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1.
JAMA Netw Open ; 4(4): e215329, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33890993

RESUMO

Importance: Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes. Objective: To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations. Design, Setting, and Participants: This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020. Exposures: Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication. Main Outcomes and Measures: The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation. Results: Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses. Conclusions and Relevance: In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.

3.
J Alzheimers Dis ; 81(1): 329-338, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33780369

RESUMO

BACKGROUND: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer's disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor. OBJECTIVE: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD. METHODS: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed > 2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections. RESULTS: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12-30 years (OR, 1.11; 95% CI, 1.05-1.17). The risk did not increase with cumulative number of infections. CONCLUSION: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection.

4.
Arthritis Rheumatol ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33645906

RESUMO

OBJECTIVE: The treatment of gout with allopurinol is effective at reducing urate levels and the frequency of flares. Several observational studies reported important reductions in mortality with allopurinol use, with wide variations in results. The extent of bias in these studies, particularly time-related biases such as immortal time bias, is unclear. METHODS: We searched the literature to identify all observational studies reporting on the effect of allopurinol versus non-use on all-cause mortality. RESULTS: We identified 12 observational studies, of which three were affected by immortal time bias and three by immeasurable time bias, while the remaining six studies avoided these time-related biases. Reductions in all-cause mortality with allopurinol use were observed among the studies with immortal time bias, with a pooled hazard ratio of death associated with allopurinol of 0.71 (95% CI: 0.50-1.01) and those with immeasurable time bias (pooled hazard ratio 0.62; 95% CI: 0.56-0.67). The six studies that avoided these biases found a null effect of allopurinol on mortality (pooled hazard ratio 0.99; 95% CI: 0.87-1.11), though the lack of an analysis based on treatment adherence could have attenuated somewhat the effect. CONCLUSION: Observational studies are important to provide evidence from real-world data on medication effects. The observational studies reporting significantly decreased mortality with allopurinol use cannot be used as evidence, mainly because of time-related biases that tend to greatly exaggerate the potential benefit of treatments. The ALL-HEART randomised trial, currently underway, comparing allopurinol versus usual care, will provide reliable evidence on this major outcome of mortality.

5.
COPD ; 18(1): 1-8, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33569990

RESUMO

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.

6.
Am J Epidemiol ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33564823

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented effort to generate real-world evidence on the safety and effectiveness of various treatments. A growing number of observational studies evaluating the effects of certain drugs have been conducted, including several assessing whether hydroxychloroquine improves outcomes in infected individuals and whether renin-angiotensin-aldosterone system inhibitors have detrimental effects. We review and illustrate how immortal time bias and selection bias were present in several of these studies. Understanding these biases and how they can be avoided may prove important for future observational studies assessing the effectiveness and safety of potentially promising drugs during the COVID-19 pandemic.

7.
Semin Arthritis Rheum ; 51(1): 211-218, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385861

RESUMO

OBJECTIVE: Randomized controlled trials of the effectiveness of statins on rheumatic disease outcomes have shown limited or no benefit. On the other hand, observational studies have reported remarkable effectiveness of statins at reducing mortality in patients with rheumatic diseases. We evaluated these observational studies for the presence of immortal time bias, which tends to exaggerate the effectiveness of drugs by creating a survival advantage for exposed patients. METHODS: We searched PubMed for observational studies investigating the impact of statins in patients with common rheumatic diseases, including rheumatoid arthritis, osteoarthritis, lupus, ankylosing spondylitis, gout and systemic autoimmune diseases. Studies were included if estimates for all-cause mortality among statin users compared to non-users were reported. We evaluated each study for the presence of immortal time bias and estimated the impact of the bias on the published results. RESULTS: We found eight observational studies investigating the impact of statins on mortality among patients with rheumatic diseases. Four studies were affected by the classical variant of immortal time bias, while the others introduced immortal time into the comparator via random-calendar date assignment. The studies with the classical form of immortal time bias, which tends to exaggerate drug effectiveness, reported protective effects of statins on mortality ranging from 13% to 57% reductions. In contrast, immortal time bias through random-calendar date assignment, which tends to play down the effectiveness by introducing immortal time in the comparator, reported 16% to 37% reductions in mortality. CONCLUSION: Bias in observational studies may explain the discrepancy in findings with randomized controlled trials on the effectiveness of statins in patients with rheumatic diseases. Future observational studies will need to rely on incident and prevalent new-user designs that emulate randomized trials and avoid immortal time bias.

8.
Epidemiology ; 32(1): 94-100, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33009252

RESUMO

BACKGROUND: Regulatory agencies now recognize single-arm trials with external historical controls, particularly common in oncology, to assess promising treatments for rare or specific indications. When a new treatment indication depends on events over time, such as treatment failures, this design can introduce time-related biases in comparisons with external controls. METHODS: We describe two potential biases resulting from calendar time and choice of time zero. We illustrate these biases using simulated data, emulating those from a single-arm trial of the effectiveness of blinatumomab in treating relapsed or refractory acute lymphoblastic leukemia on the outcome of mortality. RESULTS: The trial compared 189 patients treated with blinatumomab with 1112 external historical control patients. First, calendar time was not concurrent, with the blinatumomab arm diagnosed during 2010-2014 and the control cohort during 1990-2013. The median survival under blinatumomab was 6.1 months compared with 3.3 months in the control arm, though for the latter it increased from 2.4 to 4.2 months over the 24-year period. Second, using the latest line of salvage treatment as cohort, entry for the control cohort introduces selection bias. The corresponding hazard ratio of death with blinatumomab compared with control was 0.56 (95% CI = 0.47, 0.67) but became 0.98 (95% CI = 0.83, 1.15) after redefining cohort entry by the matched line of salvage treatment rather than the latest line. CONCLUSION: While single-arm trials with external historical controls are gaining recognition, a proper understanding of time-related sources of bias is essential if such trials will be used to provide valid evidence for drug approval from regulatory agencies.

9.
Am J Epidemiol ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33124647

RESUMO

The prevalent new-user cohort design is useful to assess the effectiveness of a drug in the absence of an active comparator. Alternative approaches, particularly in the presence of informative censoring, include a variant of this design based on never-users of the study drug and the marginal structural Cox model approach. These were compared in assessing the effectiveness of proton pump inhibitors (PPI) on mortality in idiopathic pulmonary fibrosis using a cohort of patients with idiopathic pulmonary fibrosis identified from 2003-2016 in the UK's Clinical Practice Research Datalink. The cohort included 2944 patients, with 1916 initiating PPIs during follow-up and 2136 deaths (rate 25.8 per 100 person-years). The conventional prevalent new-user design found a hazard ratio (HR) of death associated with PPI use compared with non-use of 1.07 (95% confidence interval (CI) 0.94-1.22). The variant to the prevalent new-user design comparing with never-users found a HR of 0.82 (95% CI 0.73-0.91) while the marginal structural Cox model found a HR of 1.08 (95% CI 0.85-1.38). In conclusion, the marginal structural model and the conventional prevalent new-user design, both accounting for informative censoring, produced similar results. However, the prevalent new-user design variant based on never-users introduces selection bias and should be avoided.

10.
BMJ ; 370: m3342, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967856

RESUMO

OBJECTIVE: To compare the risk of cardiovascular events between sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors among people with type 2 diabetes in a real world context of clinical practice. DESIGN: Multi-database retrospective cohort study using a prevalent new user design with subsequent meta-analysis. SETTING: Canadian Network for Observational Drug Effect Studies (CNODES), with administrative healthcare databases from seven Canadian provinces and the United Kingdom, 2013-18. POPULATION: 209 867 new users of a SGLT2 inhibitor matched to 209 867 users of a DPP-4 inhibitor on time conditional propensity score and followed for a mean of 0.9 years. MAIN OUTCOME MEASURES: The primary outcome was major adverse cardiovascular events (MACE, a composite of myocardial infarction, ischaemic stroke, or cardiovascular death). Secondary outcomes were the individual components of MACE, heart failure, and all cause mortality. Cox proportional hazards models were used to estimate site specific adjusted hazards ratios and 95% confidence intervals, comparing use of SGLT2 inhibitors with use of DPP-4 inhibitors in an as treated approach. Site specific results were pooled using random effects meta-analysis. RESULTS: Compared with DPP-4 inhibitors, SGLT2 inhibitors were associated with decreased risks of MACE (incidence rate per 1000 person years: 11.4 v 16.5; hazard ratio 0.76, 95% confidence interval 0.69 to 0.84), myocardial infarction (5.1 v 6.4; 0.82, 0.70 to 0.96), cardiovascular death (3.9 v 7.7; 0.60, 0.54 to 0.67), heart failure (3.1 v 7.7; 0.43, 0.37 to 0.51), and all cause mortality (8.7 v 17.3; 0.60, 0.54 to 0.67). SGLT2 inhibitors had more modest benefits for ischaemic stroke (2.6 v 3.5; 0.85, 0.72 to 1.01). Similar benefits for MACE were observed with canagliflozin (0.79, 0.66 to 0.94), dapagliflozin (0.73, 0.63 to 0.85), and empagliflozin (0.77, 0.68 to 0.87). CONCLUSIONS: In this large observational study conducted in a real world clinical practice context, the short term use of SGLT2 inhibitors was associated with a decreased risk of cardiovascular events compared with the use of DPP-4 inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov NCT03939624.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reino Unido , Adulto Jovem
11.
Chest ; 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32882251

RESUMO

BACKGROUND: Gastroesophageal reflux disease is a common comorbidity in idiopathic pulmonary fibrosis (IPF) and may contribute to its progression. Anti-acid therapy, such as proton pump inhibitors (PPIs), has been considered as a potential treatment option for IPF. The evidence for this treatment comes from several observational studies affected by time-related bias. RESEARCH QUESTION: Is use of PPIs in patients with IPF associated with a reduction in all-cause mortality, respiratory-related mortality, and respiratory-related hospitalization? STUDY DESIGN AND METHODS: We used the UK Clinical Practice Research Datalink to identify a cohort of patients diagnosed with IPF between 2003 and 2016. The prevalent new-user cohort design was used to match patients initiating PPIs with non-users using time-conditional propensity scores, with follow-up until death or end of observation. Cox models were used to estimate hazard ratios (HR) and 95% CIs of death and of a respiratory-related hospitalization, correcting for informative censoring by weighted inverse probability. RESULTS: There were 1,852 PPI users who were matched to 1,852 non-users identified among the cohort of patients with IPF, with 2.8 years' median survival (mortality rate, 26.7 per 100 per year). The HR of all-cause mortality with PPI use was 1.07 (95% CI, 0.94-1.22), relative to non-use. For respiratory-related mortality, the HR was 1.10 (95% CI, 0.94-1.28) and 1.00 (95% CI, 0.86-1.16) for respiratory-related hospitalizations. INTERPRETATION: PPI use was not associated with lower mortality or hospitalization incidence in this large study conducted among patients with IPF within a real-world setting of clinical practice and designed to avoid biases affecting previous studies. PPIs may not be as beneficial in treating IPF as suggested by some studies and conditionally recommended in treatment guidelines.

13.
Pharmacoepidemiol Drug Saf ; 29(9): 1101-1110, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32783283

RESUMO

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.

14.
Chest ; 158(2): 832-833, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32768072
16.
Artigo em Inglês | MEDLINE | ID: mdl-32722764

RESUMO

AIMS: To determine the risk of fracture associated with direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients with nonvalvular atrial fibrillation (NVAF), accounting for cumulative duration of use. METHODS AND RESULTS: Using Quebec administrative healthcare databases, we formed a cohort of all patients aged 40 years or older newly diagnosed with NVAF, who filled a first prescription for DOACs or VKAs between 2011 and 2014. Exposure was modelled as a time-varying variable whereby patients were considered unexposed up to 180 days of cumulative duration of use (to account for a biologically meaningful exposure) and exposed thereafter. The final cohort included 10,306 new users of DOACs and 15,357 new users of VKAs. After propensity score-based fine stratification and weighting, use of DOACs for 180 days or greater was associated with a 35% decreased risk of fracture (crude incidence rates 7.5 vs 15.3 per 1000 person-years; adjusted hazard ratio [HR] 0.65, 95%CI 0.46 - 0.91) compared to VKA duration ≥ 180 days. DOACs use was also associated with a lower risk of hip fracture (HR 0.51, 95%CI 0.31 - 0.86) compared with VKAs. There was no difference in the rate of fracture for shorter duration of use (HR 1.10; 95%CI 0.79 - 1.53). The risk was not modified by age, sex, chronic kidney disease, osteoporosis, history of fracture or falls. CONCLUSION: Prolonged use of DOACs is associated with a lower risk of fracture compared with VKAs. These findings support the first-line recommendation for DOACs in patients with NVAF.

17.
Eur Respir J ; 55(6)2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32366483

RESUMO

Inhaled corticosteroids (ICS) combined with bronchodilators can reduce the frequency of exacerbations in some patients with chronic obstructive pulmonary disease (COPD). There is evidence, however, that ICS are frequently used in patients where their benefit has not been established. Therefore, there is a need for a personalised approach to the use of ICS in COPD and to consider withdrawal of ICS in patients without a clear indication. This document reports European Respiratory Society recommendations regarding ICS withdrawal in patients with COPD.Comprehensive evidence synthesis was performed to summarise all available evidence relevant to the question: should ICS be withdrawn in patients with COPD? The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles. The evidence synthesis was discussed and recommendations formulated by a committee with expertise in COPD and guideline methodology.After considering the balance of desirable and undesirable consequences, quality of evidence, and feasibility and acceptability of interventions, the guideline panel made: 1) conditional recommendation for the withdrawal of ICS in patients with COPD without a history of frequent exacerbations, 2) strong recommendation not to withdraw ICS in patients with blood eosinophil counts ≥300 eosinophils·µL-1 and 3) strong recommendation to treat with one or two long-acting bronchodilators if ICS are withdrawn.A conditional recommendation indicates that there was uncertainty about the balance of desirable and undesirable consequences of the intervention, and that well-informed patients may make different choices regarding whether to have or not have the specific intervention.

18.
Chest ; 157(5): 1395-1396, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32386643
20.
Chest ; 157(4): 1045-1046, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32252914
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