The ALPACA study: (In)Appropriate LAMA prescribing in asthma: A cohort analysis.

INTRODUCTION: Since long-acting muscarinic antagonists (LAMA) are only indicated as add-on therapy in subjects with moderate-to-severe asthma, there are concerns whether LAMA monotherapy is associated with worse asthma control. AIM: To study the prevalence of LAMA monotherapy and its potential association with severe asthma exacerbations (SAE) in patients with asthma. METHODS: A cohort study (2007-2017) in the IPCI primary care database, in asthma patients aged 6-50, using LAMA during follow-up. Respiratory prescriptions were retrieved from the electronic medical records based on ATC code. Asthma treatment periods were created and categorized as LAMA mono, dual (LAMA + ICS), or triple therapy (LAMA + ICS + LABA). Relative rates (RR) of SAE, adjusting for patient characteristics, were estimated to compare treatments. RESULTS: From a total of 66,508 asthma patients, 1236 (1.9%) LAMA users were identified. Median age was 41 years, 65.9% were females. LAMA users were responsible for 3596 LAMA treatment periods of which 1390 (38.7%) were LAMA monotherapy, 553 (15.4%) dual therapy and 1653 (46.0%) triple therapy. The RR of SAE during LAMA monotherapy compared to dual therapy was 1.5 (95% CI 0.6-3.8). In patients alternating between mono and dual therapy (but never triple therapy), the RR for LAMA monotherapy increased to 5.7 (95% CI 1.4-23.6). CONCLUSIONS: This observational study shows that when LAMA is prescribed, it is often prescribed without concurrent ICS (LAMA monotherapy). LAMA monotherapy was associated with an increased risk of exacerbations when not used concurrently with ICS. This emphasizes the importance that LAMA should never be prescribed without concomitant ICS use in patients with asthma.

Disease Systems Analysis of Bone Mineral Density and Bone Turnover Markers in Response to Alendronate, Placebo, and Washout in Postmenopausal Women.

A previously established mechanism-based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women (n = 1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone-specific alkaline phosphatase activity (BSAP), urinary N-telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model. The final model gave an accurate description of all four biomarkers for the different treatments. Simulations were used to visualize the dynamics of the underlying network and the natural disease progression upon alendronate treatment and discontinuation. These results complement the previous applications of this mechanism-based disease systems model to data from various treatments for osteoporosis.

Real life data on incidence and risk factors of severe asthma exacerbations in children in primary care.

Real-life data on the incidence rates (IR) and risk factors of severe asthma exacerbations in children are sparse. We aimed to assess IR and risk factors of severe asthma exacerbations in children in real life. We conducted a population-based cohort study using a Dutch GP database containing complete medical records of >1 million patients. All records of children with physician-diagnosed asthma aged 5-18 years between 2000 and 2012 were examined for exacerbations, defined as either hospitalization, emergency department visit or need of systemic steroids for asthma. IR was expressed as number of exacerbations per person year (PY). We identified 14,303 asthmatic children with 35,118 PY of follow-up and 732 exacerbations. The overall IR was 2.1/100PY (95% CI 1.9-2.2), 4.1/100PY (3.8-4.4) for children on asthma treatment. Re-exacerbation occurred in 2% (1.3-4.3) of patients within 1 month, in 25% (20.6-28.8) within 1 year. Predictors for (frequent) exacerbations were age, medication use and prior exacerbations (all p < 0.001). The overall IR of severe asthma exacerbations was 4/100PY in children on asthma treatment, highest in spring and fall. 25% of the patients with an exacerbation will experience a next exacerbation within 1 year. More severe asthma is a predictor of subsequent and future exacerbations.

Hypertension in older patients, a retrospective cohort study.

BACKGROUND: It is unknown to what extent General Practitioners (GPs) manage hypertension (HT) differently in older patients, as compared to younger age groups. The purpose of our study was to compare HT management in older patients to younger age groups. METHODS: We performed a retrospective cohort study of patients of 159 GP's practices in the Integrated Primary Care Information (IPCI) database. The study period lasted from September 2010 through December 2012. The study population consisted of all patients aged 60 years or older with at least one blood pressure (BP) measurement during the inclusion period, without pre-existent HT, diabetes mellitus (DM) or atherosclerotic cardiovascular disease at time of study start. Study outcomes were a diagnosis of HT within one month after cohort entry and the use of antihypertensive medication within 4 months after cohort entry in HT diagnosed patients. We compared the incidence of outcomes between the age groups, stratified by systolic blood pressure (SBP). Logistic regression analysis was used to assess the influence of age-adjusted SBP Z-scores, age and gender on the outcomes. RESULTS: We included 19,500 patients from 159 GP's practices of whom 1,181 (6.1 %) were newly diagnosed with HT. Corrected for age-adjusted SBP, older patients were less likely to be diagnosed with HT (odds ratio per year age increase 0.98, p < 0.001). Corrected for age-adjusted SBP, no significant effect of age on the probability of treatment in newly diagnosed HT patients was observed (p = 0.82). CONCLUSIONS: This study showed that GPs are less inclined to diagnose HT with increasing patient age, but do not withhold treatment when they diagnose HT in older patients.

Application of a Systems Pharmacology-Based Placebo Population Model to Analyze Long-Term Data of Postmenopausal Osteoporosis.

Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.

Tiotropium Handihaler and the risk of cardio- or cerebrovascular events and mortality in patients with COPD.

BACKGROUND: Tiotropium has been associated with an increased risk of mortality and/or cardiovascular events. Recent data from RCTs suggests tiotropium Handihaler to be safe, but its safety has not yet been fully investigated under real-life circumstances. METHODS: We conducted 2 nested case-control studies in a COPD cohort from the Dutch IPCI database. In the first case-control study, cases had a cardiovascular or cerebrovascular endpoint (CCVE): stroke and transient ischemic attack (TIA), myocardial infarction, heart failure and/or ventricular arrhythmia. In the second, cases were all patients who died. Cases were matched to controls on age, sex and index date. Conditional logistic regression analysis was used to calculate adjusted odds ratios (OR(adj)) with 95% confidence intervals (CI) for tiotropium vs. long-acting beta-agonists (LABA). RESULTS: Within a cohort of 6788 COPD patients, 784 CCVE's and 1032 deaths were reported. Compared to current LABA use, use of tiotropium Handihaler was neither associated with an increased risk of a CCVE (OR(adj) 0.89, 95% 0.55-1.44) nor with an increased risk of death (OR(adj) 0.79, 95% CI 0.49-1.28). CONCLUSIONS: In real life, use of tiotropium Handihaler in COPD patients is not associated with an increased risk of a CCVE or mortality compared to LABA.

[Increased risk of gastrointestinal bleeding or ulcers when using spironolactone: a case-control study]. / Toegenomen kans op gastro-intestinale bloedingen of ulcera bij gebruik van spironolacton: patiënt-controlestudie.

OBJECTIVE: To study the association between the use of spironolactone and the risk of upper gastrointestinal bleeding or ulcers. DESIGN: Case-control study. METHOD: The study used the computerized 'integrated primary care information' (IPCI) database in the Netherlands. All persons, 18 years or older during the study period from January 1st 1996 through September 30th 2003 with at least one year of valid case history were included. Patients with a medical history of alcoholism or gastrointestinal cancer were excluded. For each case of gastroduodenal ulcer or upper gastrointestinal bleeding, 10 controls were sampled from the same database, matched on age (year of birth), gender and index date. The association between the use ofspironolactone, calculated from the number of general practitioners' prescriptions, and the occurrence of an upper gastrointestinal event (upper gastrointestinal bleeding or ulcers) was analysed by means of a conditional logistic regression analysis. RESULTS: Within the source population of 306,645 patients, 523 cases with gastric or duodenal ulcers or upper gastrointestinal bleeding were identified and matched with 5,230 controls. Current use of spironolactone was associated with a 2.7-fold (adjusted odds ratio (OR); 95% CI: 1.2-6.0) increased risk of gastrointestinal events. This risk was higher in patients on high dosages and was the highest in patients using spironolactone in combination with an ulcerogenic drug (NSAIDs, platelet aggregation inhibitors, corticosteroids or vitamin K antagonist) (adjusted OR: 7.3; 95% CI: 2.9-18.7). CONCLUSION: The risk of upper gastrointestinal bleeding or ulcer was increased 2.7 times when spironolactone was used.

Adherence to gastroprotection and the risk of NSAID-related upper gastrointestinal ulcers and haemorrhage.

BACKGROUND: Upper gastrointestinal (UGI) complications are a well-recognized risk of NSAID treatment, requiring preventive measures in high-risk patients. Adherence to gastroprotective agents (GPAs) in NSAID users has been suggested to be suboptimal. AIM: To investigate the association between adherence to GPAs (proton pump inhibitors or H(2)-receptor antagonists) and the risk of NSAID-related UGI ulcers or haemorrhage in high-risk patients. METHODS: A population-based nested case-control study was conducted within a cohort of new NSAID users with at least one risk factor for a NSAID-related UGI complication, identified in the Dutch IPCI database during 1996-2005. Adherence to GPAs was calculated as the proportion of NSAID treatment days covered (PDC) by a GPA prescription. Multivariate conditional logistic regression analysis was used to calculate odds ratios with 95% confidence intervals (95% CI). RESULTS: Fifteen percent of the non-selective NSAID users received GPAs. The risk of a NSAID-related UGI complication among NSAID users increased 16% for every 10% decrease in adherence. Compared to patients with a PDC of >80%, patients with PDCs of 20-80% and <20% had a 2.5-fold (95% CI: 1.0-6.7) respectively 4.0-fold (95% CI: 1.2-13.0) increased risk. CONCLUSION: There is a strong inverse relationship between adherence to GPAs and the risk of UGI complications in high-risk NSAID users.

Pathogens in early-onset and late-onset intensive care unit-acquired pneumonia.

OBJECTIVES: To compare the type of pathogens isolated from patients with early-onset intensive care unit (ICU)-acquired pneumonia with those isolated from patients with late-onset ICU-acquired pneumonia and to study risk factors for the isolation of pathogens that are potentially resistant to multiple drugs. DESIGN: Prospective cohort study. SETTING: Patients admitted to the ICU of a 677-bed, university-affiliated teaching hospital in Belgium during 1997-2002. METHODS: ICU-acquired pneumonia was defined as a case of pneumonia that occurred 2 days or more after admission to the ICU in combination with a positive results of radiologic analysis, clinical signs and symptoms, and a positive culture result. All cases of pneumonia were categorized as either early onset (within 7 days after admission) and late onset (7 days or more after admission), with or without previous antibiotic treatment, and the corresponding pathogens were analyzed. Risk factors for the isolation of pathogens potentially resistant to multiple drugs (ie, Pseudomonas aeruginosa, Serratia marcescens, Enterobacter species, Morganella morganii, methicillin-resistant Staphylococcus aureus, Citrobacter species, Acinetobacter species, Burkholderia species, extended-spectrum beta -lactamase-producing pathogens, and Stenotrophomonas maltophilia) were analyzed using logistic regression analysis. RESULTS: A total of 4,200 patients stayed at the ICU for 2 or more days, 298 of whom developed ICU-acquired pneumonia, for an overall incidence of 13 cases (95% confidence interval [CI], 11-14 cases) per 1,000 ICU-days. Pathogens potentially resistant to multiple drugs were isolated from 52% of patients with early-onset pneumonia. Risk factors for the isolation of these pathogens were greater age and previous receipt of antibiotic prophylaxis (adjusted odds ratio [aOR], 4.6 [95% CI, 1.6-13.0]) or antibiotic therapy (aOR, 8.2 [95% CI, 2.8-23.8]). The length of ICU admission and hospital stay were weaker risk factors for the isolation of these pathogens. CONCLUSIONS: Pathogens potentially resistant to multiple drugs were isolated in 52% of cases of early-onset ICU-acquired pneumonia. Previous antibiotic use (both prophylactic and therapeutic) is the main risk factor for the isolation of these pathogens.

Low incidence of acute urinary retention in the general male population: the triumph project.

OBJECTIVE: To describe the incidence of acute urinary retention (AUR) in the general male population and in a population of men newly diagnosed with lower urinary tract symptoms suggestive of BPH (LUTS/BPH). METHODS: We performed a retrospective cohort study in the Integrated Primary Care Information (IPCI) database, a GP research database in The Netherlands, during the period 1995-2000. All males, > or =45 years, without a history of AUR or radical cystectomy were included in the study. In addition, we followed a sub-cohort of men, newly diagnosed with LUTS/BPH. AUR was defined as the sudden inability to urinate, requiring catheterization. RESULTS: Amongst 56,958 males with a mean follow-up of 2.8 years, 344 AUR cases occurred (incidence rate 2.2/1000 man-years) of whom more than 40% were precipitated. AUR was the first symptom of LUTS/BPH in 73 (49%) of the 149 AUR cases that occurred in men newly diagnosed with LUTS/BPH. The risk of AUR was 11-fold higher in patients newly diagnosed with LUTS/BPH (RR 11.5; 95%CI: 8.4-15.6) with an overall incidence rate of 18.3/1000 man-years (95%CI: 14.5-22.8). CONCLUSIONS: The incidence rate of AUR is low in the general population but substantial in a population of men newly diagnosed with LUTS/BPH. The incidence rate increases with age and AUR is precipitated in approximately 40% of all cases. Within the LUTS/BPH cohort, AUR is the first presenting symptom of BPH in 50% of all AUR cases.

Treatment strategies, patterns of drug use and treatment discontinuation in men with LUTS suggestive of benign prostatic hyperplasia: the Triumph project.

OBJECTIVES: We aimed to describe treatment strategies for lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), adherence to and persistence with pharmacological treatment and the association between the type of LUTS/BPH complaints and early treatment discontinuation. METHODS: Within a large GP database (IPCI) in the Netherlands we identified all males > or =45 years newly diagnosed with LUTS/BPH during 1995-2000. Details on treatment were assessed from the electronic patient records. Logistic regression analysis was used to estimate the association between the type of main urinary complaints and early treatment discontinuation. RESULTS: Of the 2214 men with incident LUTS/BPH, 1075 received pharmacological treatment and 238 underwent prostate surgery. The average adherence differed slightly between drugs: 67% for alpha-blockers, 73% for 5alpha-reductase inhibitors and 71% for combination therapy. 26% of the treated patients discontinued treatment early. The probability of early discontinuation was higher if patients mainly expressed one type of complaint: voiding (OR(adj) 3.38; 95%CI: 1.89-6.04), post micturition (OR(adj) 2.37; 95%CI: 1.15-4.87) or storage symptoms (OR(adj) 1.85; 95%CI: 1.16-2.95) as compared to patients expressing a combination of symptoms. The risk of early discontinuation was higher if patients had a normal PSA measurement. Older age and a higher chronic disease score protected against early treatment discontinuation. CONCLUSIONS: Almost half of newly diagnosed LUTS/BPH patients are pharmacologically treated, and a quarter discontinues very rapidly. Stopping early is more frequent among younger persons, persons with only one type of main urinary complaint, no other co-morbidity and a normal PSA.

Incidence and prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in primary care--the Triumph project.

OBJECTIVE: Benign prostatic hyperplasia (BPH) is one of the most common conditions associated with ageing in men. BPH often presents as lower urinary tract symptoms (LUTS) due to difficulties in voiding and irritability of the bladder. We conducted a retrospective cohort study within the Integrated Primary Care Information (IPCI) database, a general practitioners database in The Netherlands, to assess the incidence of LUTS suggestive of BPH (LUTS/BPH) in the general population. MATERIALS: Our study population comprised all males, 45 years or older who were registered for at least 6 months prior to start of follow-up. The study period lasted from 1 January 1995 to 31 December 2000. Cases of LUTS/BPH were defined as persons with a diagnosis of BPH, treatment or surgery for BPH, or urinary symptoms suggestive of BPH that could not be explained by other co-morbidity. RESULTS: The study cohort comprised 80,774 males who contributed 141,035 person-years of follow-up. We identified 2181 incident and 5605 prevalent LUTS/BPH cases. The overall incidence rate of LUTS/BPH was 15 per 1000 man-years (95% CI: 14.8-16.1). The incidence increased linearly (r(2) = 0.99) with age from three cases per 1000 man-years at the age of 45-49 years (95% CI: 2.4-3.6) to a maximum of 38 cases per 1000 man-years at the age of 75-79 years (95% CI: 34.1-42.9). After the age of 80 years, the incidence rate remained constant. For a symptom-free man of 46 years, the risk to develop LUTS/BPH over the coming 30 years, if he survives, is 45%. The overall prevalence of LUTS/BPH was 10.3% (95% CI: 10.2-10.5). The prevalence rate was lowest among males 45-49 years of age (2.7%) and increased with age until a maximum at the age of 80 years (24%). CONCLUSIONS: The incidence rate of LUTS/BPH increases linearly with age and reaches its maximum at the age of 79 years.