODS: We identified all Danish patients with CU who initiated omalizumab from March 2014 to December 2018 and evaluated new and ongoing nsAH1 treatments using the Danish nationwide registries. RESULTS: A total of 955 CU patients initiated treatment with omalizumab within the study period (median age 40 years [IQR 28-50], 74.5% females). During the 12 months prior to omalizumab initiation, 95.6% of the patients filled at least one prescription with nsAH1 at some point, while 84.7% filled at least one prescription during the three months before omalizumab. From 3 months before omalizumab initiation till 3 months after, the proportions of users of high-dose nsAH1 was maximum 31.1%. CONCLUSIONS: Omalizumab was usually administered before sufficient nsAH1 treatment was tried. In despite of the labelling that omalizumab should be co-administered with high dose nsAH1, this does not happen This may lead to substantial unnecessary costs.

Indirect comparison of efficacy of dupilumab versus mepolizumab and omalizumab for severe type 2 asthma.

This indirect comparison of dupilumab, mepolizumab and omalizumab for patients with severe type 2 asthma fulfilling start-up criteria for more than one drug shows no significant efficacy differences https://bit.ly/3pK9Nf9.

Sodium-glucose cotransporter 2 inhibitors and risk of nephrolithiasis.

AIMS/HYPOTHESIS: Sodium-glucose cotransporter 2 inhibitors (SGLT2Is) may reduce nephrolithiasis risk by increasing urine flow. We aimed to investigate whether initiation of SGLT2I was associated with reduced nephrolithiasis risk. METHODS: We conducted an active-comparator new-user cohort study using the Danish health registries in the period 11 November 2012 to 31 December 2018. Individuals aged ≥40 years initiating SGLT2Is or glucagon-like peptide-1 receptor agonists (GLP1 RAs) were followed from treatment initiation until an inpatient or outpatient diagnosis of nephrolithiasis, death, emigration or end of study. New users of SGLT2Is were matched 1:1 on propensity scores to new users of GLP1 RAs. In supplementary analyses, risk of recurrent nephrolithiasis was assessed in individuals with a history of nephrolithiasis before treatment initiation. RESULTS: We identified 24,290 and 19,576 eligible users of SGLT2Is and GLP1 RAs, respectively. After matching, 12,325 patient pairs remained. The median age was 61 years and median follow-up was 2.0 years. The nephrolithiasis rate was 2.0 per 1000 person-years in SGLT2I initiators compared with 4.0 per 1000 person-years in GLP1 RA initiators, with a rate difference of -1.9 per 1000 person-years (95% CI -2.8, -1.0) and an HR of 0.51 (95% CI 0.37, 0.71). For recurrent nephrolithiasis (n = 731 patient pairs), the rate difference was -17 per 1000 person-years (95% CI -33, -1.5) and the HR was 0.68 (95% CI 0.48, 0.97). CONCLUSIONS/INTERPRETATION: Initiation of treatment with SGLT2Is was associated with a clinically significant reduced risk of incident and recurrent nephrolithiasis.

Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma.

BACKGROUND: Omalizumab is approved for treating severe allergic asthma from age 6, but the definition of severe asthma including a systematic assessment to rule out difficult-to-treat asthma has changed since the drug was approved in 2003. METHODS: We conducted a systematic review and meta-analysis of two critical (exacerbation rate, oral corticosteroid (OCS) treatment) and eight important clinical outcomes in children, adolescents and adults, and specifically searched papers for systematic assessment of severe asthma. RESULTS: Adults: seven studies (n = 2159) ascertaining exacerbation rate showing a 37% (95% CI 21-50) reduction in favor of omalizumab, larger than the pre-specified minimal clinically important difference (MCID) of 25%. Only one open-label study (n = 82) was identified assessing the percentage of patients experiencing reduction of OCS-maintenance treatment showing a significantly greater decrease in the omalizumab group (- 45% vs. + 18.3%, p = 0.002). Children and adolescents: four studies (n = 1551) reported data on exacerbations (no meta-analysis conducted), showed overall improvements in exacerbation rate and some passed MCID. No OCS studies were identified. No included studies provided systematic assessment of severe asthma according to current guidelines. CONCLUSIONS: Omalizumab provides clinically relevant improvements in exacerbation rate among children, adolescents, and adults and in OCS-reduction among adults. New studies incorporating a guideline-approached definition of severe asthma are warranted.

Progression-free survival in oncology: Caveat emptor!

Overall survival (OS) is the undisputed gold standard efficacy end-point in cancer drug trials. It is with growing concern that we observe how progression-free survival (PFS) gains ground as surrogate end-point in its place. PFS has appeal because it is resource-efficient, but it has severe shortcomings. Our concern is that uncritical use of PFS will harm the evidence-based evaluation of cancer drugs when considering them for standard use in publicly financed health care systems. PFS is only valid as a surrogate end-point for OS if it correlates strongly with OS and if the cancer drug being investigated has the same effect on PFS and OS such that effects on one predict effects on the other. The latter might be less obvious than the former but is no less critical. Research indicates that in a majority of cases, correlation between surrogate end-points and OS is of medium strength or lower. PFS is therefore unreliable as a surrogate for OS. We do not find it justified to use PFS as surrogate for OS without first having assessed its validity. Stakeholders who take part in evaluating cancer drugs considered for standard use in a health care system must be particularly vigilant about this issue to minimize the risk of introducing cancer drugs that have an unacceptable cost-risk-benefit profile.

Efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab anti-IL-5 treatments of severe asthma - a systematic review and meta-analysis.

Background: New, complex, and expensive therapies targeting Interleukin-5 (IL-5) to treat severe eosinophilic asthma are emerging. Objective: To assess efficacy, adverse events, and inter-drug comparison of mepolizumab and reslizumab for treating severe eosinophilic asthma. Design: A systematic review and meta-analysis on randomized, placebo-controlled, clinical trials elucidating two critical (exacerbation rate and oral corticosteroid (OCS) use) and six important clinical outcomes on the efficacy and safety of mepolizumab and reslizumab. Results: Five studies (N = 2197) contributed with data for exacerbation rate, showing a reduction of 53% (95% CI 46; 59) in favour of anti-IL-5, corresponding to -0.94 annual exacerbations (95% CI -1.08;-0.82), thus exceeding the predefined minimal clinical important difference (MCID) of 25% reduction of the estimated ≥2 annual exacerbations. Quality of evidence was considered moderate, with low heterogeneity in study findings (I2 = 0%). One study (N = 135) contributed with data on percentage of patients experiencing ≥50% reduction inoral corticosteroid treatment, showing an effect of 20% (95% CI 2.3;47) in favour of anti-IL-5 treatment (mepolizumab), thus exceeding the predefined MCID of 10%. Quality of evidence was considered low. Compared to placebo, anti-IL-5 showed significant improvements in lung function, asthma control, and asthma-related quality of life, but below the MCIDs. No differences were observed for serious adverse events and number of patients, who dropped out. No studies evaluating sickleave or head-to-head comparisons were identified. By indirect comparison, we found no significant difference between mepolizumab and reslizumab in any ofthe predefined clinical outcomes. OCS treatment reduction could not be compared due to lack of reslizumab studies investigating this outcome. Conclusions: Mepolizumab and reslizumab provide significant and clinically relevant improvements in exacerbation rate and OCS reduction. Indirect, inter-study comparisons revealed no differences between the anti-IL-5 drugs in efficacy or safety measures.

A Long-Time Follow-Up Study of a Single-Center Endovascular Aneurysm Repair (Evar) Endoleak Outcomes.

PURPOSE: The aim of this study was to evaluate the incidence, risk factors, and outcome of endoleaks related to endovascular aneurysm repair (EVAR) procedure at a single center with up to 10 years' surveillance. MATERIALS AND METHODS: All patients treated with EVAR for an abdominal aorta or iliac aneurysm in a 10-year period at a single cardiovascular center in Denmark were included. Data were collected from a national database and patient journals. Follow-up computed tomography angiography and plain abdominal X-ray reports were reviewed. RESULTS: A total of 421 patients were included. There were 125 endoleaks observed in 117 (27.8%) patients after a median 95 days (interquartile range: 90-106 days). There were 16 type I, 107 type II, 1 type III, and 1 type V endoleaks. A total of 33 (7.8%) patients had at least 1 reintervention. Patients with type II endoleaks had significantly fewer active smokers and lower plasma creatinine at baseline. They also more often had one, or both, internal iliac arteries embolized as well as an identified endoleak at the procedural completion angiogram. Non-type II endoleaks were associated with internal iliac artery embolization. There was no association between the occurrence of endoleaks and increased mortality. CONCLUSION: Type II endoleaks are common after EVAR, yet few lead to reintervention. Absence of smoking, low plasma creatinine, embolized iliac arteries, and endoleak on completion angiogram were associated with type II endoleaks, whereas only embolized iliac arteries were associated with non-type II endoleaks. Overall, endoleaks are not associated with increased mortality.

Early Discontinuation of Montelukast Treatment; A Danish Nationwide Utilization Study.

Montelukast, a leukotriene receptor antagonist, was marketed in 1998 as an oral supplementary treatment to patients with mild to moderate asthma. The aim of this study was to describe the early discontinuation pattern among montelukast users in Denmark in the period of 1 March 1998 to 31 December 2016, and to identify demographic characteristics possibly associated with early discontinuation. This nationwide drug utilization study was based on data collected from three nationwide Danish registers. All montelukast users who redeemed at least one prescription in the study period were identified. Early discontinuation was defined as failing to fill a second prescription for montelukast within at least a year after the initial montelukast prescription. Among 135,271 included montelukast users, 47,480 (35%) discontinued the use of montelukast after a single redeemed prescription. The trend in early discontinuation increased throughout the years. The most predominant demographic risk factors for early discontinuation were prescription for only nasal topical anti-allergic treatment up to a year prior to montelukast initiation [adjusted odds ratio (OR) 2.25; 95% confidence interval (CI) 2.13-2.38], as well as suspected off-label use (adjusted OR 2.02; 95% CI 1.97-2.08). Several risk factors were associated with a decreased risk of early discontinuation; most pronounced was a prescription of inhaled corticosteroids within a year up to montelukast initiation [adjusted OR 0.47 (95% CI 0.46-0.49)]. Early discontinuation was more pronounced after patent expiry in 2012 [adjusted OR 1.42 (95% CI 1.38-1.45)]. In conclusion, we found that early montelukast discontinuation increased during the last 19 years. Appropriateness of the treatment indication as estimated by concomitant prescription of adequate inhalation therapy was associated with a low risk of early discontinuation. A more pronounced early discontinuation was observed after patent expiry in 2012, which could reflect a more liberal approach to montelukast prescription.

Lung ultrasound has limited diagnostic value in rare cystic lung diseases: a cross-sectional study.

Background: Lung ultrasound (LUS) used to identify interstitial syndrome (IS) and pleural thickening related to diffuse parenchymal lung disease (DPLD) has shown significant correlations with ground glass opacity (GGO) on high-resolution computed tomography (HRCT). However, the applicability of LUS in patients with DPLD subtypes as rare cystic lung diseases has not previously been investigated. This study aimed to observe if distinctive LUS findings could be found in patients with lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), and Birt-Hogg-Dubé syndrome (BHDS). Methods: This single centre case-based cross-sectional study of patients diagnosed with LAM, PCLH and BHDS was conducted at a Danish DPLD specialist centre. Patients underwent clinical examination including LUS. LUS findings were compared to findings scored according to a modified Belmaati score on HRCT and reviewed in consensus between two pulmonologists and one radiologist. Results: Twelve patients with HRCT proven cystic lung disease were included, six with LAM, three with PLCH, two with BHDS, and one with uncharacteristic cystic lung disease. The mean age was 48.7 years (SD ± 15.8). In general all had normal LUS findings. IS could not be found in any patients despite GGO presentation on HRCT among 75% of the patients with a Belmaati in the highest category of 0.76-1.00. Pleural thickening on LUS was present in three patients, but with inconsistent findings. Conclusion: This study indicates that LUS has limited value as a diagnostic tool in patients with LAM, PLCH, and BHDS as normal LUS findings did not rule out severe cystic lung disease.

Intermediate-term and long-term mortality among acute medical patients hospitalized with community-acquired sepsis: a population-based study.

OBJECTIVE: Admission with severe sepsis is associated with an increased short-term mortality, but it is unestablished whether sepsis severity has an impact on intermediate-term and long-term mortality following admission to an acute medical admission unit. PATIENTS AND METHODS: This was a population-based study of all adults admitted to an acute medical admission unit, Odense University Hospital, Denmark, from September 2010 to August 2011, identified by symptoms and clinical findings. We categorized the mortality periods into intermediate-term (31-180 days) and long-term (181-365, 366-730, and 731-1096 days). Mortality hazard ratios (HRs), comparing patients admitted with sepsis with those of a well-defined background population, were estimated using multivariable Cox regression. HRs were presented with 95% confidence intervals. RESULTS: In total, 621 (36.3%) presented with sepsis, 1071 (62.5%) presented with severe sepsis, and 21 (1.2%) presented with septic shock. Thirty-day all-cause mortality for patients with sepsis, severe sepsis, and septic shock was 6.1, 18.8, and 38.1%, respectively. The adjusted HR among patients with sepsis of any severity within the time periods 31-180, 181-365, 366-720, and 721-1096 days was 7.1 (6.0-8.5), 2.8 (2.3-3.5), 2.1 (1.8-2.6), and 2.2 (1.7-2.9), respectively. Long-term mortality was unrelated to sepsis severity [721-1096 days: sepsis HR: 2.2 (1.5-3.2), severe sepsis HR: 2.1 (1.5-3.0)]. CONCLUSION: Patients admitted with community-acquired sepsis showed high intermediate-term mortality, increasing with sepsis severity. Long-term mortality was increased two-fold compared with sepsis-free individuals, but might be explained by unmeasured confounding. Further, long-term mortality was unrelated to sepsis severity.

Combined use of the National Early Warning Score and D-dimer levels to predict 30-day and 365-day mortality in medical patients.

AIM: To investigate the combined use of NEWS and D-dimer levels to predict the 30-day and 365-day mortality rates of a cohort of Danish patients with complete follow-up. METHODS: Post-hoc retrospective observational study of acutely admitted medical patients aged 18 years or older who had D-dimer measured within 6h after arrival to two medical admission units in Denmark. RESULTS: The final study population consisted of 1201 patients with a median age of 65.0 years (range 18.0-107.0 years), and 44.7% were of male sex. Four patients (0.3%) died within 24h of admission, 69 (5.7%) within 30 days and 198 (16.5%) within 365 days. On admission, 576 (48%) patients had a NEWS≥3 - of these 441 had a D-dimer≥0.50mgL(-1): 55 (12.5%) of these patients died within 30 days, compared with 5 (3.7%) of the 135 patients with a D-dimer<0.50mgL(-1) (odds ratio 3.7, 95%CI 1.4-10.8). Nine of the 625 patients with a NEWS on admission <3 died within 30 days and all of these patients had a D-dimer≥0.50mgL(-1). None of the 218 patients with a D-dimer<0.50mgL(-1) died within 30 days of admission. CONCLUSION: The combination of NEWS score<3 and D-dimer levels below 0.50mgL(-1) appears to identify patients of low risk of mortality within 30 days and, therefore, may prove to be a powerful risk assessment tool for acutely ill medical patients.

Increasing incidence of hypotension in the emergency department; a 12 year population-based cohort study.

BACKGROUND: The epidemiology of hypotension as presenting symptom among patients in the Emergency Department (ED) is not clarified. The aim of this study was to describe the incidence, etiology, and overall mortality of hypotensive patients in the ED. METHODS: Population-based cohort study at an University Hospital ED in Denmark from January 1, 2000, to December 31, 2011. Patients aged ≥18 years living in the hospital catchment area with a first time presentation to the ED with hypotension (systolic blood pressure (SBP) ≤100 mm Hg) were included. Outcomes were annual incidence rates (IRs) per 100,000 person years at risk (pyar) and etiological characteristics by means of the International Classification of Diseases, Tenth Revision (ICD-10), as well as 7-day, 30-day, and 90-day all-cause mortality. RESULTS: We identified 3,268 of 438,198 (1 %) cases with a mean overall IR of 125/100,000 pyar (95% CI: 121-130). The IR increased 28% during the period (from 113 to 152 cases per 100,000 pyar). Patients ≥65 years had the highest IR compared to age <65 years (rate ratio for men 6.3 (95% CI: 5.6-7.1) and for women 4.2 (95% CI: 3.6-4.9)). The etiology was highly diversified with trauma (17%) and cardiovascular diseases (15%) as the most common. The overall 7-day, 30-day and 90-day mortality rates were 15% (95% CI: 14-16), 22 % (95% CI: 21-24) and 28% (95% CI: 27-30) respectively. CONCLUSION: During 2000-2011 the overall incidence of ED hypotension increased and remained highest among the elderly with a diversified etiology and a 90-day all-cause mortality of 28%.

Mortality and prognostic factors of patients who have blood cultures performed in the emergency department: a cohort study.

BACKGROUND: Early identification and treatment of patients with severe infection improve their prognosis. The aims of this study were to describe the 30-day mortality and to identify prognostic factors among blood-cultured patients in a medical emergency department (MED). PATIENTS AND METHODS: This was a hospital-based cohort study including all adult (≥15 years old) blood-cultured patients at the MED at Odense University Hospital between 1 August 2009 and 31 August 2011. RESULTS: During the study period, 5499/11 988 (45.9%) patients had blood cultures performed within 72 h of arrival and were included in the study. Of those included, 2631 (47.8%) were men, median age 69 years (range 15-103), and 418 (7.6%) were diagnosed with bacteraemia. The overall 30-day mortality among blood-cultured patients was 11.0% (10.2-11.9). In a multivariate Cox regression model, age of more than 80 years [hazard ratio (HR) 4.6 (95% CI 3.6-6.0)], at least two organ failure [HR 3.6 (2.9-4.5)], bacteraemia [HR 1.4 (1.1-1.8)], Charlson Comorbidity Index of at least 2 h [HR 1.7 (1.3-2.0)], SIRS [HR 1.5 (1.2-1.7)], a history of alcohol dependency [HR 1.7 (1.3-2.3)] and late drawing of blood cultures 24-48 h after arrival [HR 1.7 (1.3-2.2)] were found to be prognostic factors of mortality among blood-cultured patients in the MED. CONCLUSION: Among blood-cultured patients in the MED, we found an 11.0% overall 30-day mortality. Factors associated with 30-day mortality were age more than 80 years, at least two organ failure, bacteraemia, Charlson Comorbidity Index of at least 2, SIRS, a history of alcohol dependency and late drawing of blood cultures.

Lactate is associated with increased 10-day mortality in acute medical patients: a hospital-based cohort study.

An increased lactate level is related to increased mortality in subpopulations of critically ill patients. The aim of this study was to investigate whether lactate was related to mortality in an emergency department (ED) setting of undifferentiated medical patients. All adult patients admitted from March 2009 to August 2011 to a medical ED with lactate measured within 6 h after arrival were studied. Lactate was stratified into 1-mmol/l intervals and analysed in a multivariate logistic regression analysis. A total of 5317 patients were included, 46.9% men, median age 71 years (5-95% percentiles 25-90 years). The median lactate level was 1.2 mmol/l (5-95% percentiles 0.6-3.8 mmol/l, range 0.2-22 mmol/l). Lactate was associated with 10-day mortality independent of age, comorbidity and presence of hypotension, with an odds ratio of 1.54 (95% confidence interval 1.44-1.63) per 1 mmol/l increase. Lactate is an independent predictor of 10-day mortality among patients admitted to a medical ED.

Drug dosing in patients with renal insufficiency in a hospital setting using electronic prescribing and automated reporting of estimated glomerular filtration rate.

In patients with impaired renal function, drug dose adjustment is often required. Non-adherence to clinical prescribing recommendations may result in severe adverse events. In previous studies, the prevalence rate of non-adherence to recommended dosing has been reported to be 19-67%. Using the clinical support system Renbase(®) as reference, we investigated the use and dosing of drugs in patients with impaired renal function in a university hospital setting using electronic prescription and automatic reporting of estimated glomerular filtration rate (eGFR). In all, 232 patients with an eGFR in the range of 10-49 ml/min./1.73 m(2) were included. We identified 436 episodes with administration of renal risk drugs (prescribed to 183 patients): 410 drugs required dose adjustment according to the eGFR and 26 should be avoided. In total, the use or dosing of 66 (15%) of the 436 renal risk drugs was not in agreement with recommendations in Renbase(®) . This reflects less disagreement with expert guidelines than reported previously, indicating a possible beneficial effect of electronic prescribing and reporting of eGFR. However, we also found that disagreement to some extent reflected inappropriate drug use. We conclude that despite implementation of electronic prescribing and automated reporting of eGFR, patients with renal insufficiency may still be exposed to inappropriate drug use, with potential increased risk of adverse effects. Initiatives to reduce medication errors such as the use of electronic decision support systems should be explored.