Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease : A Population-Based Cohort Study.

BACKGROUND: North American and European health agencies recently warned of severe breathing problems associated with gabapentinoids, including in patients with chronic obstructive pulmonary disease (COPD), although supporting evidence is limited. OBJECTIVE: To assess whether gabapentinoid use is associated with severe exacerbation in patients with COPD. DESIGN: Time-conditional propensity score-matched, new-user cohort study. SETTING: Health insurance databases from the Régie de l'assurance maladie du Québec in Canada. PATIENTS: Within a base cohort of patients with COPD between 1994 and 2015, patients initiating gabapentinoid therapy with an indication (epilepsy, neuropathic pain, or other chronic pain) were matched 1:1 with nonusers on COPD duration, indication for gabapentinoids, age, sex, calendar year, and time-conditional propensity score. MEASUREMENTS: The primary outcome was severe COPD exacerbation requiring hospitalization. Hazard ratios (HRs) associated with gabapentinoid use were estimated in subcohorts according to gabapentinoid indication and in the overall cohort. RESULTS: The cohort included 356 gabapentinoid users with epilepsy, 9411 with neuropathic pain, and 3737 with other chronic pain, matched 1:1 to nonusers. Compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation across the indications of epilepsy (HR, 1.58 [95% CI, 1.08 to 2.30]), neuropathic pain (HR, 1.35 [CI, 1.24 to 1.48]), and other chronic pain (HR, 1.49 [CI, 1.27 to 1.73]) and overall (HR, 1.39 [CI, 1.29 to 1.50]). LIMITATION: Residual confounding, including from lack of smoking information. CONCLUSION: In patients with COPD, gabapentinoid use was associated with increased risk for severe exacerbation. This study supports the warnings from regulatory agencies and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research and Canadian Lung Association.

Effectiveness of Aspirin on Major COPD Outcomes: A Prevalent New-User Design Observational Study.

Observational studies that have reported an association between aspirin use in chronic obstructive pulmonary disease (COPD) with reductions in mortality and COPD exacerbations were shown to be affected by time-related biases. We assessed this association using a prevalent new-user study design that avoids these biases. We used the United Kingdom's Clinical Practice Research Datalink (CPRD) to form a cohort of patients with COPD. Aspirin initiators were matched on time and propensity score with nonusers during 2002-2018. The outcomes were all-cause mortality and COPD exacerbation within a one-year follow-up. Hazard ratios (HR) and 95% confidence interval (CI) of each outcome associated with aspirin use compared to nonuse were estimated using an as-treated approach. The study cohort included 10,287 initiators of aspirin and 10,287 matched nonusers. The cumulative incidence of all-cause mortality at one year was 11.5% for aspirin users and 9.2% for nonusers. The HR of all-cause mortality associated with aspirin initiation was 1.22 (95% CI: 1.08-1.37), while for severe exacerbation it was 1.21 (95% CI 1.08-1.37), compared with nonuse. The HR of a first moderate or severe exacerbation with aspirin use was 0.90 (95% CI 0.85-0.95). These estimates did not vary by platelet count. This large population-based study, designed to emulate a trial, found aspirin use in patients with COPD associated with a higher risk of all-cause mortality and severe exacerbation, but a lower risk of moderate or severe exacerbation. Further research is warranted to assess this reduction in moderate or severe exacerbations, particularly in patients with cardiovascular risk factors.

Real-World Effectiveness of Single-Inhaler Triple Therapy for COPD: Impact of Diabetes Comorbidity.

Type 2 diabetes is a frequent comorbidity in chronic obstructive pulmonary disease (COPD) patients, with the GOLD treatment recommendations asserting that the presence of diabetes be disregarded in the choice of treatment.In a cohort of COPD patients with frequent exacerbations, initiators of single-inhaler triple therapy or dual bronchodilators were compared on the incidence of COPD exacerbation and pneumonia over one year, adjusted by propensity score weighting and stratified by type 2 diabetes.The COPD cohort included 1,114 initiators of triple inhalers and 4,233 of dual bronchodilators (28% with type 2 diabetes). The adjusted hazard ratio (HR) of exacerbation with triple therapy was 1.04 (95% CI: 0.86-1.25) among COPD patients with type 2 diabetes and 0.74 (0.65-0.85) in those without. The incidence of severe pneumonia was elevated with triple therapy among patients with type 2 diabetes (HR 1.77; 1.14-2.75).Triple therapy in COPD is effective among those without, but not those with, type 2 diabetes. Future therapeutic trials in COPD should consider diabetes comorbidity.

Triple therapy for frequent COPD exacerbators is effective in patients without type 2 diabetes but not in those with type 2 diabetes. The impact of comorbidities should be considered in future COPD therapeutic trials.

Real-world comparative effectiveness of three single-inhaler dual bronchodilators for the treatment of COPD.

BACKGROUND: Single-inhaler dual bronchodilators are now recommended as initial treatment of COPD for patients with multiple exacerbations or with moderate or severe dyspnoea. It is unclear whether there are differences in effectiveness among commonly used dual bronchodilators. METHODS: We identified a cohort of COPD patients, aged ≥40 years, treated during 2017-2020, from the UK Clinical Practice Research Datalink, a real-world practice setting. Inhaled corticosteroid-naïve patients initiating vilanterol-umeclidinium (VIL-UME) were compared with those initiating olodaterol-tiotropium (OLO-TIO) or indacaterol-glycopyrronium (IND-GLY) dual bronchodilators primarily on the incidence of moderate and severe COPD exacerbation over 1 year, and corresponding hazard ratios (HRs), after adjustment by propensity score weighting. RESULTS: The cohort included 15 224 initiators of VIL-UME, 5536 initiators of OLO-TIO and 5059 initiators of IND-GLY. The HR of a moderate or severe exacerbation with VIL-UME was 0.91 (95% CI 0.85-0.97) compared with OLO-TIO and 0.96 (95% CI 0.89-1.03) compared with IND-GLY. The risk of severe exacerbation was not different for VIL-UME when compared with OLO-TIO (HR 1.04, 95% CI 0.86-1.26) and IND-GLY (HR 1.05, 95% CI 0.86-1.28). All-cause mortality was lower with VIL-UME compared with IND-GLY (HR 0.82, 95% CI 0.68-0.98), but not compared with OLO-TIO (HR 0.87, 95% CI 0.72-1.04). CONCLUSION: In a real-world setting of COPD treatment, the three dual bronchodilator combinations were similarly effective on the risk of a severe exacerbation of COPD. However, the VIL-UME and IND-GLY combinations may confer slightly superior effectiveness than OLO-TIO on the risk of moderate or severe exacerbation. The potential lower mortality with VIL-UME warrants further investigation.

Characteristics of new users of recent antidiabetic drugs in Canada and the United Kingdom.

BACKGROUND: Characteristics of patients using newer 2nd and 3rd line antidiabetic drugs in a real-world setting are poorly understood. We described the characteristics of new users of sodium-glucose co-transporter-2 inhibitors (SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i), and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in Canada and the United Kingdom (UK) between 2016 and 2018. METHODS: We conducted a multi-database cohort study using administrative health databases from 7 Canadian provinces and the UK Clinical Practice Research Datalink. We assembled a base cohort of antidiabetic drug users between 2006 and 2018, from which we constructed 3 cohorts of new users of SGLT-2i, DPP-4i, and GLP-1 RA between 2016 and 2018. RESULTS: Our cohorts included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. New users of GLP-1 RA were more likely to be younger (mean ± SD: 56.7 ± 12.2 years) than new users of DPP-4i (67.8 ± 12.3 years) or SGLT-2i (64.4 ± 11.1 years). In Canada, new users of DPP-4i were more likely to have a history of coronary artery disease (22%) than new users of SGLT-2i (20%) or GLP-1 RA (15%). CONCLUSION: Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2nd or 3rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Contrary to existing guidelines, new users of DPP-4i had a higher prevalence of cardiovascular disease at baseline than new users of SGLT2i or GLP-1RA.

Discontinuation of Inhaled Corticosteroids from Triple Therapy in COPD: Effects on Major Outcomes in Real World Clinical Practice.

Recent reports provide evidence-based guidelines for the withdrawal of inhaled corticosteroids (ICS) in COPD, but data on patients treated with ICS-based triple therapy are sparse and contradictory. We assessed the effect of ICS discontinuation on the incidence of severe exacerbation and pneumonia in a real-world population of patients with COPD who initiated triple therapy. We identified a cohort of patients with COPD treated with LAMA-LABA-ICS triple therapy during 2002-2018, age 50 or older, from the UK's CPRD database. Subjects who discontinued ICS were matched 1:1 on time-conditional propensity scores to those continuing ICS and followed for one year. Hazard ratios (HR) of severe exacerbation and pneumonia were estimated using Cox regression. The cohort included 42,667 patients who discontinued ICS matched to 42,667 who continued ICS treatment. The hazard ratio of a severe exacerbation with ICS discontinuation relative to ICS continuation was 0.86 (95% CI: 0.78-0.95), while for severe pneumonia it was 0.96 (95% CI: 0.88-1.05). The incidence of severe exacerbation after ICS discontinuation was numerically higher than after continuation among patients with two or more exacerbations in the prior year (HR 1.09; 95% CI: 0.94-1.26) and among those with FEV1 <30% predicted (HR 1.29; 95% CI: 1.04-1.59). This large real-world study in the clinical setting of COPD treatment suggests that certain patients on triple therapy can be safely withdrawn from ICS and remain on bronchodilator therapy. As residual confounding cannot be ruled out, ICS discontinuation is not warranted for patients with multiple exacerbations and with very severe airway obstruction.

Fluticasone-Based versus Budesonide-Based Triple Therapies in COPD: Real-World Comparative Effectiveness and Safety.

Triple therapy for chronic obstructive pulmonary disease (COPD) is recommended for some patients, but the inhaled corticosteroids (ICS) may differ in effectiveness and safety. We compared budesonide-based and fluticasone-based triple therapy given in two inhalers on the incidence of exacerbation, mortality and severe pneumonia, using an observational study approach. We identified a cohort of patients with COPD, new users of triple therapy given in two inhalers during 2002-2018, age 50 or older, from the UK's CPRD database, and followed for one year. The hazard ratio (HR) of exacerbation, all-cause death and pneumonia was estimated using the Cox regression model, weighted by fine stratification of the propensity score of treatment initiation. The cohort included 29,716 new users of fluticasone-based triple therapy and 9,646 of budesonide-based. The HR of a first moderate or severe exacerbation with budesonide-based triple therapy was 0.98 (95% CI: 0.94-1.03), relative to fluticasone-based, while for a severe exacerbation it was 0.97 (95% CI: 0.87-1.07). The incidence of all-cause death was lower with budesonide-based therapy among patients with no prior exacerbations (HR 0.80; 95% CI: 0.66-0.98). The HR of severe pneumonia with budesonide-based therapy was 0.84 (95% CI: 0.75-0.95). In a real-world clinical setting of COPD treatment, budesonide-based triple therapy given in two inhalers was generally as effective at reducing exacerbations as fluticasone-based triple therapy. However, the budesonide-based triple therapy was associated with a lower incidence of severe pneumonia and possibly also of all-cause death, especially among patients with no prior exacerbations for whom triple therapy is not recommended.

Triple Inhaler versus Dual Bronchodilator Therapy in COPD: Real-World Effectiveness on Mortality.

Randomized trials of triple therapy including an inhaled corticosteroid (ICS) for chronic obstructive pulmonary disease (COPD) reported remarkable benefits on mortality compared with dual bronchodilators, likely resulting from ICS withdrawal at randomization. We compared triple therapy with dual bronchodilator combinations on major COPD outcomes in a real-world clinical practice setting. We identified a cohort of COPD patients, age 50 or older, treated during 2002-2018, from the United Kingdom's Clinical Practice Research Datalink. Patients initiating treatment with a long-acting muscarinic antagonist (LAMA), a long-acting beta2-agonist (LABA) and an ICS on the same day, were compared with patients initiating a LAMA and LABA, weighted by fine stratification of propensity scores. Subjects were followed-up one year for all-cause mortality, severe exacerbation and pneumonia. The cohort included 117,729 new-users of LAMA-LABA-ICS and 26,666 of LAMA-LABA. The adjusted hazard ratio (HR) of all-cause mortality with LAMA-LABA-ICS compared with LAMA-LABA was 1.17 (95% CI: 1.04-1.31) while for severe exacerbation and pneumonia it was 1.19 (1.08-1.32) and 1.29 (1.16-1.45) respectively. However, mortality was not elevated with triple therapy among patients with asthma diagnosis (HR 0.99; 95% CI: 0.74-1.34), with two or more prior exacerbations (HR 0.88; 95% CI: 0.70-1.11), and with FEV1 percent predicted >30%. In a real-world setting of COPD treatment, triple therapy initiation was not more effective than dual bronchodilators at preventing all-cause mortality and severe COPD exacerbations. Triple therapy may be unsafe among patients without prior exacerbations, in whom ICS are not recommended, with no asthma diagnosis and with very severe airflow obstruction.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1977789 .

Regional variation in the potentially inappropriate first-line use of fluoroquinolones in Canada as a key to antibiotic stewardship? A drug utilization review study.

BACKGROUND: Serious adverse effects of fluoroquinolone antibiotics have been described for more than decade. Recently, several drug regulatory agencies have advised restricting their use in milder infections for which other treatments are available, given the potential for disabling and possibly persistent side effects. We aimed to describe variations in fluoroquinolone use for initial treatment of urinary tract infection (UTI), acute bacterial sinusitis (ABS), and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in the outpatient setting across Canada. METHODS: Using administrative health data from six provinces, we identified ambulatory visits with a diagnosis of uncomplicated UTI, uncomplicated AECOPD or ABS. Antibiotic exposure was determined by the first antibiotic dispensed within 5 days of the visit. RESULTS: We identified 4,303,144 uncomplicated UTI events among 2,170,027 women; the proportion of events treated with fluoroquinolones, mostly ciprofloxacin, varied across provinces, ranging from 18.6% (Saskatchewan) to 51.6% (Alberta). Among 3,467,678 ABS events (2,087,934 patients), between 2.2% (Nova Scotia) and 11.2% (Ontario) were dispensed a fluoroquinolone. For 1,319,128 AECOPD events among 598,347 patients, fluoroquinolones, mostly levofloxacin and moxifloxacin, ranged from 5.8% (Nova Scotia) to 35.6% (Ontario). The proportion of uncomplicated UTI and ABS events treated with fluoroquinolones declined over time, whereas it remained relatively stable for AECOPD. CONCLUSIONS: Fluoroquinolones were commonly used as first-line therapies for uncomplicated UTI and AECOPD. However, their use varied widely across provinces. Drug insurance formulary criteria and enforcement may be a key to facilitating better antibiotic stewardship and limiting potentially inappropriate first-line use of fluoroquinolones.

SGLT-2 inhibitors and the risk of hospitalization for community-acquired pneumonia: A population-based cohort study.

PURPOSE: Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have been associated with an increased risk of genitourinary tract infections. Through similar biological mechanisms, they may also increase the risk of community-acquired pneumonia. Our objective was to compare the rate of hospitalization for community-acquired pneumonia (HCAP) with SGLT-2i compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) among patients with type 2 diabetes. METHODS: We used the United Kingdom's Clinical Practice Research Datalink Gold, linked to hospitalization data, to construct a cohort of patients with type 2 diabetes. Using a time-dependent Cox proportional hazards model, we estimated the adjusted hazard ratio (HR) for HCAP with current use of SGLT-2i versus DPP-4i. RESULTS: Among 29 896 patients, 705 HCAPs occurred over a mean follow-up of 1.7 years (SD: 1.2). Incidence rates for SGLT-2i and DPP-4i users were 6.2 (95% confidence interval [CI]: 3.7, 10.2) and 17.8 (95% CI: 15.3, 20.7) per 1000 person-years, respectively. Current use of SGLT-2i was associated with a decreased risk of HCAP compared to current use of DPP-4i (adjusted HR: 0.48, 95% CI: 0.28, 0.82). However, a comparison of SGLT-2i versus glucagon-like peptide-1 receptor agonists (GLP-1 RA) found no difference in risk of HCAP (adjusted HR: 0.94, 95% CI: 0.44, 1.89). CONCLUSIONS: SGLT-2i are associated with a decreased rate of HCAP compared to DPP-4i, but not when compared to GLP-1 RA, among patients with type 2 diabetes.

Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies.

OBJECTIVE: To establish the risk of major bleeding in direct oral anticoagulant (DOAC) users (overall and by class) versus vitamin K antagonist (VKA) users, using health care databases from four European countries and six provinces in Canada. METHODS: A retrospective cohort study was performed according to a similar protocol. First-users of VKAs or DOACs with a diagnosis of non-valvular atrial fibrillation (NVAF) were included. The main outcome of interest was major bleeding and secondary outcomes included gastrointestinal (GI) bleeding and intracranial haemorrhage (ICH). Incidence rates of events per 1000 person years were calculated. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard regression model. Exposure and confounders were measured and analysed in a time-dependant way. Risk estimates were pooled using a random effect model. RESULTS: 421 523 patients were included. The risk of major bleeding for the group of DOACs compared to VKAs showed a pooled HR of 0.94 (95% CI: 0.87-1.02). Rivaroxaban showed a modestly increased risk (HR 1.11, 95% CI: 1.06-1.16). Apixaban and dabigatran showed a decreased risk of respectively HR 0.76 (95% CI: 0.69-0.84) and HR 0.85 (95% CI: 0.75-0.96). CONCLUSIONS: This study confirms that the risk of major bleeding of DOACs compared to VKAs is not increased when combining all DOACs. However, we observed a modest higher risk of major bleeding for rivaroxaban, whereas for apixaban and dabigatran lower risks of major bleeding were observed compared to VKAs.

Validity of an algorithm to identify cardiovascular deaths from administrative health records: a multi-database population-based cohort study.

BACKGROUND: Cardiovascular death is a common outcome in population-based studies about new healthcare interventions or treatments, such as new prescription medications. Vital statistics registration systems are often the preferred source of information about cause-specific mortality because they capture verified information about the deceased, but they may not always be accessible for linkage with other sources of population-based data. We assessed the validity of an algorithm applied to administrative health records for identifying cardiovascular deaths in population-based data. METHODS: Administrative health records were from an existing multi-database cohort study about sodium-glucose cotransporter-2 (SGLT2) inhibitors, a new class of antidiabetic medications. Data were from 2013 to 2018 for five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, Quebec) and the United Kingdom (UK) Clinical Practice Research Datalink (CPRD). The cardiovascular mortality algorithm was based on in-hospital cardiovascular deaths identified from diagnosis codes and select out-of-hospital deaths. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for the cardiovascular mortality algorithm using vital statistics registrations as the reference standard. Overall and stratified estimates and 95% confidence intervals (CIs) were computed; the latter were produced by site, location of death, sex, and age. RESULTS: The cohort included 20,607 individuals (58.3% male; 77.2% ≥70 years). When compared to vital statistics registrations, the cardiovascular mortality algorithm had overall sensitivity of 64.8% (95% CI 63.6, 66.0); site-specific estimates ranged from 54.8 to 87.3%. Overall specificity was 74.9% (95% CI 74.1, 75.6) and overall PPV was 54.5% (95% CI 53.7, 55.3), while site-specific PPV ranged from 33.9 to 72.8%. The cardiovascular mortality algorithm had sensitivity of 57.1% (95% CI 55.4, 58.8) for in-hospital deaths and 72.3% (95% CI 70.8, 73.9) for out-of-hospital deaths; specificity was 88.8% (95% CI 88.1, 89.5) for in-hospital deaths and 58.5% (95% CI 57.3, 59.7) for out-of-hospital deaths. CONCLUSIONS: A cardiovascular mortality algorithm applied to administrative health records had moderate validity when compared to vital statistics data. Substantial variation existed across study sites representing different geographic locations and two healthcare systems. These variations may reflect different diagnostic coding practices and healthcare utilization patterns.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors could increase the risk for diabetic ketoacidosis (DKA). OBJECTIVE: To assess whether SGLT-2 inhibitors, compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, are associated with an increased risk for DKA in patients with type 2 diabetes. DESIGN: Population-based cohort study; prevalent new-user design between 2013 and 2018. (ClinicalTrials.gov: NCT04017221). SETTING: Electronic health care databases from 7 Canadian provinces and the United Kingdom. PATIENTS: 208 757 new users of SGLT-2 inhibitors were matched by using time-conditional propensity scores to 208 757 recipients of DPP-4 inhibitors. MEASUREMENTS: Cox proportional hazards models estimated site-specific hazard ratios (HRs) with 95% CIs of DKA comparing receipt of SGLT-2 inhibitors with receipt of DPP-4 inhibitors, which were pooled by using random-effects models. Secondary analyses were stratified by molecule, age, sex, and prior receipt of insulin. RESULTS: Overall, 521 patients were diagnosed with DKA during 370 454 person-years of follow-up (incidence rate per 1000 person-years, 1.40 [95% CI, 1.29 to 1.53]). Compared with DPP-4 inhibitors, SGLT-2 inhibitors were associated with an increased risk for DKA (incidence rate, 2.03 [CI, 1.83 to 2.25] versus 0.75 [CI, 0.63 to 0.89], respectively; HR, 2.85 [CI, 1.99 to 4.08]). Molecule-specific HRs were 1.86 (CI, 1.11 to 3.10) for dapagliflozin, 2.52 (CI, 1.23 to 5.14) for empagliflozin, and 3.58 (CI, 2.13 to 6.03) for canagliflozin. Age and sex did not modify the association; prior receipt of insulin appeared to decrease the risk. LIMITATIONS: There was unmeasured confounding and no laboratory data were available for the majority of patients, and molecule-specific analyses were conducted at a limited number of sites. CONCLUSION: SGLT-2 inhibitors were associated with an almost 3-fold increased risk for DKA, with molecule-specific analyses suggesting a class effect. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

Comparative Effectiveness of Initial LAMA versus LABA in COPD: Real-World Cohort Study.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations for the initial bronchodilator to use in newly diagnosed chronic obstructive pulmonary disease (COPD) are based on trials of patients with longstanding disease and treatment. We compared the real world effectiveness of initial treatment with long-acting muscarinic agents (LAMA) versus long-acting beta2-agonists (LABA) on the incidence of exacerbations in newly diagnosed patients. We identified a cohort of patients with COPD, new users of a LAMA or LABA (not combined with an inhaled corticosteroid (ICS)) during 2002-2018, age 50 or older, from the UK's CPRD database, and followed for one year. The hazard ratio (HR) of exacerbation estimated using the Cox regression model, weighted by fine stratification of propensity scores. The cohort included 40,538 initiators of LAMA and 10,680 of LABA. The adjusted hazard ratio (HR) of a first moderate or severe exacerbation comparing LAMA with LABA initiation was 0.96 (95% CI: 0.90-1.02), while for severe exacerbation it was 0.92 (95% CI: 0.75-1.12). The incidence of exacerbation on LAMA was significantly lower than on LABA (HR 0.88; 95% CI: 0.80-0.96) among patients with a prior exacerbation, and the HR of exacerbation increased with percent predicted FEV1. This study in the real world clinical setting of COPD treatment found that using a LAMA or a LABA (no ICS) as the initial bronchodilator is generally as effective at reducing exacerbation incidence and frequency. However, a LAMA may be more effective in patients with prior exacerbations, which supports the GOLD recommendations for newly diagnosed COPD. The role of airway obstruction on the effectiveness of bronchodilators warrants further investigation.

ß 2-Agonists and the Incidence of Parkinson Disease.

A recent study found a decreased risk of Parkinson disease (PD) associated with the ß2 adrenergic agonist (ß2-agonist) salbutamol. However, other mechanisms might explain this apparent association. Using the UK Clinical Practice Research Datalink, we formed a cohort of 2,430,884 patients aged 50 years or older between 1995 and 2016. During follow-up, 8,604 cases of PD were identified and matched to 86,040 controls on sex, age, date of cohort entry, and duration of follow-up, after applying a 1-year latency time window. Incidence rate ratios of PD associated with use of ß2-agonists were estimated using conditional logistic regression. Ever-use of ß2-agonists was associated with a 17% decreased rate of PD (rate ratio = 0.83, 95% confidence interval: 0.75, 0.91) compared with no use. However, this association was limited to early short-term use and was no longer observed after more than 2 years of cumulative duration of use (rate ratio = 0.97, 95% confidence interval: 0.80, 1.17). A similar pattern was observed when stratifying by time since first ß2-agonist prescription and by duration of follow-up. The apparent association of ß2-agonists with a decreased risk of PD is likely the result of reverse causality rather than a biological effect of these drugs on the risk of PD.

Inhaled corticosteroid use and the incidence of lung cancer in COPD.

BACKGROUND: Inhaled corticosteroids (ICS) are suggested for potential chemoprevention of lung cancer. Several observational studies in patients with chronic obstructive pulmonary disease (COPD) reported inconsistent results, either significant reductions in lung cancer incidence with ICS use or no effect. We assessed this association, using an approach that avoided biases affecting some of the studies. METHODS: A cohort of patients with COPD, new users of long-acting bronchodilators over 2000-2014, was formed using the Quebec healthcare databases, and followed until 2015 for a first diagnosis of lung cancer. A 1-year delay after cohort entry was used to avoid protopathic bias and a 1-year latency period was included after the initiation of ICS use. A time-dependent Cox regression model was used to estimate the hazard ratio (HR) of lung cancer associated with ICS exposure, adjusted for covariates. RESULTS: The cohort involved 63 276 subjects, including 63% receiving ICS, with 3743 lung cancers occurring during a mean follow-up of 5 years. The adjusted HR of lung cancer associated with any ICS exposure was 1.01 (95% CI 0.94-1.08), relative to no ICS use. The HR with longer time (>4 years) since ICS initiation was 0.92 (95% CI 0.83-1.03), while with higher mean daily ICS dose (>1000 µg fluticasone equivalents) was 1.36 (95% CI 1.03-1.81). CONCLUSIONS: Inhaled corticosteroid use is not associated with a reduction in lung cancer incidence in patients with COPD. Observational studies reporting such reduction may have been affected by time-related biases and the inclusion of patients with asthma. The proposition of a randomised trial warrants some caution.

Comparative safety of biologic versus conventional synthetic DMARDs in rheumatoid arthritis with COPD: a real-world population study.

OBJECTIVES: Abatacept, a biologic DMARD, was associated with respiratory adverse events in a small subgroup of RA patients with chronic obstructive pulmonary disease (COPD) in a trial. Whether this potential risk is specific to abatacept or extends to all biologics and targeted synthetic DMARDs (tsDMARDs) is unclear. We assessed the risk of adverse respiratory events associated with biologic and tsDMARDs compared with conventional synthetic DMARDs (csDMARDs) among RA patients with concomitant COPD in a large, real-world cohort. METHODS: We used a prevalent new-user design to study RA patients with COPD in the US-based MarketScan databases. New users of biologic DMARDs and/or tsDMARDs were matched on time-conditional propensity scores to new users of csDMARDs. Adverse respiratory events were estimated using Cox models comparing current use of biologic/tsDMARDs with csDMARDs. RESULTS: The cohort included 7424 patients initiating biologic/tsDMARDs and 7424 matched patients initiating csDMARDs. The adjusted hazard ratio of hospitalized COPD exacerbation comparing biologic/tsDMARD vs csDMARD was 0.76 (95% CI: 0.55, 1.06), while it was 1.02 (95% CI: 0.82, 1.27) for bronchitis, 1.21 (95% CI: 0.92, 1.58) for hospitalized pneumonia or influenza and 0.99 (95% CI: 0.87, 1.12) for outpatient pneumonia or influenza. The hazard ratio of the combined end point of COPD exacerbation, bronchitis and hospitalized pneumonia or influenza was 1.04 (95% CI: 0.89, 1.21). CONCLUSION: In this large, real-world comparative safety study, biologic and tsDMARDs, including abatacept, were not associated with an increased risk of adverse respiratory events when compared with csDMARDs in patients with RA and COPD.

Sodium-glucose co-transporter-2 inhibitors and the risk of urosepsis: A multi-site, prevalent new-user cohort study.

AIM: To compare urosepsis rates in patients with type 2 diabetes treated using sodium-glucose co-transporter-2 inhibitors (SGLT2i) with dipeptidyl peptidase-4 inhibitors (DPP4i) in a real-world setting. METHODS: We conducted a matched cohort study using a prevalent new-user design with time-conditional propensity scores. New users of SGLT2i from seven Canadian provinces and the UK were matched to DPP4i users. The primary outcome was hospitalization with a diagnosis of urosepsis and the secondary outcome was Fournier's gangrene. Site-specific hazard ratios for urosepsis comparing SGLT2i with DPP4i were estimated using Cox proportional hazards models and pooled using a random effects meta-analysis. RESULTS: We included 208 244 users of SGLT2i and 208 244 users of DPP4i. Among SGLT2i users, 42% initiated canagliflozin, 31% dapagliflozin and 27% empagliflozin. During a mean follow-up of 0.9 years, patients initiating SGLT2i had a lower rate of urosepsis compared with those receiving DPP4i. The pooled adjusted hazard ratio was 0.58 (95% confidence interval [CI]: 0.42-0.80). The incidence rates of Fournier's gangrene were numerically similar in SGLT2i (0.08 per 1000 person-years; 95% CI: 0.05-0.13) and DPP4i users (0.14; 95% CI: 0.09-0.21). CONCLUSIONS: In this large, multi-site study, we did not observe an increased risk for urosepsis associated with SGLT2i compared with DPP4i among patients with type 2 diabetes in a real-world setting.

A Multicenter Observational Study of Incretin-based Drugs and Heart Failure.

BACKGROUND: There is concern that antidiabetic incretin-based drugs, including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogues, can increase the risk of heart failure. Ongoing clinical trials may not have large enough samples to effectively address this issue. METHODS: We applied a common protocol in the analysis of multiple cohorts of patients with diabetes. We used health care data from four Canadian provinces, the United States, and the United Kingdom. With the use of a nested case-control analysis, we matched each patient who was hospitalized for heart failure with up to 20 controls from the same cohort; matching was based on sex, age, cohort-entry date, duration of treated diabetes, and follow-up time. Cohort-specific hazard ratios for hospitalization due to heart failure among patients receiving incretin-based drugs, as compared with those receiving oral antidiabetic-drug combinations, were estimated by means of conditional logistic regression and pooled across cohorts with the use of random-effects models. RESULTS: The cohorts included a total of 1,499,650 patients, with 29,741 hospitalized for heart failure (incidence rate, 9.2 events per 1000 persons per year). The rate of hospitalization for heart failure did not increase with the use of incretin-based drugs as compared with oral antidiabetic-drug combinations among patients with a history of heart failure (hazard ratio, 0.86; 95% confidence interval [CI], 0.62 to 1.19) or among those without a history of heart failure (hazard ratio, 0.82; 95% CI, 0.67 to 1.00). The results were similar for DPP-4 inhibitors and GLP-1 analogues. CONCLUSIONS: In this analysis of data from large cohorts of patients with diabetes, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure, as compared with commonly used combinations of oral antidiabetic drugs. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT02456428.).

Beta-Blockers in COPD: A Methodological Review of the Observational Studies.

The use of beta-blockers in patients with chronic obstructive pulmonary disease (COPD) has received much attention. Several observational studies reported important reductions in mortality and exacerbations with these drugs, but the extent of bias in these studies is unclear. Nevertheless, the large ongoing randomized trial (ßLOCK-COPD) was initiated specifically to evaluate these effects. We searched the literature to identify all observational studies investigating the effectiveness of beta-blockers in COPD patients on major outcomes, including death and COPD exacerbation. We identified 18 observational studies, with 10 studies affected by confounding bias and six by immortal time bias, while two addressed these biases. Reductions in all-cause mortality with beta-blocker use were observed among the studies with confounding bias (pooled rate ratio 0.72; 95% CI 0.59-0.88) and those with immortal time bias (pooled rate ratio 0.64; 95% CI 0.53-0.77). A large five-database study that addressed these two biases reported hazard ratios of 0.90 (95% CI: 0.78-1.02) for death and 0.54 (95% CI: 0.47-0.61) for COPD hospitalization. However, this latter estimate was the same as for the first 30 days after treatment initiation, thus indicating that important residual confounding cannot be ruled out. Observational studies, important to provide evidence from real-world data on medication effects, are unsupportive for beta-blockers in COPD. Even if immortal time bias is properly avoided, confounding bias cannot be fully controlled due to their relative contraindication in COPD. In the case of beta-blockers, randomized trials such as ßLOCK-COPD are necessary to eliminate the uncertainty from residual confounding bias.