Development of a tool to detect small airways dysfunction in asthma clinical practice.

BACKGROUND: Small airways dysfunction (SAD) in asthma is difficult to measure and a gold standard is lacking. The aim of this study was to develop a simple tool including items of the Small Airways Dysfunction Tool (SADT) questionnaire, basic patient characteristics and respiratory tests available depending on the clinical setting to predict SAD in asthma. METHODS: This study was based on the data of the multinational ATLANTIS (Assessment of Small Airways Involvement in Asthma) study including the earlier developed SADT questionnaire. Key SADT items together with clinical information were now used to build logistic regression models to predict SAD group (less likely or more likely to have SAD). Diagnostic ability of the models was expressed as area under the receiver operating characteristic curve (AUC) and positive likelihood ratio (LR+). RESULTS: SADT item 8, "I sometimes wheeze when I am sitting or lying quietly", and the patient characteristics age, age at asthma diagnosis and body mass index could reasonably well detect SAD (AUC 0.74, LR+ 2.3). The diagnostic ability increased by adding spirometry (percentage predicted forced expiratory volume in 1 s: AUC 0.87, LR+ 5.0) and oscillometry (resistance difference between 5 and 20 Hz and reactance area: AUC 0.96, LR+ 12.8). CONCLUSIONS: If access to respiratory tests is limited (e.g. primary care in many countries), patients with SAD could reasonably well be identified by asking about wheezing at rest and a few patient characteristics. In (advanced) hospital settings patients with SAD could be identified with considerably higher accuracy using spirometry and oscillometry.

Identifying critical inhalation technique errors in Dry Powder Inhaler use in patients with COPD based on the association with health status and exacerbations: findings from the multi-country cross-sectional observational PIFotal study.

BACKGROUND: Correct inhaler use depends on a complex interplay of factors, including device preparation and generating sufficient inspiratory flow. It is currently unknown which inhalation technique errors can be considered critical in Chronic Obstructive Pulmonary Disease (COPD) patients on Dry Powder Inhaler (DPI) maintenance therapy. OBJECTIVE: To investigate the association between inhalation technique errors and health status or exacerbations in patients with COPD. Additionally, the association between the number of errors and COPD outcomes was determined. METHODS: The PIFotal study is a cross-sectional multi-country observational study in a primary care setting, including 1434 COPD patients aged ≥ 40 years (50.1% female; mean age 69.2 yrs) using a DPI for their maintenance therapy. Inhalation technique was video recorded and scored by two independent researchers using inhaler-specific checklists. Health status was assessed with two questionnaires; the Clinical COPD Questionnaire (CCQ) and the COPD Assessment Test (CAT). The number of moderate and severe exacerbations in the past 12 months was recorded. Critical errors were identified based on their association with health status or exacerbations through multi-level prediction models adjusted for identified confounding. RESULTS: Errors in inhalation technique steps 'Breathe in', 'Hold breath', and 'Breathe out calmly after inhalation' were significantly associated with poorer CCQ and CAT outcomes and thus deemed critical. None of the errors were significantly associated with moderate exacerbations. Patients with errors 'Preparation', 'Hold inhaler in correct position during inhalation', and 'Breathe in' had significantly more severe exacerbations, and therefore these errors were also deemed critical. 81.3% of patients with COPD made at least one critical error. Specific combinations of errors were associated with worse outcomes. The more inhalation technique errors identified, the poorer the health status and the higher the exacerbation rate. CONCLUSION: In this study, we identified multiple critical inhalation technique errors in COPD patients using DPIs each associated with poorer outcomes. Explorative analysis revealed that specific combinations of errors may be of clinical relevance, especially those related to the inhalation manoeuvre. COPD outcomes worsened with increasing error count. These results warrant further prospective longitudinal studies to establish the effect of correcting these errors on COPD control. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04532853 (31/08/2020).

Association between COPD exacerbations and lung function decline during maintenance therapy.

BACKGROUND: Little is known about the impact of exacerbations on COPD progression or whether inhaled corticosteroid (ICS) use and blood eosinophil count (BEC) affect progression. We aimed to assess this in a prospective observational study. METHODS: The study population included patients with mild to moderate COPD, aged ≥35 years, with a smoking history, who were followed up for ≥3 years from first to last spirometry recording using two large UK electronic medical record databases: Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD). Multilevel mixed-effects linear regression models were used to determine the relationship between annual exacerbation rate following initiation of therapy (ICS vs non-ICS) and FEV1 decline. Effect modification by blood eosinophils was studied through interaction terms. RESULTS: Of 12178 patients included (mean age 66 years; 48% female), 8981 (74%) received ICS. In patients with BEC ≥350 cells/µL not on ICS, each exacerbation was associated with subsequent acceleration of FEV1 decline of 19.4 mL/year (95% CI 12.0 to 26.7, p<0.0001). This excess decline was reduced by 15.1 mL/year (6.6 to 23.6) to 4.3 mL/year (1.9 to 6.7, p<0.0001) in those with BEC ≥350 cells/µL treated with ICS. CONCLUSION: Exacerbations are associated with a more rapid loss of lung function among COPD patients with elevated blood eosinophils, defined as ≥350 cells/µL, not treated with ICS. More aggressive prevention of exacerbations using ICS in such patients may prevent excess loss of lung function.

Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma.

BACKGROUND: Although systemic corticosteroid (SCS) treatment, irrespective of duration or dosage, is associated with adverse outcomes for patients with asthma, the longitudinal effects of this treatment on adverse outcomes, healthcare resource utilization (HCRU), and healthcare costs are unknown. METHODS: We identified patients initiating intermittent or long-term SCS who were diagnosed with active asthma from UK general practice with linked secondary care data. Control (non-SCS) patients were matched by sex and index date with those initiating SCS. Minimum baseline period was 1 year prior to index date; minimum follow-up duration was 2 years post-index date. Cumulative incidence of SCS-associated adverse outcomes and associated HCRU and costs were compared between SCS and non-SCS patient groups and among average SCS daily exposure categories. Associations between exposure and annualized HCRU and costs were assessed, adjusted for confounders. RESULTS: Analyses included 9413 matched pairs. Median (interquartile range) follow up was as follows: SCS group: 7.1 (4.1-11.8) years; control group: 6.4 (3.8-10.0) years. Greater SCS dosages were correlated with greater cumulative incidence. For example, patients with type 2 diabetes receiving an average daily dosage of ≥7.5 mg had a 15-year cumulative incidence (37.5%) that was 1.5-5 times greater than those receiving lower dosages. HCRU and costs increased annually for SCS patients but not for non-SCS patients. Increases in all-cause adverse outcome (excluding asthma)-associated HCRU and costs were dose-dependent. CONCLUSIONS: Over the long term, adverse outcomes associated with SCS initiation were relatively frequent and costly, with a positive dosage-response relationship with SCS exposure.

Development and validation of prescribing quality indicators for patients with type 2 diabetes.

AIM: Quality indicators are used to measure whether healthcare professionals act according to guidelines, but few indicators focus on the quality of pharmacotherapy for diabetes. The aim of this study was to develop and validate a set of prescribing quality indicators (PQIs) for type 2 diabetes in primary care, and to apply this set in practice. To take into account the stepwise treatment of chronic disease, clinical action indicators were specifically considered. METHODS: Potential PQIs were derived from clinical practice guidelines and evaluated using the RAND/UCLA Appropriateness Method, a modified Delphi panel. Thereafter, the feasibility of calculating the PQIs was tested in two large Dutch primary care databases including >80 000 diabetes patients in 2012. RESULTS: 32 PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on vaccination, medication safety and adherence were assessed by ten experts. After the Delphi panel, the final list of twenty PQIs was tested for feasibility. All PQIs definitions were feasible for measuring the quality of medication treatment using these databases. Indicator scores ranged from 18.8% to 90.8% for PQIs focusing on current medication use, clinical action and medication choice, and from 2.1% to 37.2% for PQIs focusing on medication safety. DISCUSSION AND CONCLUSIONS: Twenty PQIs focusing on treatment with glucose, lipid, blood pressure and albuminuria lowering drugs, and on medication safety in type 2 diabetes were developed, considered valid and operationally feasible. Results showed room for improvement, especially in initiation and intensification of treatment as measured with clinical action indicators.

Development and initial validation of prescribing quality indicators for patients with chronic kidney disease.

BACKGROUND: Quality assessment is a key element for improving the quality of care. Currently, a comprehensive indicator set for measuring the quality of medication treatment in patients with chronic kidney disease (CKD) is lacking. Our aim was to develop and validate a set of prescribing quality indicators (PQIs) for CKD care, and to test the feasibility of applying this set in practice. METHODS: Potential indicators were based on clinical practice guidelines and evaluated using the RAND/UCLA Appropriateness Method. This is a structured process in which an expert panel assesses the validity of the indicators. Feasibility was tested in a Dutch primary care database including >4500 diabetes patients with CKD. RESULTS: An initial list of 22 PQIs was assessed by 12 experts. After changing 10 PQIs, adding 2 and rejecting 8, a final list of 16 indicators was accepted by the expert panel as valid. These PQIs focused on the treatment of hypertension, albuminuria, mineral and bone disorder, statin prescribing and possible unsafe medication. The indicators were successfully applied to measure treatment quality in the primary care database, but for some indicators the number of eligible patients was too small for reliable calculation. Results showed that there was room for improvement in the treatment quality of this population. CONCLUSIONS: We developed a set of 16 PQIs for measuring the quality of treatment in CKD patients, which had sufficient content and face validity as well as operational feasibility. These PQIs can be used to point out priority areas for improvement.

Identification of major cardiovascular events in patients with diabetes using primary care data.

BACKGROUND: Routine primary care data are increasingly being used for evaluation and research purposes but there are concerns about the completeness and accuracy of diagnoses and events captured in such databases. We evaluated how well patients with major cardiovascular disease (CVD) can be identified using primary care morbidity data and drug prescriptions. METHODS: The study was conducted using data from 17,230 diabetes patients of the GIANTT database and Dutch Hospital Data register. To estimate the accuracy of the different measures, we analyzed the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) relative to hospitalizations and/or records with a diagnosis indicating major CVD, including ischaemic heart diseases and cerebrovascular events. RESULTS: Using primary care morbidity data, 43% of major CVD hospitalizations could be identified. Adding drug prescriptions to the search increased the sensitivity up to 94%. A proxy of at least one prescription of either a platelet aggregation inhibitor, vitamin k antagonist or nitrate could identify 85% of patients with a history of major CVD recorded in primary care, with an NPV of 97%. Using the same proxy, 57% of incident major CVD recorded in primary or hospital care could be identified, with an NPV of 99%. CONCLUSIONS: A substantial proportion of major CVD hospitalizations was not recorded in primary care morbidity data. Drug prescriptions can be used in addition to diagnosis codes to identify more patients with major CVD, and also to identify patients without a history of major CVD.

Association between performance measures and glycemic control among patients with diabetes in a community-wide primary care cohort.

BACKGROUND: Performance measures are used for assessing quality of care. Higher performance shown by these measures is expected to reflect better care, but little is known whether they predict better patient outcomes. OBJECTIVE: To assess the predictive value of performance measures of glucose management on glycemic control, and evaluate the impact of patient characteristics on this association. RESEARCH DESIGN: Cohort study (2007-2009). SUBJECTS: A total of 15,454 type 2 diabetes patients (mean age, 66.5 y; 48% male) from the GIANTT cohort. MEASURES: We included performance measures assessing frequency of HbA1c monitoring, glucose-lowering treatment status, and treatment intensification. Associations between performance and glycemic control were tested using multivariate linear regression adjusted for confounding, reporting estimated differences in HbA1c with 95% confidence intervals (CI). Impact of patient characteristics was examined through interactions. RESULTS: Annual HbA1c monitoring was associated with better glycemic control when compared with no such monitoring (HbA1c -0.29%; 95% CI -0.37, -0.22). This association lost significance in patients with lower baseline HbA1c, older age, and without macrovascular comorbidity. Treatment status was associated with better glycemic control only in patients with elevated baseline HbA1c. Treatment intensification after elevated HbA1c levels was associated with better glycemic control compared with no intensification (HbA1c -0.21; 95% CI -0.26, -0.16). CONCLUSIONS: Performance measures of annual HbA1c monitoring and of treatment intensification did predict better patient outcomes, whereas the measure of treatment status did not. Predictive value of annual monitoring and of treatment status varied across patient characteristics, and it should be used with caution when patient characteristics cannot be taken into account.

Is albuminuria screening and treatment optimal in patients with type 2 diabetes in primary care? Observational data of the GIANTT cohort.

BACKGROUND: Failure of diagnosing and treatment of albuminuria play a role in morbidity and mortality in type 2 diabetes (T2DM). We evaluated guideline adherence and factors associated with albuminuria screening and treatment in T2DM patients in primary care. METHODS: Guidelines recommend annual measurement of albuminuria and, if increased, treatment with renin-angiotensin-aldosterone system (RAAS) blockers. We performed a cohort study of T2DM patients managed by 182 Dutch general practitioners (GPs; Groningen Initiative to Analyse Type 2 diabetes Treatment database), and evaluated guideline adherence in the years 2007-2009. We assessed whether demographic, clinical, organizational or provider factors determined guideline adherence with multilevel analyses. RESULTS: Data were available for 14 120 T2DM patients [47.6% male, mean age 67.3 ± 11.7 years, median diabetes duration 6 (IQR: 3-10) years]. The albumin-creatinine ratio (ACR) was measured in 45.2% in 2007, 57.4% in 2008 and 56.8% in 2009. Only 23.7% of all patients were measured every year and 21.4% were never measured. The ACR was more often measured in patients <75 years, with a previous ACR measurement, using anti-diabetic medication, and receiving additional care by a diabetes support facility. RAAS treatment was prescribed to 78.4% of patients with prevalent micro/macroalbuminuria, 66.5% with incident micro/macroalbuminuria, 59.3% with normoalbuminuria and 52.1% of those without ACR measurements. In those not treated with RAAS blockers, it was initiated in 14.3, 12.3, 3.0 and 2.3%, respectively. The presence of micro/macroalbuminuria, higher blood pressure, incidence of cardiovascular events and treatment with antihypertensive medication were the determinants of RAAS-treatment initiation. CONCLUSIONS: Guideline implementation regarding the management of albuminuria in T2DM patients in primary care should be further improved.

The Relationship between Nursing Practice Environment and Pressure Ulcer Care Quality in Portugal's Long-Term Care Units.

BACKGROUND: The morbidity associated with ageing has contributed to an increase in the prevalence of Pressure Ulcers (PUs) in all care settings. The impact of these on people's quality of life and the extent of the associated economic and social burden constitutes today, by their importance, a serious public health problem. This study aims to describe the nursing work environment in Portuguese long-term care (LTC) units and to assess how this environment relates to the quality of PU care. METHODS: A longitudinal study among inpatients with PUs was conducted in LTC units. The Nursing Work Index-Revised Scale (NWI-R) was sent to all nurses in these units. Cox proportional hazard models were used to relate the satisfaction degree with the service (measured by the NWI-R-PT items) to the healing time of the PUs, adjusting for confounders. RESULTS: A total of 165 of 451 invited nurses completed the NWI-R-PT. Most were women (74.6%) and had 1 to 5 years of professional experience. Less than half (38.4%) had education in wound care. Of the 88 patients identified with PUs, only 63 had their PU documented, highlighting the difficulties in updating electronic records. The results showed that the level of concordance with Q28 "Floating so that staffing is equalised among units" is strongly associated with a shorter PU healing time. CONCLUSION: A good distribution of nursing staff over the units will likely improve the quality of wound care. We found no evidence for possible associations with the questions on participation in policy decisions, salary level, or staffing educational development and their relationship with PUs healing times.

Content Validity and Reliability of the Pressure Ulcer Knowledge Test and the Knowledge Level of Portuguese Nurses at Long-Term Care Units: A Cross-Sectional Survey.

(1) Background: Improvement in pressure ulcer care depends both on the dissemination of knowledge and its implementation. This study aims to translate the Pressure Ulcer Knowledge Test into Portuguese from Portugal and evaluate the internal consistency of the questionnaire. The second aim is to assess nurses' pressure ulcer knowledge level. (2) Methods: The Pressure Ulcer Knowledge Test was translated into Portuguese, and the translated test's internal consistency and content validity were assessed. Further, the authors conducted a cross-sectional survey using the test among 221 nurses working in long-term care units. (3) Results: The Cronbach's alpha internal coefficient of reliability recorded for the 47 items was 0.738, which is higher than the minimum acceptable level of 0.7. The Cronbach's alpha for the subscales was 0.709 for prevention/risk and less than 0.5 for staging and wound description. Only two of the 221 nurses achieved a score of 90% correct answers or more. The nurses scored lower in questions related to prevention/risk (Me = 67.4%, IQR = 60.6-75.8% vs. staging: ME = 85.7%, IQR = 71.4-85.7%, description: ME = 85.7%, IQR = 71.4-85.7%, p < 0.001). (4) Conclusion: The internal consistency of the instrument was acceptable. The instrument can accurately measure Portuguese nurses' knowledge of pressure ulcers, and its information can help improve education and implementation of best practices.

Association Between a Type 2 Inflammatory Disease Burden Score and Outcomes Among Patients with Asthma.

BACKGROUND: Although prevalence of co-existing type 2 inflammatory diseases (cT2) in asthma patients has been reported, limited data exist regarding their impact on asthma outcomes. OBJECTIVE: To assess the impact of cT2 burden on asthma outcomes and to evaluate patterns of clustering of cT2 in a real-world setting. METHODS: From medical records of 4.5 million enrollees in 650 primary care practices in the UK (January 2010-December 2017), patients with ≥1 diagnosis code for asthma at any time pre-index date (date of most recent asthma-related medical encounter) and ≥2 asthma-related prescriptions during the year before index date were categorized into the Global Initiative of Asthma (GINA) guideline severity steps. A cT2 burden score (range 0-9) was assigned based on the total number of co-existing conditions (allergic conjunctivitis, allergic rhinitis, anaphylaxis, eczema/atopic dermatitis, chronic rhinosinusitis, eosinophilic esophagitis, food allergy, nasal polyps, or urticaria) for which patients received a medical diagnosis. Multivariate regression models evaluated associations between cT2 burden score and asthma exacerbations and asthma control. Factor analysis was performed to assess which cT2 comorbidities were correlated and exhibited patterns of clustering. RESULTS: Overall, 245,893 patients with asthma were included (mean [SD] age 44.8 [22.1] years; 43.8% male). Between 55% (GINA step 1) and 60% (GINA step 5) of asthma patients had a medical diagnosis for ≥1 other type2dx. Patients with increased cT2 burden were significantly more likely to experience asthma exacerbations and less likely to achieve asthma control. CONCLUSION: Asthma patients with a higher cumulative cT2 burden score were more likely to experience worse asthma outcomes than those without any cT2 (burden score of 0).

Identifying targets to improve treatment in type 2 diabetes; the Groningen Initiative to aNalyse Type 2 diabetes Treatment (GIANTT) observational study.

PURPOSE: Assessment of quality of cardiometabolic risk management in diabetes in primary care. METHODS: In a descriptive cohort study including 95 Dutch general practices, we assessed medication treatment in relation to the level of control for HbA1c, systolic blood pressure (SBP) and LDL-cholesterol (LDL-c) in 2007. We also applied a prospective measure of treatment quality by assessing treatment modifications in not well-controlled patients. In a subpopulation of 23 practices, we studied trends in these quality indicators from 2004 (2059 patients) to 2007 (2929 patients). RESULTS: In 2007, averages for HbA1c, SBP and LDL-c were 6.9%, 142 mmHg and 2.3 mmol/l, respectively. Of the patients with an HbA1c > 8.5%, 16% were treated with one oral drug class and 50% used insulin. In 27% of these patients, therapy modification occurred subsequently. During the 4-year period, a slight decrease in average HbA1c was observed, but no changes in treatment level. In 2007, 56% of the patients had an SBP ≥ 140 mmHg, 19% of whom were not using antihypertensives. In the 13% with an SBP > 160 mmHg, 23% received a therapy modification. During the 4-year period, the average SBP decreased with 6 mmHg but the treatment level showed no substantial increase. In 2007, 39% had an LDL-c level ≥ 2.5 mmol/l, 49% of whom were not using statins. Of the patients with an LDL-c > 3.5 mmol/l, only 9% received a therapy modification. CONCLUSIONS: The decreasing population averages of HbA1c, SBP and LDL-c values suggest improvement in quality of care. However, the relatively few therapy modifications observed in insufficiently controlled patients show room for improvement.

A systematic literature review: prescribing indicators related to type 2 diabetes mellitus and cardiovascular risk management.

PURPOSE: Valid prescribing indicators (PI) are needed for reliable assessment of prescribing quality. The purpose of this study is to describe the validity of existing PI for type 2 diabetes mellitus and cardiovascular risk management. METHODS: We conducted a systematic literature search for studies describing the development and assessment of relevant PIs between January 1990 and January 2009. We grouped identified PI as drug- or disease-oriented, and according to the aspects of prescribing addressed and the additional clinical information included. We reviewed the clinimetric characteristics of the different types of PI. RESULTS: We identified 59 documents describing the clinimetrics of 16 types of PI covering relevant prescribing aspects, including first-choice treatment, safety issues, dosing, costs, sufficient and timely treatment. We identified three types of drug-oriented, and five types of disease-oriented PI with proven face and content validity as well as operational feasibility in different settings. PI focusing on treatment modifications were the only indicators that showed concurrent validity. Several solutions were proposed for dealing with case-mix and sample size problems, but their actual effect on PI scores was insufficiently assessed. Predictive validity of individual PI is not yet known. CONCLUSION: We identified a range of existing PI that are valid for internal quality assessment as they are evidence-based, accepted by professionals, and reliable. For external use, problems of patient case-mix and sample size per PI should be better addressed. Further research is needed for selecting indicators that predict clinical outcomes.

Evaluating the real-life effect of MP-AzeFlu on asthma outcomes in patients with allergic rhinitis and asthma in UK primary care.

BACKGROUND: MP-AzeFlu (Dymista®; spray of azelastine/fluticasone propionate) is the most effective allergic rhinitis (AR) treatment available. Its effect on asthma outcomes in patients with AR and asthma is unknown. METHODS: This pre-post historical cohort study, using the Optimum Patient Care Research Database, included patients aged ≥12 years, from UK general practice with active asthma (defined as a recorded diagnosis, with ≥1 prescription for reliever or controller inhaler) in the year before or at the initiation date. The primary study outcome was change in number of acute respiratory events (i.e. exacerbation or antibiotic course for a respiratory event) between baseline and outcome years. The effect size of MP-AzeFlu was quantified as the difference in % of patients that improved and worsened. RESULTS: Of the 1,188 patients with AR and asthma included, many had a record of irreversible obstruction (67%), and uncontrolled asthma (70.4%), despite high mean daily doses of reliever/controller therapy and acute oral corticosteroid use, in the year pre-MP-AzeFlu initiation. MP-AzeFlu initiation was associated with fewer acute respiratory events (effect size (e) = 5.8%, p = 0.0129) and a reduction in daily use of short-acting ß2-agonists, with fewer patients requiring >2 SABA puffs/week (e = 7.7% p < 0.0001). More patients had well-controlled asthma 1-year post-MP-AzeFlu initiation (e = 4.1%; p = 0.0037), despite a reduction in inhaled corticosteroids (e = 4.8%; p = 0.0078). CONCLUSIONS: This study provides the first direct evidence of the beneficial effect of MP-AzeFlu on asthma outcomes in co-morbid patients in primary care in the United Kingdom. TRIAL REGISTRATION: EUPAS30940. Registered August 13, 2019.

Extrafine Beclometasone Dipropionate/Formoterol Fumarate vs Double Bronchodilation Therapy in Patients with COPD: A Historical Real-World Non-Inferiority Study.

Purpose: This study aimed to evaluate the non-inferiority of initiating extrafine beclometasone dipropionate/formoterol fumarate (BDP/FF) versus double bronchodilation (long-acting beta-agonists [LABA]/long-acting muscarinic antagonists [LAMA]) among patients with a history of chronic obstructive pulmonary disease (COPD) exacerbations. Patients and Methods: A historical cohort study was conducted using data from the UK's Optimum Patient Care Research Database. Patients with COPD ≥40 years at diagnosis were included if they initiated extrafine BDP/FF or any LABA/LAMA double therapy as a step-up from no maintenance therapy or monotherapy with inhaled corticosteroids (ICS), LAMA, or LABA and a history of ≥2 moderate/severe exacerbations in the previous two years. The primary outcome was exacerbation rate from therapy initiation until a relevant therapy change or end of follow-up. Secondary outcomes included rate of acute respiratory events, acute oral corticosteroids (OCS) courses, and antibiotic prescriptions with lower respiratory indication, modified Medical Research Council score (mMRC) ≥2, and time to first pneumonia diagnosis. The non-inferiority boundary was set at a relative difference of 15% on the ratio scale. Five potential treatment effect modifiers were investigated. Results: A total of 1735 patients initiated extrafine BDP/FF and 2450 patients initiated LABA/LAMA. The mean age was 70 years, 51% were male, 41% current smokers, and 85% had FEV1 <80% predicted. Extrafine BDP/FF showed non-inferiority to LABA/LAMA for rate of exacerbations (incidence rate ratio [IRR] = 1.01 [95% CI 0.94-1.09]), acute respiratory events (IRR = 0.98 [0.92-1.04]), acute OCS courses (IRR = 1.01 [0.91-1.11]), and antibiotic prescriptions (IRR = 0.99 [0.90-1.09]), but not for mMRC (OR = 0.93 [0.69-1.27]) or risk of pneumonia (HR = 0.50 [0.14-1.73]). None of the a priori defined effect modifier candidates affected the comparative effectiveness. Conclusion: This study found that stepping up to extrafine BDP/FF from no maintenance or monotherapy was not inferior to stepping up to double bronchodilation therapy in patients with a history of exacerbations.

The Long-Term Burden of COPD Exacerbations During Maintenance Therapy and Lung Function Decline.

Introduction: Early identification of preventable risk factors of COPD progression is important. Whether exacerbations have a negative impact on disease progression is largely unknown. We investigated whether the long-term occurrence of exacerbations is associated with lung function decline at early stages of COPD. Methods: Patients diagnosed with mild/moderate COPD (obstruction and FEV1% predicted 50-90%), aged ≥35 years, and a smoking history, who had ≥6 years of UK electronic medical records after initiation of maintenance therapy were studied. Multilevel mixed-effect linear regression was performed to determine the association between the count of any year in which the patient had ≥1 exacerbation over a 6-year period and FEV1 decline, adjusted for sex, age, anthropometrics and smoking habits. Exacerbations were defined as any prescription for an acute oral corticosteroid course and/or lower respiratory-related antibiotics and/or any COPD-related emergency or inpatient hospitalization. Results: Of 11,337 patients included (mean age 65 years; 49% female) 31.6%, 23.3%, 16.6%, 11.6%, 8.1%, 5.3% and 3.4% had 0, 1, 2, 3, 4, 5 and 6 years with ≥1 exacerbation. The mean annual FEV1 decline accelerated by 1.50 mL/year (95% Confidence Interval 1.02; 1.98) with every additional year with ≥1 exacerbation from 31.0 mL/year in subjects without any exacerbation to 40.0 mL/year in patients experiencing ≥1 exacerbation every year. Patients with more years with ≥1 exacerbation had a lower mean FEV1 at first diagnosis: 14.7 mL (11.7; 17.8) lower with every additional year with exacerbations. When counting years with ≥2 exacerbations, greater effects were observed (2.19 [1.50; 2.88]  mL/year excess decline per year with ≥2 exacerbations; 16.5 mL [12.1; 20.8] lower FEV1 at diagnosis). Conclusion: Patients who experienced a greater exacerbation burden after initiation of maintenance therapy had worse lung function at diagnosis and a more rapid lung function decline thereafter, which emphasizes the need for better treatment strategies.

Historical database cohort study addressing the clinical patterns prior to idiopathic pulmonary fibrosis (IPF) diagnosis in UK primary care.

OBJECTIVE: To explore the clinical pathways, including signs and symptoms, and symptom progression patterns preceding idiopathic pulmonary fibrosis (IPF) diagnosis. DESIGN AND SETTING: A historical cohort study was conducted using primary care patient records from the Optimum Patient Care Research Database. PARTICIPANTS: Patients included were at least 30 years, had IPF diagnosis, identified via clinical-coding and free-text records and had a consultation with a chest specialist prior to IPF diagnosis. OUTCOME MEASURES: The signs and symptoms in the year prior to IPF diagnosis from clinical codes and free-text in primary care electronic records included: cough, dyspnoea, dry cough, weight loss, fatigue/malaise, loss of appetite, crackles and clubbed fingers. The time course of presentations of clinical features and investigations in the years prior to IPF diagnosis were mapped. RESULTS: Within 462 patients identified, the majority (77.9%) had a respiratory consultation within 365 days prior to the chest specialist visit preceding the IPF diagnosis recorded in their primary care records. The most common symptoms recorded in the 1 year prior to IPF diagnosis were dyspnoea (48.7%) and cough (40.9%); other signs and symptoms were rarely recorded (<5%). The majority of patients with cough (58.0%) and dyspnoea (55.0%) in the 1 year before IPF diagnosis had multiple recordings of the respective symptoms. Both cough and dyspnoea were recorded in 23.4% of patients in the year prior to diagnosis. Consultation rates for cough, dyspnoea and both, but not other signs or symptoms, began to increase 4 to 5 years prior diagnosis, with the sharpest increase in the last year. Cough and dyspnoea were often preceded by a reduction in measured weight over 5 years leading to IPF diagnosis. CONCLUSION: Prolonged cough and/or progressive dyspnoea, especially if accompanied with weight loss, should signal for a referral to specialist assessment at the earliest opportunity.

Comparative effectiveness of triple therapy versus dual bronchodilation in COPD.

This real-world study compared the effectiveness of triple therapy (TT; long-acting muscarinic antagonists (LAMAs)/long-acting inhaled ß-agonists (LABAs)/inhaled corticosteroids (ICSs)) versus dual bronchodilation (DB; LAMAs/LABAs) among patients with frequently exacerbating COPD. A matched historical cohort study was conducted using United Kingdom primary care data. Patients with COPD aged ≥40 years with a history of smoking were included if they initiated TT or DB from no maintenance/LAMA therapy and had two or more exacerbations in the preceding year. The primary outcome was time to first COPD exacerbation. Secondary outcomes included time to treatment failure, first acute respiratory event, and first acute oral corticosteroid (OCS) course. Potential treatment effect modifiers were investigated. In 1647 matched patients, initiation of TT reduced exacerbation risk (adjusted hazard ratio (HR) 0.87, 95% CI 0.76-0.99), risk of acute respiratory event (HR 0.74, 95% CI 0.66-0.84) and treatment failure (HR 0.83, 95% CI 0.73-0.95) compared with DB. Risk reduction for acute respiratory events was greater for patients with higher rates of previous exacerbations. At baseline blood eosinophil counts (BECs) ≥ 0.35×109 cells·L-1, TT was associated with lower risk of OCS prescriptions than DB. This study provides real-life evidence of TT being more effective in reducing exacerbation risk than DB, which became more accentuated with increasing BEC and previous exacerbation rate.

Inhaled corticosteroids in COPD and onset of type 2 diabetes and osteoporosis: matched cohort study.

Some studies suggest an association between onset and/or poor control of type 2 diabetes mellitus and inhaled corticosteroid (ICS) therapy for chronic obstructive pulmonary disease (COPD), and also between increased fracture risk and ICS therapy; however, study results are contradictory and these associations remain tentative and incompletely characterized. This matched cohort study used two large UK databases (1983-2016) to study patients (≥ 40 years old) initiating ICS or long-acting bronchodilator (LABD) for COPD from 1990-2015 in three study cohorts designed to assess the relation between ICS treatment and (1) diabetes onset (N = 17,970), (2) diabetes progression (N = 804), and (3) osteoporosis onset (N = 19,898). Patients had ≥ 1-year baseline and ≥ 2-year outcome data. Matching was via combined direct matching and propensity scores. Conditional proportional hazards regression, adjusting for residual confounding after matching, was used to compare ICS vs. LABD and to model ICS exposures. Median follow-up was 3.7-5.6 years/treatment group. For patients prescribed ICS, compared with LABD, the risk of diabetes onset was significantly increased (adjusted hazard ratio 1.27; 95% CI, 1.07-1.50), with overall no increase in risk of diabetes progression (adjusted hazard ratio 1.04; 0.87-1.25) or osteoporosis onset (adjusted hazard ratio 1.13; 0.93-1.39). However, the risks of diabetes onset, diabetes progression, and osteoporosis onset were all significantly increased, with evident dose-response relationships for all three outcomes, at mean ICS exposures of 500 µg/day or greater (vs. < 250 µg/day, fluticasone propionate-equivalent). Long-term ICS therapy for COPD at mean daily exposure of ≥ 500 µg is associated with an increased risk of diabetes, diabetes progression, and osteoporosis.