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 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.

The Prevalent New-user Design for Studies With no Active Comparator: The Example of Statins and Cancer.

BACKGROUND: Observational studies evaluating the effect of a drug versus "non-use" are challenging, mainly when defining cohort entry for non-users. The approach using successive monthly cohorts to emulate the randomized trial can be perceived as somewhat opaque and complex. Alternatively, the prevalent new-user design can provide a potentially simpler more transparent emulation. This design is illustrated in the context of statins and cancer incidence. METHODS: We used the Clinical Practice Research Datalink to identify a cohort of subjects with low-density lipoprotein cholesterol level <5 mmol/L. We used a prevalent new-user design, matching each statin initiator to a non-user from the same time-based exposure set on time-conditional propensity scores with all subjects followed for 10 years for cancer incidence. We estimated the hazard ratio and 95% confidence interval (CI) of cancer incidence with statin use versus non-use using a Cox proportional hazards model, and the results were compared with those using the method of successive monthly cohorts. RESULTS: The study cohort included 182,073 statin initiators and 182,073 matched non-users. The hazard ratio of any cancer after statin initiation versus non-use was 1.01 (95% CI = 0.98, 1.04), compared with 1.04 (95% CI = 1.02, 1.06) under the successive monthly cohorts approach. We estimated similar effects for specific cancers. CONCLUSION: Using the prevalent new-user design to emulate a randomized trial when compared to "non-use" led to results comparable with the more complex successive monthly cohorts approach. The prevalent new-user design emulates the trial in a potentially more intuitive and palpable manner, providing simpler data presentations in line with those portrayed in a classical trial while producing comparable results.

Incidence and Factors Associated With Mental Health Disorders in Patients With Rectal Cancer Post-Restorative Proctectomy.

BACKGROUND: Most patients with rectal cancer experience bowel symptoms post-restorative proctectomy. The incidence of mental health disorders post-restorative proctectomy and its association with bowel symptoms are unknown. OBJECTIVES: This study aimed 1) to describe the incidence of mental health disorders in patients who underwent restorative proctectomy for rectal cancer and 2) to study the association between incident mental health disorders and bowel dysfunction after surgery. DESIGN: This retrospective cohort study used the Clinical Practice Research Datalink and Hospital Episode Statistics databases. SETTINGS: The databases were based in the United Kingdom. PATIENTS: All adult patients who underwent restorative proctectomy for a rectal neoplasm between 1998 and 2018 were included. MAIN OUTCOME MEASURES: The primary outcome was an incident mental health disorder. The associations between bowel, sexual, and urinary dysfunctions and incident mental health disorders were studied using Cox proportional hazard regression models. RESULTS: In total, 2197 patients who underwent restorative proctectomy were identified. Of 1858 patients without preoperative bowel, sexual, or urinary dysfunction, 1455 had no preoperative mental health disorders. In this cohort, 466 patients (32.0%) developed incident mental health disorders following restorative proctectomy during 6333 person-years of follow-up. On multivariate Cox regression, female sex (adjusted HR 1.30; 95% CI, 1.06-1.56), metastatic disease (adjusted HR 1.57; 95% CI, 1.14-2.15), incident bowel dysfunction (adjusted HR 1.41, 95% CI, 1.13-1.77), and urinary dysfunction (adjusted HR 1.57; 95% CI, 1.16-2.14) were found to be associated with developing incident mental health disorders post-restorative proctectomy. LIMITATIONS: This study was limited by its observational study design and residual confounding. CONCLUSIONS: Incident mental health disorders after restorative proctectomy for rectal cancer are common. The presence of bowel and urinary functional impairment significantly increases the risk of poor psychological outcomes among rectal cancer survivors. CON LOS TRASTORNOS DE SALUD MENTAL EN PACIENTES CON CNCER DE RECTO POSTERIOR A PROCTECTOMA RESTAURADORA: ANTECEDENTES: La mayoría de los pacientes con cáncer de recto experimentan síntomas intestinales después de la proctectomía restauradora. Se desconoce la incidencia de trastornos de salud mental posteriores a la proctectomía restauradora y su asociación con síntomas intestinales.OBJETIVOS: Los objetivos de nuestro estudio son: a) describir la incidencia de trastornos de salud mental en pacientes sometidos a proctectomía restauradora por cáncer de recto; b) estudiar la asociación entre los trastornos de salud mental incidentes y la disfunción intestinal después de la cirugía.DISEÑO: Este fue un estudio de cohorte retrospectivo que utilizó las bases de datos Clinical Practice Research Datalink y Hospital Episode Statistics.ENTORNO CLÍNICO: Las bases de datos se basaron en el Reino Unido.PACIENTES: Se incluyeron todos los pacientes adultos que se sometieron a una proctectomía restauradora por una neoplasia rectal entre 1998 y 2018.PRINCIPALES MEDIDAS DE VALORACIÓN: El resultado primario fue un trastorno de salud mental incidente. Las asociaciones entre la disfunción intestinal, sexual y urinaria y los trastornos de salud mental incidentes se estudiaron utilizando modelos de regresión de riesgos proporcionales de Cox.RESULTADOS: En total, se identificaron 2.197 pacientes que se sometieron a proctectomía restauradora. De 1.858 pacientes sin disfunción intestinal, sexual o urinaria preoperatoria, 1.455 personas tampoco tenían trastornos de salud mental preoperatorios. En esta cohorte, 466 (32,0 %) pacientes desarrollaron trastornos de salud mental incidentes después de la PR durante 6333 años-persona de seguimiento. En la regresión multivariada de Cox, sexo femenino (HRa 1,30, IC 95% 1,06-1,56), enfermedad metastásica (HRa 1,57, IC 95% 1,14-2,15) e incidencia intestinal (HRa 1,41, IC del 95 %: 1,13 a 1,77) y la disfunción urinaria (aHR 1,57, IC del 95 %: 1,16 a 2,14) se asociaron con el desarrollo de trastornos de salud mental incidentes después de la proctectomía restauradora.LIMITACIONES: Este estudio estuvo limitado por el diseño del estudio observacional y la confusión residual.CONCLUSIÓN: Los trastornos de salud mental incidentes después de la proctectomía restauradora para el cáncer de recto son comunes. La presencia de deterioro funcional intestinal y urinario aumenta significativamente el riesgo de malos resultados psicológicos entre los sobrevivientes de cáncer de recto. (Traducción- Dr. Ingrid Melo ).

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 .

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.

Comparative cardiovascular and hypoglycaemic safety of glimepiride in type 2 diabetes: A population-based cohort study.

AIM: To assess the incidence of cardiovascular and hypoglycaemic adverse events associated with glimepiride compared with other second-generation sulphonylureas among patients with type 2 diabetes in a real-world clinical setting. MATERIALS AND METHODS: We identified all sulphonylurea initiators between 1998 and 2017 in the UK Clinical Practice Research Datalink. Using a prevalent new-user design, glimepiride initiators were matched 1:4 with initiators of other second-generation sulphonylureas on calendar time, prior sulphonylurea use, and time-conditional high-dimensional propensity score. Cox proportional hazards models yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for myocardial infarction, ischaemic stroke, severe hypoglycaemia, cardiovascular death, and all-cause mortality. RESULTS: Among 66 032 sulphonylurea new users, 6438 initiated glimepiride and were matched to up to 20 582 initiators of other second-generation sulphonylureas. During a mean follow-up of 1.3 years, glimepiride was associated with a similar incidence of myocardial infarction (HR 0.99, 95% CI 0.75-1.30) and ischaemic stroke (HR 0.96, 95% CI 0.72-1.27) compared with other second-generation sulphonylureas, while there was a non-significant trend towards a higher incidence of severe hypoglycaemia (HR 1.24, 95% CI 0.92-1.68). Glimepiride was also associated with a lower incidence of all-cause mortality (HR 0.77, 95% CI 0.67-0.89), and a non-significant but similar trend for cardiovascular death (HR 0.83, 95% CI 0.65-1.05). CONCLUSIONS: Glimepiride was associated with a lower incidence of all-cause mortality compared with other second-generation sulphonylureas.

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.

Time-related biases in pharmacoepidemiology.

PURPOSE: Observational studies using computerized healthcare databases have become popular to investigate the potential effectiveness of old drugs for new indications. Many of these studies reporting remarkable effectiveness were shown to be affected by different time-related biases. We describe these biases and illustrate their effects using a cohort of patients treated for chronic obstructive pulmonary disease (COPD). METHODS: The Quebec healthcare databases were used to form a cohort of 124 030 patients with COPD, 50 years or older, treated between 2000 and 2015. Inhaled corticosteroids (ICS) and long-acting bronchodilators were used as exposures, with diverse outcomes, including lung cancer, acute myocardial infarction and death, to illustrate protopathic, latency time, immortal time, time-window, depletion of susceptibles, and immeasurable time biases. RESULTS: Protopathic bias affected bronchodilator-defined cohort entry with an incident rate of lung cancer of 23.9 per 1000 in the first year, compared with around 12.0 in the subsequent years. When latency and immortal times were misclassified, ICS were associated with decreased incidence of lung cancer (hazard ratio [HR] 0.32; 95% CI: 0.30-0.34), compared with 0.50 (95% CI: 0.48-0.53) after correcting for immortal time bias and 0.96 (95% CI: 0.91-1.02) after also correcting for latency time bias. Time-window, depletion of susceptibles and immeasurable time biases also affected the findings similarly. CONCLUSIONS: Many observational studies of new indications for older drugs reporting unrealistic effectiveness were affected by avoidable time-related biases. The apparent effectiveness often disappears with proper design and analysis. Future studies should consider these time-related issues to avoid severely biased results.

Extreme restriction design as a method for reducing confounding by indication in pharmacoepidemiologic research.

PURPOSE: Confounding by indication is a concern in observational pharmacoepidemiologic studies, including those that use active comparator, new user (ACNU) designs. Here, we present a method of restriction to an indication, which we call "extreme restriction," to reduce confounding in such studies. METHODS: As a case study, we evaluated the effect of proton pump inhibitors (PPIs) on hospitalization for community-acquired pneumonia (HCAP). PPI use has been associated with increased HCAP risk, but this association likely results from confounding by indication due to gastroesophageal reflux disease (GERD). Using the UK's Clinical Practice Research Datalink, we compared the risk of HCAP within 180 days between PPI users and histamine-2 receptor antagonist (H2RA) users in an ACNU cohort using Cox proportional hazard models with a time-fixed exposure definition adjusted for high-dimensional propensity score deciles. We then performed the same analysis on an "extremely-restricted" cohort of incident nonsteroidal anti-inflammatory drug (NSAID) users, some of whom received PPIs for prophylaxis. Because PPIs were given as prophylaxis in this population, confounding due to GERD should be limited. We compared effect estimates between ACNU and restricted cohorts to evaluate confounding in both analyses. RESULTS: In the ACNU cohort, PPIs were associated with an increased risk of HCAP (hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 1.05, 1.47), but this association was not present in the restricted cohort (HR: 1.06; 95% CI: 0.75, 1.49). CONCLUSIONS: Restriction to a single indication for treatment may reduce confounding by indication in studies conducted in distributed data networks and other large databases.