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Observational studies are increasingly used to provide real-world evidence in regulatory decision-making. The RCT-DUPLICATE initiative conducted observational studies emulating two trials in patients with asthma and three in COPD. For each trial, new-user cohorts were constructed from two US healthcare claims databases, comparing initiators of the study and comparator drugs, matched on propensity scores. Proportional hazards models were used to compare the treatments on study outcomes. The observational studies involved more subjects than the corresponding trials, with treatment arms well-matched on baseline characteristics. An asthma example involved emulation of the 26-week FDA-mandated D5896 trial. With 6,494 asthma patients per arm, the hazard ratio (HR) of a serious asthma-related event with budesonide-formoterol versus budesonide was 1.29 (95% CI: 0.63-2.65), compared with 1.07 (95% CI: 0.70-1.65) in the trial. A COPD example is the emulation of the one-year IMPACT trial. With 4,365 COPD patients per arm, the HR of a COPD exacerbation with triple therapy versus dual bronchodilators was 1.08 (95% CI: 1.00-1.17), compared with 0.84 (95% CI: 0.78-0.91) in the trial. We found mainly discordant results between observational analyses and randomized trials, likely from the forced discontinuation of treatments prior to randomization in the trials, not mimicable in the observational analyses.
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OBJECTIVE: Observational studies have associated glucosamine, used to treat joint pain and osteoarthritis, with reductions in cancer incidence, although their study design was affected by selection bias. We assessed this association using a study design that mitigates this selection bias. METHODS: We used the UK Clinical Practice Research Datalink to identify a cohort of patients diagnosed with osteoarthritis during 1995 through 2017. The prevalent new-user cohort design was employed to match glucosamine initiators with non-users on time-conditional propensity scores, who were observed until cancer incidence. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer incidence were estimated to compare glucosamine initiators with non-users. RESULTS: The study cohort of patients with osteoarthritis included 20,541 glucosamine initiators who were matched to 20,541 non-users. Over an average follow-up of eight years, the overall incidence rate of any cancer was 16.4 per 1,000 per year. The HR of any cancer incidence with glucosamine treatment was 0.97 (95% CI 0.91-1.02) compared with non-users. For lung cancer, the HR with glucosamine treatment was 0.99 (95% CI 0.83-1.18), whereas it was 1.11 (95% CI 0.93-1.33) for colorectal cancer, 1.07 (95% CI 0.93-1.23) for breast cancer in women, and 1.03 (95% CI 0.88-1.22) for prostate cancer. CONCLUSION: In this large, real-world study of patients with osteoarthritis, designed to emulate a trial, treatment with glucosamine did not reduce the incidence of cancer. This finding reinforces that previous studies, not based on glucosamine initiators, were affected by selection bias. Our study does not support the prescription of glucosamine to prevent cancer in patients with osteoarthritis.
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AIM: Non-randomized studies on bariatric surgery have reported large reductions in mortality within 6-12 months after surgery compared with non-surgical patients. It is unclear whether these findings are the result of bias. STUDY DESIGN AND SETTING: We searched PubMed to identify all non-randomized studies investigating the effect of bariatric surgery on all-cause mortality compared with non-surgical patients. We assessed these studies for potential confounding and time-related biases. We conducted bias analyses to quantify the effect of these biases. RESULTS: We identified 21 cohort studies that met our inclusion criteria. Among those, 11 were affected by immortal time bias resulting from the misclassification or exclusion of relevant follow-up time. Five studies were subject to potential confounding bias because of a lack of adjustment for body mass index (BMI). All studies used an inadequate comparator group that lacked indications for bariatric surgery. Bias analyses to correct for potential confounding from BMI shifted the effect estimates towards the null [reported hazard ratio (HR): 0.78 vs. bias-adjusted HR: 0.92]. Bias analyses to correct for the presence of immortal time also shifted the effect estimates towards the null (adjustment for 2-year wait time: reported HR: 0.57 vs. bias-adjusted HR: 0.81). CONCLUSION: Several important sources of bias were identified in non-randomized studies of the effectiveness of bariatric surgery versus non-surgical comparators on mortality. Future studies should ensure that confounding by BMI is accounted for, considering the choice of the comparator group, and that the design or analysis avoids immortal time bias from the misclassification or exclusion.
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Hipoglicemiantes , Metformina , Neoplasias , Humanos , Metformina/uso terapêutico , Metformina/efeitos adversos , Incidência , Neoplasias/epidemiologia , Neoplasias/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Metanálise como Assunto , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologiaRESUMO
OBJECTIVE: To determine whether the combined use of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious renal events compared with either drug class alone among patients with type 2 diabetes, and to assess the effect of the combination on the individual components of major adverse cardiovascular events, heart failure, and all cause mortality. DESIGN: Population based cohort study using a prevalent new-user design, emulating a trial. SETTING: UK Clinical Practice Research Datalink linked to Hospital Episode Statistics Admitted Patient Care and Office for National Statistics databases. PARTICIPANTS: Two prevalent new-user cohorts were assembled between January 2013 and December 2020, with follow-up until the end of March 2021. The first cohort included 6696 patients who started GLP-1 receptor agonists and added on SGLT-2 inhibitors, and the second included 8942 patients who started SGLT-2 inhibitors and added on GLP-1 receptor agonists. Combination users were matched, in a 1:1 ratio, to patients prescribed the same background drug, duration of background drug, and time conditional propensity score. MAIN OUTCOME MEASURES: Cox proportional hazards models were fitted to estimate the hazard ratios and 95% confidence intervals of major adverse cardiovascular events and serious renal events, separately, comparing the GLP-1 receptor agonist-SGLT-2 inhibitor combination with the background drug, either GLP-1 receptor agonists or SGLT-2 inhibitors, depending on the cohort. Secondary outcomes included associations with the individual components of major adverse cardiovascular events (myocardial infarction, ischaemic stroke, cardiovascular mortality), heart failure, and all cause mortality. RESULTS: Compared with GLP-1 receptor agonists, the SGLT-2 inhibitor-GLP-1 receptor agonist combination was associated with a 30% lower risk of major adverse cardiovascular events (7.0 v 10.3 events per 1000 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and a 57% lower risk of serious renal events (2.0 v 4.6 events per 1000 person years; hazard ratio 0.43, 0.23 to 0.80). Compared with SGLT-2 inhibitors, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 29% lower risk of major adverse cardiovascular events (7.6 v 10.7 events per 1000 person years; hazard ratio 0.71, 0.52 to 0.98), whereas serious renal events generated a wide confidence interval (1.4 v 2.0 events per 1000 person years; hazard ratio 0.67, 0.32 to 1.41). Secondary outcomes generated similar results but with wider confidence intervals. CONCLUSIONS: In this cohort study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse cardiovascular events and serious renal events compared with either drug class alone.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Hipoglicemiantes , Inibidores do Transportador 2 de Sódio-Glicose , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Incidência , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Reino Unido/epidemiologiaRESUMO
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.
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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.
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Aspirina , Doença Pulmonar Obstrutiva Crônica , Humanos , Aspirina/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Incidência , Progressão da DoençaRESUMO
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.
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Diabetes Mellitus Tipo 2 , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Broncodilatadores , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Administração por Inalação , Quimioterapia Combinada , Antagonistas Muscarínicos/uso terapêutico , Nebulizadores e Vaporizadores , ComorbidadeRESUMO
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.
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Projetos de Pesquisa , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Observacionais como AssuntoRESUMO
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.
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Dor Crônica , Epilepsia , Neuralgia , Doença Pulmonar Obstrutiva Crônica , Humanos , Estudos de Coortes , Canadá , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Neuralgia/tratamento farmacológico , Neuralgia/complicaçõesRESUMO
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.
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Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Neoplasias Cutâneas , Humanos , Abatacepte/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/complicações , Produtos Biológicos/uso terapêutico , Incidência , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/epidemiologiaRESUMO
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.
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Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Infecções Oportunistas , Tuberculose , Humanos , Abatacepte/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/epidemiologia , Infecções Oportunistas/induzido quimicamente , Infecções Oportunistas/epidemiologia , Produtos Biológicos/efeitos adversos , Tuberculose/induzido quimicamente , Tuberculose/epidemiologia , MarketingRESUMO
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.
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Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Neoplasias Pulmonares , Linfoma , Humanos , Abatacepte/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Linfoma/induzido quimicamente , Linfoma/tratamento farmacológico , Marketing , Produtos Biológicos/uso terapêuticoRESUMO
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.