Trends and predictors of specialist assessments in oral corticosteroid treated asthma among young adults.

Background: Repeated oral corticosteroid use indicates uncontrolled disease among asthma patients, and referral for asthma specialist assessment is recommended. We aimed to describe trends and predictors associated with specialist contacts among young adults with asthma and repeated oral corticosteroid use. Methods: Individuals aged 18-45 years with two or more dispensed asthma medication prescriptions and two dispended oral corticosteroid prescriptions (including short-term and long-term treatments) within 12 months during 1999-2018 were identified by use of Danish healthcare registers. The frequency of specialist contacts within 1 year of follow-up was assessed among individuals without previous specialist contacts within 5 years of inclusion. Factors associated with specialist contact were identified using logistic regression models. Furthermore, oral corticosteroid prescriber sources were assessed. Results: For the 11 223 individuals included, 2444 (22%) had previous specialist-contact care within 5 years prior of inclusion, and additionally 926 (8.3%) within 1 year of follow-up. Among those without previous specialist contacts (n=8779), the frequency of incident specialist contacts within 1 year of follow-up increased from 6.3% in 1999 to 18% in 2017. Factors associated with incident specialist contacts included dispensing ≥12 short-acting ß-agonist canisters and previous asthma-related emergency department visits and hospitalisations. The majority of oral corticosteroid prescriptions at baseline (71%) were prescribed by general practitioners, although with decreasing proportions from 1999 to 2018. Conclusions: The majority (70%) of young adults with asthma and repeated oral corticosteroid use do not seem to receive specialist assessment in Denmark. This highlights a potential room for improvement in the patient referral pathway for at-risk asthma patients.

Breathing Exercises for Patients with Asthma in Specialist Care: A Multicenter Randomized Clinical Trial.

Rationale: Moderate to severe asthma is associated with impaired asthma control and quality of life (QoL) despite access to specialist care and modern pharmacotherapy. Breathing exercises (BrEX) improve QoL in incompletely controlled mild asthma, but impact in moderate to severe asthma is unknown. Objectives: To investigate the effectiveness of BrEX as adjuvant treatment on QoL in patients with uncontrolled moderate to severe asthma. Methods: Adult patients with incompletely controlled asthma attending respiratory specialist clinics were randomized to usual specialist care (UC) or UC and BrEX (UC + BrEX) with three individual physiotherapist-delivered sessions and home exercises. Primary outcome was asthma-related QoL (Mini-Asthma Quality of Life Questionnaire [Mini-AQLQ]) at 6 months on the basis of intention-to-treat analysis. Secondary outcomes: Mini-AQLQ at 12 months, lung function, 6-minute-walk test, physical activity level, Nijmegen Questionnaire, Hospital Anxiety and Depression Scale, and adverse events. Repeated-measures mixed-effects models were used to analyze data. Poisson regression models were used to analyze adverse event incidence rate ratio. Results: A total of 193 participants were allocated to UC + BrEX (n = 94) or UC (n = 99). UC + BrEX was superior in the primary outcome (adjusted mean change difference, 0.35; 95% confidence interval [CI], 0.07 to 0.62). Superiority in Mini-AQLQ was sustained at 12 months (0.38; 95% CI, 0.12 to 0.65). A minor improvement in Hospital Anxiety and Depression Scale depression score at 6 months favoring UC + BrEX (-0.90; 95% CI, -1.67 to -0.14) was observed. Asthma-related adverse events occurred similarly in UC + BrEX and UC participants: 14.9% versus 18.1% (P = 0.38). Conclusions: BrEX as add-on to usual care improve asthma-related QoL in incompletely controlled asthma regardless of severity and with no evidence of harm. Clinical trial registered with www.clinicaltrials.gov (NCT03127059).

Low-dose oral corticosteroids in asthma associates with increased morbidity and mortality.

BACKGROUND: Long-term oral corticosteroid (OCS) treatment for severe asthma is known to cause significant adverse effects, but knowledge on effects of lower exposures in general asthma populations is limited. We aimed to explore this in a nationwide Danish asthma population. METHODS: Users of asthma medication aged 18-45 years were identified in the Danish nationwide registers during 1999-2018 and followed prospectively in an open-cohort design. Incident OCS users were matched 1:4 to nonusers by propensity scores with replacement. Associations between OCS use and incident comorbidities were examined by Cox regression. Mortality rates, causes of death and rates of unscheduled hospital visits were assessed. RESULTS: OCS users (n=30 352) had, compared with nonusers (n=121 408), an increased risk of all outcomes with evident dose-response relationships starting at cumulative doses of ≤500 mg (prednisolone-equivalent). Hazard ratios ranged from 1.24 (95% CI 1.18-1.30) for fractures to 8.53 (95% CI 3.97-18.33) for adrenal insufficiency. Depression/anxiety had the highest incidence rate difference at 4.3 (95% CI 3.6-5.0) per 1000 person-years. Asthma-specific mortality rates were generally low at 0.15 (95% CI 0.11-0.20) and 0.04 (95% CI 0.02-0.06) per 1000 person-years for OCS users and nonusers, respectively. Mortality rates and unscheduled hospital visits increased with increasing OCS exposure. CONCLUSION: The study findings should be interpreted with their observational nature in mind. However, we found that even at low cumulative exposure, OCS use in asthma management was associated with increased risk of comorbidities, mortality and unscheduled hospital visits. Effective strategies for optimising asthma control and reducing OCS use are pivotal in asthma management.

Changes in oral corticosteroid use in asthma treatment-A 20-year Danish nationwide drug utilisation study.

Oral corticosteroids (OCS) are used in asthma management but can cause serious adverse effects. We aimed to investigate the usage trends in a nationwide asthma cohort in Denmark from 1999 to 2018. Using national registers, we identified young adults (18-45 years) with two or more asthma drug collections within 12 months since the age of 15 years as indicative of active asthma. OCS exposure level was stratified as high use (≥5 mg prednisolone/day/year) and low use (<5 mg/day/year). Lorenz curves were computed to illustrate potential skewness of consumption among the OCS users. We identified 318 950 individuals with a median age of 29 years (IQR 20-38 years) whereof 57% were women. The 1-year prevalence of OCS users was stable at 4.8% (median, IQR 4.7%-4.8%), but with nearly 40% decrease in high-users from 0.54% in 1999 to 0.33% in 2018. The median annual exposure decreased from 500 mg/year (1999) to 250 mg/year (2018). We found a substantial skewness in the distribution of OCS usage with 10% of users accounting for almost 50% of all OCS use. The prevalence of OCS users among young adults with active asthma has been relatively stable from 1999 to 2018, but with a decreasing prevalence of high-users and annual consumption.

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.

Spontaneous pneumothorax as a clinical manifestation of neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a genetic disorder affecting the skin, nervous system, eyes and bones. Pulmonary involvement is unknown to many physicians. Yet, patients may be affected by lung bullae and cysts, which represent an increased risk for secondary spontaneous pneumothorax (SSP). We present a 56-year-old patient with a pathogenic variant of the NF1 gene, who suffered from NF1 with lung manifestations and recurrent SSP. It is essential to identify the patients having an increased risk of developing SSP as preventive surgery seem to decrease the risk of new events. Pneumothorax can be a clinical manifestation of NF1 but is not yet widely acknowledged as such.

Efficacy of bronchial thermoplasty in patients with severe asthma.

Objective: To investigate the efficacy and safety of bronchial thermoplasty (BT) in clinical practice in adults with severe, refractory asthma.Methods: Prospective, single-center, open, observational study comprising patients with uncontrolled asthma (asthma control questionnaire (ACQ) >1.5) and/or frequent exacerbations despite treatment with at least high dose inhaled corticosteroids plus a second controller. Efficacy outcomes was change from baseline 4, 8, 12 and 24 months in FEV1, FVC and FEV1/FVC ratio, asthma control questionnaire (ACQ) score and asthma quality of life score (mini-AQLQ). Results are presented as median with interquartile ranges (IQR). The following were recorded as adverse events: Un-scheduled health care contacts, rescue courses of oral corticosteroid (OCS) and/or antibiotics for exacerbation for exacerbations/respiratory tract infections (RTI).Results: Six-teen patients were enrolled (nine males, median age 50 years; 14 followed for 24 months). Compared to baseline, an improvement in FEV1, FVC, FEV1/FVC ratio, mini-AQLQ and ACQ was observed, i.e.FEV1 (IQR) 1.98 L (1.65-2.45) vs. 2.45 L (2.09-2.93) (p = 0.006), FVC (IQR) 3.23 L (2.76-4.05) vs. 3.75 L (3.22-4.36) (p = 0.041), FEV1/FVC 0.60 (IQR: 0.55-0.70) vs. 0.66 (IQR: 0.63-0.71) (p = 0.016), mini-AQLQ 4.0 (IQR: 3.2-4.9) vs. 5.6 (IQR 4.5-6.5) (p = 0.008, and ACQ 2.9 (IQR: 2.1-3.7) versus 1.5 (IQR 1.0-2.4) (p = 0.004). On the other hand, an increase was observed in unscheduled visits (p = 0.005), as well as use of OCS and antibiotics (p = 0.009 and p = 0.003, respectively).Conclusion: BT in adults with severe asthma improved ACQ, mini-AQLQ and lung function, but resulted in an increased frequency of unscheduled doctor-visits and rescue courses of OCS and antibiotics.

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.

Protocol for a multicentre randomised controlled trial to investigate the effect on asthma-related quality of life from breathing retraining in patients with incomplete asthma control attending specialist care in Denmark.

INTRODUCTION AND AIM: Uncontrolled asthma is a global health challenge with substantial impact on quality of life (QoL) and overall healthcare costs. Unrecognised and/or unmanaged comorbidities often contribute to presence of uncontrolled asthma. Abnormalities in breathing pattern are termed dysfunctional breathing and are not only common in asthma but also lead to asthma-like symptoms and reduced QoL, and, in keeping with this, improvement with breathing normalisation. Evidence-based guidelines recommend breathing retraining interventions as an adjuvant treatment in uncontrolled asthma. Physiotherapy-based breathing pattern modification interventions incorporating relaxation have been shown to improve asthma-related QoL in primary care patients with impaired asthma control. Despite anecdotal reports, effectiveness of breathing retraining in patients referred to secondary care with incomplete asthma control has not been formally assessed in a randomised controlled trial (RCT). We aim to investigate the effect of breathing exercises on asthma-related QoL in patients with incomplete asthma control despite specialist care. METHODS AND ANALYSIS: This two-armed assessor-blinded multicentre RCT will investigate the effect of physiotherapist-delivered breathing retraining on asthma QoL questionnaire (MiniAQLQ) in addition to usual specialist care, recruiting from seven outpatient departments and one specialised clinic representing all regions of Denmark during 2017-2019. We will include 190 consenting adults with incomplete asthma control, defined as Asthma Control Questionnaire 6-item score ≥0.8. Participants will randomly be allocated to either breathing exercise programme in addition to usual care (BrEX +UC) or UC alone. BrEX compiles three physiotherapy sessions and encouragement to perform home exercise daily. Both groups continue usual secondary care management. Primary outcome is between-group difference in MiniAQLQ at 6 months. Secondary outcomes include patient-reported outcome measures, spirometry and accelerometer. ETHICS AND DISSEMINATION: Ethics Committee, Region Zealand (SJ-552) and Danish Data Protection Agency (REG-55-2016) approved the trial. Results will be reported in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT03127059; Pre-results.

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.

Appropriate selection for omalizumab treatment in patients with severe asthma?

Background: Omalizumab improves asthma control in patients with uncontrolled severe allergic asthma; however, appropriate patient selection is crucial. Information in this field is sparse. Objective: We aimed to estimate whether potential omalizumab candidates were appropriately selected according to guidelines, and the clinical effect of omalizumab treatment over time. Design: We performed a retrospective observational study on adult patients with asthma treated with omalizumab during 2006-2015 at the Department of Respiratory Medicine at Odense University Hospital (OUH), Denmark. Data were obtained from the Electronic Patient Journal of OUH and Odense Pharmaco-Epidemiological Database. Guideline criteria for omalizumab treatment were used to evaluate the appropriateness of omalizumab candidate selection, and the Asthma Control Test (ACT) to assess the clinical effects of omalizumab at weeks 16 and 52 from treatment initiation. Results: During the observation period, 24 patients received omalizumab, but only 10 patients (42%) fulfilled criteria recommended by international guidelines. The main reasons for not fulfilling the criteria were inadequately reduced lung function, insufficient number of exacerbations, and asthma standard therapy below Global Initiative for Asthma (GINA) step 4-5. Seventeen and 11 patients completed treatment at weeks 16 and 52, with a statistically significant increase in ACT score of 5.1 points [95% confidence interval (CI) 3.1-7.2, p = 0.0001] and 7.7 points (95% CI 4.3-11.1, p = 0.0005), respectively. Conclusion: Only 42% of the omalizumab-treated patients were appropriately selected according to current guidelines. Still, as omalizumab showed significant improvement in asthma control over time, it is important to keep this drug in mind as an add-on to asthma therapy in well-selected patients.

[Specific bronchial and nasal provocations with work-related allergens]. / Specifikke bronkiale og nasale provokationer for erhvervsallergener.

Specific inhalation challenge (SIC) is the golden standard for identifying specific causes of work-related asthma and rhinoconjunctivitis. Few centres offer SIC as it requires experience, resources and acute treatment facilities. Prior to SIC treatment should be carefully reduced. A control challenge is performed on a separate day. Many new asthma causes have been identified with SIC. SIC provides the basis for optimal treatment and advice.

Plasma YKL-40 and all-cause mortality in patients with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is hallmarked by inflammatory processes and a progressive decline of lung function. YKL-40 is a potential biomarker of inflammation and mortality in patients suffering from inflammatory lung disease, but its prognostic value in patients with COPD remains unknown. We investigated whether high plasma YKL-40 was associated with increased mortality in patients with moderate to very severe COPD. METHODS: Four hundred and ninety-three patients with moderate to very severe COPD were followed prospectively for up to 10 years. Patients were divided into two groups according to plasma YKL-40: concentration higher than the 75th percentile for age-matched healthy subjects (i.e. high levels) and normal levels. Outcome was overall survival (OS) and was evaluated in uni- and multivariate proportional hazards Cox regression analyses and adjusted for factors affecting mortality. RESULTS: Median plasma YKL-40 was increased in patients with COPD (81 ng/ml, p < 0.001) compared to healthy subjects (40 ng/ml). Patients with high plasma YKL-40 had a hazard ratio (HR) of 1.42 (95% CI: 1.15-1.75, p = 0.001) for all-cause mortality. Multivariate analysis showed that YKL-40 (HR 1.38; 95% CI: 1.11-1.72, p = 0.004), age (HR 1.05; 95% CI: 1.03-1.06, p < 0.0001), Severe COPD (HR 1.35; 95 CI: 1.03-1.76, p = 0.03) very severe COPD (HR 2.19; 95% CI: 1.60 - 2.99 < 0.0001), neutrophil granulocyte count (HR 1.05; 95% CI: 1.01-1.08, p = 0.01), and a smoking history of > 40 years (HR 1.38; 95% CI: 1.11-1.71, p = 0.003) were independent prognostic markers of OS. CONCLUSION: High plasmaYKL-40 is associated with increased mortality in patients with moderate to very severe COPD, suggesting a role for YKL-40 as a potential biomarker of mortality in this patient group.

The effect of real-time teleconsultations between hospital-based nurses and patients with severe COPD discharged after an exacerbation.

We investigated the effect of daily real-time teleconsultations for one week between hospital-based nurses specialised in respiratory diseases and patients with severe COPD discharged after acute exacerbation. Patients admitted with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) at two hospitals were recruited at hospital discharge. They were randomly assigned to intervention or control. The telemedicine equipment consisted of a briefcase with built-in computer including a web camera, microphone and measurement equipment. The primary outcome was the mean number of total hospital readmissions within 26 weeks of discharge. A total of 266 patients (mean age 72 years) were allocated to either intervention (n = 132) or control (n = 134). There was no significant difference in the unconditional total mean number of hospital readmissions after 26 weeks: mean 1.4 (SD 2.1) in the intervention group and 1.6 (SD 2.4) in the control group. In a secondary analysis, there was no significant difference between the two groups in mortality, time to readmission, mean number of total hospital readmissions, mean number of readmissions with AECOPD, mean number of total hospital readmission days or mean number of readmission days with AECOPD calculated at 4, 8, 12 and 26 weeks. Thus the addition of one week of teleconsultations between hospital-based nurses and patients with severe COPD discharged after hospitalisation did not significantly reduce readmissions or affect mortality.

Calprotectin--a marker of mortality in COPD? Results from a prospective cohort study.

Calprotectin comprises more than 45% of the cytosolic content of neutrophil granulocytes. Because pathogenesis, disease activity and disease progression in COPD are believed to be partly dependent of neutrophil driven inflammation we decided to investigate whether plasma level of calprotectin (p-calprotectin) was associated with all-cause mortality in patients with COPD. We measured p-calprotectin in blood samples from 460 patients with moderate to very severe COPD in stable phase. Patients were stratified into three groups according to p-calprotectin level. Outcome measure was all-cause mortality. Analyses were adjusted for factors known to influence mortality using a Cox regression analysis. We found a time dependent correlation between p-calprotectin levels and mortality during the first 5 years of follow-up. Increasing levels of p-calprotectin were associated with concomitant increases in mortality from HR 1.56 (CI 95%: 1.03 -2.38) at calprotectin between 100 -200 ng/ml to HR 2.02 (CI 95%: 1.27-3.19) at calprotectin >200 ng/ml. P-calprotectin could be a useful marker of all-cause mortality in patients suffering from moderate to very severe COPD.

Serum vitamin D in patients with chronic obstructive lung disease does not correlate with mortality--results from a 10-year prospective cohort study.

BACKGROUND: Recent studies have found vitamin D (25-OHD) deficiency and insufficiency to be common among patients with COPD. Serum level of 25-OHD seems to correlate to pulmonary function, COPD disease staging, and increased susceptibility to respiratory infections. We wanted to investigate whether vitamin D deficiency or insufficiency was associated with mortality rate in patients suffering from advanced COPD. METHODS: 25-OHD serum levels were measured in 462 patients suffering from moderate to very severe COPD. Patients were stratified into three groups according to serum levels of 25-OHD. Outcome measure was mortality in a 10 year follow-up period. Kaplan-Meier curves (KM) were plotted and mortality hazard ratios (HR) were calculated using Cox Proportional Hazard regression (Cox PH). RESULTS: Serum 25-OHD deficiency and insufficiency were prevalent. We were unable to demonstrate any association between baseline serum levels of 25-OHD and mortality rate. We found an association between mortality and age [HR 1.05 (CI 95%: 1.03-1.06)], Charlson score [HR 1.49 (CI 95%: 1.06-2.09)], increasing neutrophil count [HR 1.05 (CI 95%: 1.02-1.09)], severe [HR 1.41 (CI 95%: 1.06-1.86)]/very severe COPD [HR 2.19 (CI 95%: 1.58-3.02)] and a smoking history of more than 40 pack years [HR 1.27 (CI 95%: 1.02-1.70)]. CONCLUSIONS: Serum level of 25-OHD does not seem to be associated with mortality rate, suggesting no or only a minor role of 25-OHD in disease progression in patients with moderate to very severe COPD.

Concurrent use of tramadol and oral vitamin K antagonists and the risk of excessive anticoagulation: a register-based nested case-control study.

OBJECTIVES: The objective was to assess whether the concurrent use of tramadol and vitamin K antagonists (VKAs) leads to an increased risk of excessive anticoagulation. DESIGN: The study was designed as a case-control study, nested within users of VKA and with tramadol use as our main exposure. We used conditional logistic regression to control for potential confounders. SETTING: Prescription data from primary care were obtained from Odense Pharmacoepidemiological Database (OPED). Information about hospital admissions was obtained from the patient administrative system of Funen County (FPAS). SUBJECTS: Both cases and controls were selected from users of VKA. Cases were defined by being hospitalised with a main diagnosis indicating excessive anticoagulation. For each case, we selected 15 controls among VKA users, matched by age and sex. MAIN OUTCOME MEASURE: Odds ratio for experiencing excessive anticoagulation attributable to the use of tramadol. RESULTS: A total of 178 patients were included, 30 of which were exposed to tramadol, along with 2643 controls, 114 of which were exposed to tramadol. The adjusted odds-ratio for experiencing excessive anticoagulation during use of tramadol was 3.1 (1.9-5.2). This corresponds to, on average, one excess case per 250 treatment years (CI 125-584). The result is potentially confounded by concomitant paracetamol use and the presence of acute illness. CONCLUSION: Caution is advised when using tramadol in patients using VKA, and if possible, an alternative pain-medication should be used.

Excessive anticoagulation with warfarin or phenprocoumon may have multiple causes.

INTRODUCTION: Excessive anticoagulation with vitamin K antagonists is a serious condition with a substantial risk of an adverse outcome. We thus found it of interest to review a large case series to characterize the underlying causes of excessive anticoagulation. MATERIAL AND METHODS: Patients were identified both retrospectively and prospectively. The inclusion criteria were an international normalized ratio (INR) > 6.5 or INR > 3.5 and significant bleeding. Patient charts were reviewed for a predefined set of possible causes: Drug-drug interactions, alcohol abuse, disease, start-up or recent change in dosage and dosage errors. RESULTS: In 86 of 107 admissions one or more causal event were identified. The two most common causes of excessive anticoagulation were disease and drug-drug interactions. The two most common drug-drug interactions were with paracetamol and tramadol. In 44 admissions, a single cause was identified; in 42, two or more causes were identified. CONCLUSION: Although it is difficult to identify single initiatives that may reduce the number of admissions due to excessive anticoagulation, interesting areas include a stronger focus on frequent INR control during the various states of disease and heightened attention to drug-drug interactions. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant.

[Successful implementation of pharmaceutical intervention at an acute medical admission unit]. / Vellykket implementering af farmaceutisk intervention på Akut Modtage Afdeling.

We document the process of implementing a clinical pharmacist service at the acute medical admission unit at Odense University Hospital. During the period December 2009 through April 2010 we reviewed 915 medication lists, which resulted in 628 interventions with generic substitution as the most frequent. The overall acceptance rate was 80%, albeit varying from 99% for generic substitution to 25% for change of administration route.