Effectiveness and Safety of Edoxaban Compared With Apixaban in Elderly Patients With Nonvalvular Atrial Fibrillation: A Real-World Population-Based Cohort Study.

BACKGROUND: The very elderly (≥80 years) are at high risk of nonvalvular atrial fibrillation and thromboembolism. Given its recent approval, the comparative effectiveness and safety of edoxaban in this population, relative to the commonly used apixaban, remain unknown. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified a cohort of patients aged ≥80 with incident nonvalvular atrial fibrillation and newly treated with edoxaban or apixaban between 2015 and 2021. Cohort entry was defined as the first prescription for one of the 2 drugs. We used propensity score fine stratification and weighting for confounding adjustment. A weighted Cox proportional hazards model was used to estimate the hazard ratios (HR) with 95% CI of ischemic stroke/transient ischemic attack/systemic embolism (primary effectiveness outcome) and of major bleeding (primary safety outcome) associated with edoxaban compared with apixaban. We also assessed the risk of all-cause mortality and a composite outcome of ischemic stroke/transient ischemic attack, systemic embolism, gastrointestinal bleeding, and intracranial hemorrhage as secondary outcomes. RESULTS: The cohort included 7251 new-users of edoxaban and 39 991 of apixaban. Edoxaban and apixaban had similar incidence rates of thromboembolism (adjusted rates, 20.38 versus 19.22 per 1000 person-years; adjusted HR, 1.06 [95% CI, 0.89-1.26]), although the rates of major bleeding were higher with edoxaban (adjusted rates, 45.57 versus 31.21 per 1000 person-years; adjusted HR, 1.42 [95% CI, 1.26-1.61]). The risk of the composite outcome was 21% higher with edoxaban (adjusted HR, 1.21 [95% CI, 1.07-1.38]). All-cause mortality was similar between edoxaban and apixaban (adjusted HR, 1.04 [95% CI, 0.96-1.12]). CONCLUSIONS: In very elderly patients with nonvalvular atrial fibrillation, edoxaban resulted in similar thromboembolism prevention as apixaban, although it was associated with a higher risk of major bleeding. These findings may improve the management of nonvalvular atrial fibrillation by informing physicians on the choice of anticoagulant for this vulnerable population.

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.

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.

Observational studies to emulate randomized trials: Some real-world barriers.

The randomized controlled trial (RCT) forms the basis for drug approval by regulatory agencies. Observational studies using existing data from healthcare databases now also provide real-world evidence (RWE) in regulatory decision-making. Several initiatives are assessing the value of RWE by conducting observational studies that emulate published RCTs. While many RCTs are straightforward to emulate, others are challenging. We describe three RCT design aspects that pose challenges for observational studies. First are trials that enrol already treated subjects who must discontinue these treatments at the time of randomization, which can distort the comparison with observational studies. Second is the inclusion of a run-in phase, especially to exclude non-compliant subjects from the trial. Third are trials that evaluate the effect of weaning off treatment. In conclusion, future randomized trials that aim to be emulated by observational studies could consider study designs that allow emulation and thus provide valid and complementary RWE.

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.

Infection outcomes in patients with rheumatoid arthritis treated with abatacept and other disease-modifying antirheumatic drugs: Results from a 10-year international post-marketing study.

OBJECTIVE: To evaluate risk of infections requiring hospitalization and opportunistic infections, including tuberculosis, in patients with rheumatoid arthritis (RA) treated with abatacept versus conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biologic/targeted synthetic (b/ts) DMARDs. METHODS: Five international observational data sources were used: two biologic registries (Sweden, Germany), a disease registry (USA) and two healthcare claims databases (Canada, USA). Crude incidence rates (IRs) per 1000 patient-years, with 95 % CIs, were used to estimate rate ratios (RRs) comparing abatacept versus csDMARDs or other b/tsDMARDs. RRs were adjusted for demographic factors, comorbidities, and other potential confounders and then pooled across data sources using a random effects model (REM). RESULTS: The data sources included 6450 abatacept users, 136,636 csDMARD users and 54,378 other b/tsDMARD users, with a mean follow-up range of 2.2-6.2 years. Across data sources, the IRs for infections requiring hospitalization ranged from 16 to 56 for abatacept, 19-46 for csDMARDs, and 18-40 for other b/tsDMARDs. IRs for opportunistic infections were 0.4-7.8, 0.3-4.3, and 0.5-3.8; IRs for tuberculosis were 0.0-8.4, 0.0-6.0, and 0.0-6.3, respectively. The pooled adjusted RR (95 % CI), only reported for infections requiring hospitalization, was 1.2 (0.6-2.2) for abatacept versus csDMARDs and 0.9 (0.6-1.3) versus other b/tsDMARDs. CONCLUSIONS: Data from this international, observational study showed similar hospitalized infection risk for abatacept versus csDMARDs or other b/tsDMARDs. IRs for opportunistic infections, including tuberculosis, were low. These data are consistent with the known safety profile of abatacept.

Abatacept and non-melanoma skin cancer in patients with rheumatoid arthritis: a comprehensive evaluation of randomised controlled trials and observational studies.

OBJECTIVES: This study aims to evaluate non-melanoma skin cancer (NMSC) risk associated with abatacept treatment for rheumatoid arthritis (RA). METHODS: This evaluation included 16 abatacept RA clinical trials and 6 observational studies. NMSC incidence rates (IRs)/1000 patient-years (p-y) of exposure were compared between patients treated with abatacept versus placebo, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biological/targeted synthetic (b/ts)DMARDs. For observational studies, a random-effects model was used to pool rate ratios (RRs). RESULTS: ~49 000 patients receiving abatacept were analysed from clinical trials (~7000) and observational studies (~42 000). In randomised trials (n=4138; median abatacept exposure, 12 (range 2-30) months), NMSC IRs (95% CIs) were not significantly different for abatacept (6.0 (3.3 to 10.0)) and placebo (4.0 (1.3 to 9.3)) and remained stable throughout the long-term, open-label period (median cumulative exposure, 28 (range 2-130 months); 21 335 p-y of exposure (7044 patients over 3 years)). For registry databases, NMSC IRs/1000 p-y were 5-12 (abatacept), 1.6-10 (csDMARDs) and 3-8 (other b/tsDMARDs). Claims database IRs were 19-22 (abatacept), 15-18 (csDMARDs) and 14-17 (other b/tsDMARDs). Pooled RRs (95% CIs) from observational studies for NMSC in patients receiving abatacept were 1.84 (1.00 to 3.37) vs csDMARDs and 1.11 (0.98 to 1.26) vs other b/tsDMARDs. CONCLUSIONS: Consistent with the warnings and precautions of the abatacept label, this analysis suggests a potential increase in NMSC risk with abatacept use compared with csDMARDs. No significant increase was observed compared with b/tsDMARDs, but the lower limit of the 95% CI was close to unity.

Malignancy outcomes in patients with rheumatoid arthritis treated with abatacept and other disease-modifying antirheumatic drugs: Results from a 10-year international post-marketing study.

OBJECTIVE: To evaluate the risk of malignancy (overall, breast, lung, and lymphoma) in patients with rheumatoid arthritis treated with abatacept, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), and other biologic/targeted synthetic (b/ts)DMARDs in clinical practice. METHODS: Four international observational data sources were included: ARTIS (Sweden), RABBIT (Germany), FORWARD (USA), and BC (Canada). Crude incidence rates (IRs) per 1000 patient-years of exposure with 95% confidence intervals (CIs) for a malignancy event were calculated; rate ratios (RRs) were estimated and adjusted for demographics, comorbidities, and other potential confounders. RRs were then pooled in a random-effects model. RESULTS: Across data sources, mean follow-up for patients treated with abatacept (n = 5182), csDMARDs (n = 73,755), and other b/tsDMARDs (n = 37,195) was 3.0-3.7, 2.9-6.2, and 3.1-4.7 years, respectively. IRs per 1000 patient-years for overall malignancy ranged from 7.6-11.4 (abatacept), 8.6-13.2 (csDMARDs), and 5.0-11.8 (other b/tsDMARDs). IRs ranged from: 0-4.4, 0-3.3, and 0-2.5 (breast cancer); 0.1-2.8, 0-3.7, and 0.2-2.9 (lung cancer); and 0-1.1, 0-0.9, and 0-0.6 (lymphoma), respectively, for the three treatment groups. The numbers of individual cancers (breast, lung, and lymphoma) in some registries were low; RRs were not available. There were a few cases of lymphoma in some of the registries; ARTIS observed an RR of 2.8 (95% CI 1.1-6.8) with abatacept versus csDMARDs. The pooled RRs (95% CIs) for overall malignancy with abatacept were 1.1 (0.8-1.5) versus csDMARDs and 1.0 (0.8-1.3) versus b/tsDMARDs. CONCLUSIONS: This international, post-marketing observational safety study did not find any statistically significant increase in the risk of overall malignancies in pooled data in patients treated with abatacept compared with csDMARDs or with other b/tsDMARDs. Assessment of larger populations is needed to further evaluate the risks for individual cancers, especially lymphoma.

Clinically apparent Helicobacter pylori infection and the risk of incident Alzheimer's disease: A population-based nested case-control study.

INTRODUCTION: Our population-based study assessed whether clinically apparent Helicobacter pylori infection (CAHPI) is associated with the risk of Alzheimer's disease (AD). METHODS: We assembled a population-based cohort of all dementia-free subjects in the United Kingdom's Clinical Practice Research Datalink (UK CPRD), aged ≥50 years (1988-2017). Using a nested case-control approach, we matched each newly developed case of AD with 40 controls. Conditional logistic regression estimated odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with CAHPI compared with no CAHPI during ≥2 years before the index date. We also used salmonellosis as a negative control exposure. RESULTS: Among 4,262,092 dementia-free subjects, 40,455 developed AD after a mean 11 years of follow-up. CAHPI was associated with an increased risk of AD (OR, 1.11; 95% CI, 1.01-1.21) compared with no CAHPI. Salmonellosis was not associated with the risk of AD (OR, 1.03; 95% CI, 0.82-1.29). DISCUSSION: CAHPI was associated with a moderately increased risk of AD. HIGHLIGHTS: CAHPI was associated with an 11% increased risk of AD in subjects aged ≥50 years. The increase in the risk of AD reached a peak of 24% a decade after CAHPI onset. There was no major effect modification by age or sex. Sensitivity analyses addressing several potential biases led to consistent results.

Statins and Mortality in COPD: A Methodological Review of Observational Studies.

Randomized controlled trials and observational studies have reported conflicting results on the potential beneficial effects of statins on mortality in patients with chronic obstructive pulmonary disease (COPD). We performed a systematic search of the literature to review all observational studies reporting relative risks of death with statin use in COPD, focusing on potential sources of bias. We identified 15 observational studies, out of 2835, of which 12 were affected by time-related and other biases and the remaining 3 by confounding bias. All 15 studies were also subject to confounding bias due to lack of adjustment for important COPD-related factors. The risk of death associated with statin use was reduced across all 15 studies (pooled relative risk (PRR) 0.66; 95% CI: 0.59-0.74). The reduction was observed in 7 studies with immortal time bias (PRR 0.62; 95%: 0.53-0.72), two with collider-stratification bias (PRR 0.60; 95% CI: 0.45-0.80), one with time-window bias (RR 0.61; 95% CI: 0.38-0.98), one with immeasurable time bias (RR 0.50; 95% CI: 0.40-0.62), and one with exposure misclassification (RR 0.86; 95% CI: 0.72-1.03). The three studies that avoided these biases were, however, affected by confounding bias resulting in a PRR of 0.77 (95% CI: 0.61-0.98). In conclusion, the observational studies investigating statin use and mortality in COPD are affected by major biases, many of which can result in spurious protective effects. Well-designed observational studies that carefully emulate randomized trials are needed to resolve this uncertainty regarding the potential beneficial benefits of statins on mortality in patients with COPD.

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.

Metformin and Cancer: Solutions to a Real-World Evidence Failure.

The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.