Article

Suissa SImmortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf 16: 241-249

Article

Suissa SImmortal time bias in observational studies of drug effects. Pharmacoepidemiol Drug Saf 16: 241-249

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Abstract

Recent observational studies suggest that various drugs are remarkably effective at reducing morbidity and mortality. These cohort studies used a flawed approach to design and data analysis which can lead to immortal time bias. We describe the bias from 20 of these studies and illustrate it by showing that unrelated drugs can be made to appear effective at treating cardiovascular disease (CVD). The illustration used a cohort of 3315 patients, with chronic obstructive pulmonary disease (COPD), identified from the Saskatchewan Health databases, hospitalised for CVD and followed for up to a year. We used the biased approach to assess the effect of two medications, namely gastrointestinal drugs (GID) and inhaled beta-agonists (IBA), both unknown to be effective in CVD, on the risk of all-cause mortality. We also estimated these effects using the proper person-time approach. Using the inappropriate approach, the rates ratios of all-cause death were 0.73 (95%CI: 0.57-0.93), with IBA and 0.78 (95%CI: 0.61-0.99), with GID. These rate ratios became 0.98 (95%CI: 0.77-1.25) and 0.94 (95%CI: 0.73-1.20), respectively, with the proper person-time analysis. Several recent observational studies used a flawed approach to design and data analysis, leading to immortal time bias, which can generate an illusion of treatment effectiveness. Observational studies, with surprising beneficial drug effects should be re-assessed to account for this source of bias.

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... This allows for the comparison of individuals newly initiated on the medication against those who were never initiated. Immortal-time bias can be minimized by analyzing the data so that time of eligibility for treatment and time when treatment is initiated is the same [25]. ...
... This analysis may give rise to bias by baseline confounders and post-baseline, time-varying confounders. An approach suggested by Danaei and colleagues used a pooled logistic regression model in order to estimate the effect of treatment [25]. They used inverse probability weighting to create a population where treatment is independent of prognostic factors history. ...
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Post-traumatic stress disorder (PTSD) is a prevalent mental disorder marked by psychological and behavioral changes. Currently, there is no consensus of preferred antipsychotics to be used for the treatment of PTSD. We aim to discover whether certain antipsychotics have decreased suicide risk in the PTSD population, as these patients may be at higher risk. A total of 38,807 patients were identified with a diagnosis of PTSD through the ICD9 or ICD10 codes from January 2004 to October 2019. An emulation of randomized clinical trials was conducted to compare the outcomes of suicide-related events (SREs) among PTSD patients who ever used one of eight individual antipsychotics after the diagnosis of PTSD. Exclusion criteria included patients with a history of SREs and a previous history of antipsychotic use within one year before enrollment. Eligible individuals were assigned to a treatment group according to the antipsychotic initiated and followed until stopping current treatment, switching to another same class of drugs, death, or loss to follow up. The primary outcome was to identify the frequency of SREs associated with each antipsychotic. SREs were defined as ideation, attempts, and death by suicide. Pooled logistic regression methods with the Firth option were conducted to compare two drugs for their outcomes using SAS version 9.4 (SAS Institute, Cary, NC, USA). The results were adjusted for baseline characteristics and post-baseline, time-varying confounders. A total of 5294 patients were eligible for enrollment with an average follow up of 7.86 months. A total of 157 SREs were recorded throughout this study. Lurasidone showed a statistically significant decrease in SREs when compared head to head to almost all the other antipsychotics: aripiprazole, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone (p < 0.0001 and false discovery rate-adjusted p value < 0.0004). In addition, olanzapine was associated with higher SREs than quetiapine and risperidone, and ziprasidone was associated with higher SREs than risperidone. The results of this study suggest that certain antipsychotics may put individuals within the PTSD population at an increased risk of SREs, and that careful consideration may need to be taken when prescribed.
... Immortal time typically occurs when there is a delay or waiting period between cohort entry and the time of the first prescription, which is falsely accounted for as drug-exposed time. Hence, exposed participants must survive the initial time period to receive treatment if they are not assigned to the unexposed cohort [5,6]. Exclusion or misclassification of observation time often leads to immortal time bias and consequently to artificial overestimation or underestimation of drug effectiveness [6,7]. ...
... Hence, exposed participants must survive the initial time period to receive treatment if they are not assigned to the unexposed cohort [5,6]. Exclusion or misclassification of observation time often leads to immortal time bias and consequently to artificial overestimation or underestimation of drug effectiveness [6,7]. ...
Article
Background and objective Observational studies may provide valuable evidence on real-world causal effects of drug effectiveness in patients with Coronavirus Disease 2019 (COVID-19). Since patients are usually observed from hospital admission to discharge and drug initiation starts during hospitalization, advanced statistical methods are needed to account for time-dependent drug exposure, confounding, and competing events. Our objective is to evaluate the observational studies on the three common methodological pitfalls in time-to-event analyses: immortal time bias, confounding bias, and competing risk bias. Methods We performed a systematic literature search on October 23, 2020, in the PubMed database to identify observational cohort studies that evaluated drug effectiveness in hospitalized patients with COVID-19. We included articles published in four journals: The British Medical Journal (The BMJ), the New England Journal of Medicine (NEJM), the Journal of the American Medical Association (JAMA), and The Lancet as well as their sub-journals. Results Overall, out of 255 articles screened, eleven observational cohort studies on treatment effectiveness with drug exposure-outcome associations were evaluated. All studies were susceptible to one or more types of bias in the primary study analysis. Eight studies had a time-dependent treatment. However, the hazard ratios were not adjusted for immortal time in the primary analysis. Even though confounders presented at baseline have been addressed in nine studies, time-varying confounding caused by time-varying treatment exposure and clinical variables was less recognized. Only one out of eleven studies addressed competing event bias by extending follow-up beyond patient’s discharge. Conclusions In the observational cohort studies on drug effectiveness for treatment of COVID-19 published in four high impact journals, the methodological biases were concerningly common. Appropriate statistical tools are essential to avoid misleading conclusion and receive a better understanding of potential treatment effects.
... The individual NSAIDs, diclofenac, ibuprofen and naproxen, were compared against the Sporadic NSAID group (2) or ASA group (4) in all analysis depending whether they had less than or more than 90 DDD of ASA exposure respectively. To examine the incidence of PD between the groups we performed a timedependent Cox regression model to correct for immortal time bias [15]. Immortal time, the time until an individual reached 90 or 365 of cumulative DDD exposure, was classified as follow-up time for the control group. ...
... If one does not correct for the immortal time bias, this could give an increased survival advantage. One way to correct for immortal time is to classify the time before exposure as unexposed and as exposed thereafter [15]. Time-dependent Cox regression analysis is a good method to control for immortal time in the exposed group [17,18]. ...
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Objective Whether use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of incident Parkinson’s disease (PD) remains unresolved. Here, we employed the Norwegian Prescription Database to examine whether NSAID use is associated with a lower incidence of PD. Methods We compared the incidence of PD among users of NSAIDs in a population-based retrospective study using the Norwegian Prescription Database from 2004 to 2017. In total 7580 PD patients were identified using dopaminergic therapy over time as proxy for PD diagnosis. Analyses were performed with minimum 90 and 365 defined daily dose (DDD) NSAID exposure, respectively. Time-dependent Cox regression model and a binary logistic regression analysis with a 5-year lag until PD diagnosis were performed for all NSAIDs. Results There was overall no decrease in incidence of PD among NSAID users compared to controls. Using a minimum of 90 or 365 DDD threshold of exposure produced similar results. Analysis of individual NSAIDs did not show difference in PD incidence compared to controls Age-specific incidence rates of PD were comparable to reported age-specific incidence rates in previous studies. Interpretation Our findings provide no evidence that cumulative high exposure to NSAIDs affects the risk of developing PD.
... 12 Chidambaram et al noted that the FEV1 capacity increased from 88% to 99% while patients were in hospital. 16 Yet the studies in this review were also consistent in reporting the deterioration of PFT upon the patients' transition to outpatient care. In the cohort study completed by Carroll et al, 5/11 patients needed to be treated with inhaled corticosteroids (ICS) in the outpatient setting for residual abnormalities, all of which experienced reduced capacity on follow up. ...
... In Section 3.1, a link between earlier admission of CS therapy and duration of hospitalization was acknowledged in the study completed by Layden et al. 10 However, it is important to consider the possible effect of the "Immortal Time Bias" noted by Suissa in the study of pharmacoepidemiology, where the outcome under study could not occur due to the exposure definition. 16 In Section 3.4, analysis of the case series completed by Corcoran et al, 11 demonstrated a small to medium effect of corticosteroids in reducing the length of hospitalization. This however, can be confounded by factors including; differing practices between hospitals, patient specifics and more. ...
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Background: Worldwide, vaping prevalence rates for youth are on the rise. Electronic cigarette and vaping product use associated lung injury (EVALI), is associated with increased use and requires effective treatment such as corticosteroid therapy. Objective To examine literature for analysis of corticosteroid treatment, including clinical course specifics and effect on the improvement of EVALI patient outcomes (aged 15-30). Methods Adhering to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines, confirmed or probable cases of EVALI in patients aged 15-30 were identified using PubMed, Scopus, Ovid, Web of Science and The Cochrane Library databases. Studies included were published in English, with e-cigarette exposure 90 days before symptom onset and assessed at least two outcomes on patient follow up. Studies excluded were patients outside of the defined age range or with comorbidities. Quality and risk of bias assessment was performed on the final 8 studies, all of which were published in 2020. Results As presented across all studies in the current review, corticosteroid (CS) treatment for adolescent and young adult EVALI patients results in improved patient outcomes, both in documented patient notes and in improved Pulmonary Function Test (PFT) capacity, association with shorter hospitalization durations and less required oxygen support on discharge. Conclusion Intravenous (IV) or oral corticosteroids, including prednisolone and methylprednisolone were prescribed in majority of cases with many cases noting improvement of outcomes due to clinical intervention. Specifics of the courses, including duration, dosage and length of taper varied significantly between cases and studies. Improvement of outcomes as measured through PFT following CS intervention was noted, but deterioration in the outpatient setting also occurred. Funding Laidlaw Undergraduate Research Scholarship.
... , 42,60 Cox model,12,46,61,62 Poisson model,62 and others. Modeling treatment status as real-time and timevarying has been considered as the gold standard for handling IMT as it provides almost unbiased estimation if done properly.21,46 ...
... , 42,60 Cox model,12,46,61,62 Poisson model,62 and others. Modeling treatment status as real-time and timevarying has been considered as the gold standard for handling IMT as it provides almost unbiased estimation if done properly.21,46 ...
Preprint
Epidemiologic studies and clinical trials with a survival outcome are often challenged by immortal time (IMT), a period of follow-up during which the survival outcome cannot occur because of the observed later treatment initiation. It has been well recognized that failing to properly accommodate IMT leads to biased estimation and misleading inference. Accordingly, a series of statistical methods have been developed, from the simplest by including or excluding IMT to various weightings and the more recent sequential methods. Our literature review suggests that the existing developments are often "scattered", and there is a lack of comprehensive review and direct comparison. To fill this knowledge gap and better introduce this important topic especially to biomedical researchers, we provide this review to comprehensively describe the available methods, discuss their advantages and disadvantages, and equally important, directly compare their performance via simulation and the analysis of the Stanford heart transplant data. The key observation is that the time-varying treatment modeling and sequential trial methods tend to provide unbiased estimation, while the other methods may result in substantial bias. We also provide an in-depth discussion on the interconnections with causal inference.
... Detection bias was minimized since EPO's precise regulation for these subjects to be covered by the national health insurance program. Furthermore, patients would only be included if they survived more than 90 days as landmark time during the follow-up period to avoid immortal bias (Suissa, 2007). ...
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Background: Chronic kidney disease (CKD) has become a worldwide burden due to the high co-morbidity and mortality. Diabetic nephropathy (DN) is one of the leading causes of CKD, and pre-dialysis is one of the most critical stages before the end-stage renal disease (ESRD). Although Chinese herbal medicine (CHM) use is not uncommon, the feasibility of using CHM among pre-dialysis DN patients remains unclear. Materials and methods: We analyzed a population-based cohort, retrieved from Taiwan’s National Health Insurance Research Database, to study the long-term outcome of using CHM among incident pre-dialysis DN patients from January 1, 2004, to December 31, 2007. All patients were followed up to 5 years or the occurrence of mortality. The risks of all-cause mortality and ESRD were carried out using Kaplan-Meier and competing risk estimation, respectively. Further, we demonstrated the CHM prescriptions and core CHMs using the Chinese herbal medicine network (CMN) analysis. Results: A total of 6,648 incident pre-dialysis DN patients were analyzed, including 877 CHM users and 5,771 CHM nonusers. With overlap weighing for balancing all accessible covariates between CHM users and nonusers, we found the use of CHM was associated with lower all-cause mortality (0.22 versus 0.56; log-rank test: p -value <0.001), and the risk of mortality was 0.42 (95% CI: 0.36–0.49; p -value <0.001) by adjusting all accessible covariates. Further, the use of CHM was associated with a lower risk of ESRD (cause-specific hazard ratio: 0.59, 95%CI: 0.55–0.63; p -value <0.001). Also, from the 5,901 CHM prescriptions, we found Ji-Sheng-Shen-Qi-Wan, Astragalus mongholicus Bunge or ( Astragalus membranaceus (Fisch.) Bge.) , Plantago asiatica L. ( or Plantago depressa Willd.), Salvia miltiorrhiza Bunge, and Rheum palmatum L. ( or Rheum tanguticum (Maxim. ex Regel) Balf. , Rheum officinale Baill.) were used as core CHMs for different CHM indications. Use of core CHMs was associated with a lower risk of mortality than CHM users without using core CHMs. Conclusions: The use of CHM seemed feasible among pre-dialysis DN patients; however, the beneficial effects still need to be validated by well-designed clinical trials.
... In this study, patients using statins before breast cancer diagnosis were excluded to ensure that no modulating effects of pre-diagnostic statin use on tumour characteristics and tumour stage had occurred as this would impact clinical outcome. Further, the new-user study design attempts to mimic a trial study design [37] and excludes prevalent statin users who have tolerated statin treatment until study entry, which is essential as studies investigating prevalent and ongoing drug use has produced misleading findings [38,39]. Moreover, many breast cancer patients have existing comorbidities at diagnosis [40], which is associated with poorer survival [41]. ...
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Background Accumulating evidence suggests that statins have a beneficial effect on breast cancer prognosis. Previous studies have reported a positive association between statin use and breast cancer survival; however, the relationship between statin use and patterns of breast cancer recurrence remains unclear. Patients and methods We identified all Malmö Diet and Cancer Study (MDCS) participants diagnosed with incident invasive breast cancer between 2005 and 2014. The follow-up period began at breast cancer diagnosis and continued until the first invasive breast cancer recurrence event, death, emigration or the end of the follow-up (June 8, 2020). We estimated incidence rates (IRs) of recurrence and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for disease recurrence to compare post-diagnosis statin users with non-users. Results The final study cohort consisted of 360 eligible patients with a median follow-up of 8.6 years. Overall, there were 71 recurrences in 2932 total person-years. According to statin use, there were 14 recurrences in 595 person-years among statin users, and 57 recurrences in 2337 person-years in non-users. Statin use was associated with a reduced risk of breast cancer recurrence (HRadj = 0.88 [95% CI: 0.82–0.96]). Regarding the pattern of recurrence, statin use was associated with a reduced risk of distant recurrence (HRadj = 0.86 [95% CI: 0.80–0.94]) but not loco-regional recurrence (HRadj = 0.97 [95% CI: 0.87–1.08]). Conclusion In the MDCS, statin use was associated with a reduced risk of distant breast cancer recurrence, whereas no association between statin use and loco-regional breast cancer recurrence was found. This site-based difference in disease recurrence may be explained by statin's inhibition of epithelial-mesenchymal transition.
... Additionally, the exclusion of acupuncture, moxibustion, or manual therapy is helpful to avoid confounding bias with possible influence on CHM prescriptions. Moreover, because there is no recommendation for initiation of CHM treatments, we found that the mean interval from diagnosis of DKD to initiation of CHM use was about 240 days among CHM users (data not shown), and immortal time bias may occur [51,52]. To overcome this problem, a 1-year landmark design was used to avoid the potential immortal time bias. ...
Article
Background Diabetic kidney disease (DKD) is one of the most crucial causes of chronic kidney disease (CKD). However, the efficacy and biomedical mechanisms of Chinese herbal medicine (CHM) for DKD in clinical settings remain unclear. Objective This study aimed to analyze the outcomes of DKD patients with CHM-only management and the possible molecular pathways of CHM by integrating web-based biomedical databases and real-world clinical data. MethodsA total of 152,357 patients with incident DKD from 2004 to 2012 were identified from the National Health Insurance Research Database (NHIRD) in Taiwan. The risk of mortality was estimated with the Kaplan-Meier method and Cox regression considering demographic covariates. The inverse probability of treatment weighting was used for confounding bias between CHM users and nonusers. Furthermore, to decipher the CHM used for DKD, we analyzed all CHM prescriptions using the Chinese Herbal Medicine Network (CMN), which combined association rule mining and social network analysis for all CHM prescriptions. Further, web-based biomedical databases, including STITCH, STRING, BindingDB, TCMSP, TCM@Taiwan, and DisGeNET, were integrated with the CMN and commonly used Western medicine (WM) to explore the differences in possible target proteins and molecular pathways between CHM and WM. An application programming interface was used to assess these online databases to obtain the latest biomedical information. ResultsAbout 13.7% (20,947/131,410) of patients were classified as CHM users among eligible DKD patients. The median follow-up duration of all patients was 2.49 years. The cumulative mortality rate in the CHM cohort was significantly lower than that in the WM cohort (28% vs 48%, P
... Recently, a pooled summary analysis of several landmarks, i.e., the landmark supermodel, has been advocated to smooth the effect of the time-varying intermediate event [14,15]. The naïve method [16] and exclusion method [6] are also alternative methods to handle guarantee time bias. But both of them are not recommended based on the results of simulation studies [4]. ...
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Background In follow-up studies, the occurrence of the intermediate event may influence the risk of the outcome of interest. Existing methods estimate the effect of the intermediate event by including a time-varying covariate in the outcome model. However, the insusceptible fraction to the intermediate event in the study population has not been considered in the literature, leading to effect estimation bias due to the inaccurate dataset. Methods In this paper, we propose a new effect estimation method, in which the susceptible subpopulation is identified firstly so that the estimation could be conducted in the right population. Then, the effect is estimated via the extended Cox regression and landmark methods in the identified susceptible subpopulation. For susceptibility identification, patients with observed intermediate event time are classified as susceptible. Based on the mixture cure model fitted the incidence and time of the intermediate event, the susceptibility of the patient with censored intermediate event time is predicted by the residual intermediate event time imputation. The effect estimation performance of the new method was investigated in various scenarios via Monte-Carlo simulations with the performance of existing methods serving as the comparison. The application of the proposed method to mycosis fungoides data has been reported as an example. Results The simulation results show that the estimation bias of the proposed method is smaller than that of the existing methods, especially in the case of a large insusceptible fraction. The results hold for small sample sizes. Besides, the estimation bias of the new method decreases with the increase of the covariates, especially continuous covariates, in the mixture cure model. The heterogeneity of the effect of covariates on the outcome in the insusceptible and susceptible subpopulation, as well as the landmark time, does not affect the estimation performance of the new method. Conclusions Based on the pre-identification of the susceptible, the proposed new method could improve the effect estimation accuracy of the intermediate event on the outcome when there is an insusceptible fraction to the intermediate event in the study population.
... First, this is a retrospective observational study. Therefore, the presence of immortal time bias in observational studies could lead to the overestimation of the results (56,57). In the present study, time-dependent Cox model analysis was performed to minimize immortal time bias (20). ...
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Backgrounds: Influenza vaccination could decrease the risk of major cardiac events in patients with chronic obstructive pulmonary disease (COPD). However, the effects of the vaccine on decreasing the risk of ventricular arrhythmia (VA) development in such patients remain unclear. Methods: We retrospectively analyzed the data of 18,658 patients with COPD (≥55 years old) from the National Health Insurance Research Database from January 1, 2001, to December 31, 2012. After a 1:1 propensity score matching by the year of diagnosis, we divided the patients into vaccinated and unvaccinated groups. Time-varying Cox proportional hazards regression was applied to assess the time to event hazards of influenza vaccination exposure. Results: The risk of VA occurrence was significantly lower in the vaccinated group during influenza season and all seasons [adjusted hazard ratio (aHR): 0.62, 95% CI: 0.41–0.95; aHR: 0.69, 95% CI: 0.44–1.08; and aHR: 0.65, 95% CI: 0.48–0.89, in the influenza season, non-influenza season, and all seasons, respectively]. Among patients with CHA2DS2-VASc scores (conditions and characteristics included congestive heart failure, hypertension, diabetes, stroke, vascular disease, age, and sex) of 2–3, receiving one time and two to three times of influenza vaccination were associated with lower risk of VA occurrence in all seasons (aHR: 0.28, 95% CI: 0.10–0.80; aHR: 0.27, 95% CI: 0.10–0.68, respectively). Among patients without stroke, peripheral vascular disease, and diabetes, a lower risk of VA occurrence after receiving one and two to three times vaccination was observed in all seasons. Among patients with a history of asthma and patients without a history of heart failure, ischemic heart disease, angina hypertension, or renal failure, a significantly lower risk of VA occurrence was observed after the first time of vaccination in all seasons. Conclusions: Influenza vaccination may be associated with lower risks of VA among patients with COPD aged 55–74. Further investigation is still needed to resolve this clinical question.
... Observational studies suffer also from time-related bias [29,30]. Particularly in the studies that assessed overall survival in patients at risk for HCC recurrence, immortal-time bias is strongly related to the heterogeneity in the time of starting observation, such as the first complete radiological response to HCC treatment or the start of DAA treatment (Fig. 1). ...
Article
Direct-acting antivirals (DAAs) revolutionized the treatment of chronic HCV-related disease achieving high rates of sustained virological response (SVR), even in advanced cirrhosis, with modest contraindications and a low rate of adverse events. However, the risk of hepatocellular carcinoma (HCC) persists due to the underlying chronic liver disease, both in patients with and without history of HCC. Although some initial studies reported a presumptive high risk of HCC development after DAA therapy, more recent observational studies denied this hypothesis. The residual risk for HCC occurrence after HCV eradication seems being progressively reduced with time after SVR. Data on recurrence of HCC after DAA exposure in patients with previously treated carcinoma initially reported conflicting results too, this being also due to methodological issues in analysis of retrospective multicenter studies. Anyway, current evidence support the use of DAAs in HCV-HCC treated patients, without any higher risk of tumor recurrence linked to antiviral therapy. Less effort has been made to evaluate the efficacy of DAA therapy in patients with untreated active HCC and it has been questioned whether a lower rate of SVR would be obtained among patients with active HCC. Studies conducted in this perspective concluded that HCC status does not influence the likelihood to obtain SVR with DAAs, making DAAs appropriate in HCC-active patients. As far as survival is concerned, recent studies conducted in cirrhotic HCV-related early-stage HCC found that DAAs improved overall survival, a benefit probably due to the reduction of hepatic decompensation.
... It is very important to avoid immortal time bias in observational studies. Immortal time bias is caused when a cohort study is designed so follow-up includes a period in which participants in the exposed group cannot experience the outcome [34]. Thalassemia is an inherited disease, and the individual index date is the date of birth regardness of the time of thalassemia was diagnosed; therefore, there was no immortal bias in this study. ...
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Introduction Patients with hemoglobinopathies have been reported to have higher rates of pulmonary complications. Few studies have investigated the association between thalassemia and asthma in children. Methods We used the data of one million individuals randomly selected from the Registry for Beneficiaries of the National Health Insurance Research Database. One thalassemic child was matched with four control children without thalassemia according to sex, birth year, birth season, prematurity, and previous enteroviral infection. Results A total of 800 hundred thalassemic children and 3200 controls were included. Children with thalassemia had higher rates of developing asthma (41.81 vs 25.70 per 1000 person-years, P < 0.001) than the non-thalassemia controls with an adjusted hazard ratio of 1.37 (95% confidence interval [CI] = 1.19–1.58). Boys in the thalassemia cohort had a significantly higher adjusted incidence hazard ratio (IRR) of asthma than those in the non-thalassemia cohort (adjusted IRR = 1.45, 95% CI = 1.02–1.73). The risk of atopic and nonatopic asthma was higher in the thalassemia cohort than in the non-thalassemia cohort (IRR = 1.3, 1.61, respectively). Conclusions Children with thalassemia were more likely to develop asthma. More attention should be paid to the early diagnosis of asthma and prevention of asthma attacks.
... First, immortal time bias arises from misspecification of exposures so that there is a span of cohort follow-up during which, because of exposure definition, the outcome under study cannot occur. 10 Second, prevalent user bias occurs when risk of an outcome changes over time in a population exposed to a drug treatment. 11 Finally, the population and treatment in the clinical trials were very precisely defined and unlikely to be typical of the general population. ...
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Objective Observational studies have suggested a beneficial effect of taking statins on frequency of chronic obstructive pulmonary disease (COPD) exacerbations. However, clinical trials of statins in people with COPD did not confirm those results. This study aimed to investigate this association using a methodological approach, which reduces the biases associated with some previous observational study designs. Design Retrospective cohort study comparing new-users of statins with non-users. Setting General practices in England contributing to the Clinical Practice Research Datalink in 2007–2017, with linkage to data on Hospital Episode Statistics inpatient episodes. Participants 48 124 people with COPD, aged over 40 years, who had not been prescribed statin in the previous year. Exposure Participants became new-users of statins at their first prescription for a statin during follow-up. They were then assumed to remain statin users. Statin users were compared with non-users. Outcomes Primary outcomes were COPD exacerbation, or severe exacerbation requiring hospitalisation. Secondary outcomes were death from any cause (for comparison with other studies) and urinary tract infection (negative-control). Maximum follow-up was 3 years. Adjusted HR were calculated using time-dependent Cox regression. The Andersen-Gill model was used for recurrent exacerbations. Covariates included demographic variables, variables related to COPD severity, cardiovascular comorbidities as time-dependent variables, and other comorbidities at baseline. Results 7266 participants became new-users of statins over an average 2.5 years of follow-up. In total, 30 961 people developed an exacerbation, 8110 severe exacerbation, 3650 urinary tract infection and 5355 died. Adjusted HR (95% CI) in statin users compared with non-users were first exacerbation 1.01 (0.96–1.06), severe exacerbation 0.92 (0.84–0.99), number of exacerbations 1.00 (0.97–1.04), urinary tract infection 1.10 (0.98–1.23) and death 0.63 (0.57–0.70). Conclusions In this study of health records from a Primary Care database, statin use in people with COPD was not associated with a lower risk of COPD exacerbation.
... The risk of CVD was calculated based on either CVD diagnoses in NPR (model 1) or CVD prescription drugs in NPDR (model 2). Only BC patients without any CVD diagnosis in NPR 5 years prior to the index date were included in model 1, and only BC patients without a history of CVD prescription drugs 5 years prior to the index date were included in model 2. We included time dependent exposure dummies that classified the patients' time-to-event' as unexposed until treatment began to avoid immortal time bias [21]. BC patients who had received surgery, but not the cancer treatment in question (chemotherapy, radiation therapy, antibody therapy or hormonal therapy) were used as reference. ...
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Background There is increasing concern about cardiovascular disease (CVD) after breast cancer (BC). The aim of this study was to estimate the prevalence of different types of CVD in women diagnosed with BC compared to cancer-free controls as well as the incidence of CVD after BC diagnosis . Methods We performed a cohort study based on data from national registries covering the entire Danish population. We followed 16,505 cancer-naïve BC patients diagnosed from 2003 to 2007 5 years before and up to 10 years after BC diagnosis compared to 165,042 cancer-free controls. Results We found that 15.6% of BC patients were registered with at least one CVD diagnosis in hospital records before BC diagnosis. Overall, BC patients and controls were similar with regard to CVD comorbidity before BC diagnosis. After BC diagnosis, the incidence of all CVD diagnoses combined was significantly higher in BC patients than controls up to approximately 6 years after the index date (BC diagnosis). After 10 years, 28% of both BC patients and controls (without any CVD diagnosis up to 5 years before the index date) had at least one CVD diagnosis according to hospital records. However, the incidence of heart failure, thrombophlebitis/thrombosis and pulmonary heart disease including pulmonary embolism remained higher in BC patients than controls during the entire 10-year follow-up period. After 10 years, 2.7% of BC patients compared to 2.5% of controls were diagnosed with heart failure, 2.7% of BC patients compared to 1.5% of controls were diagnosed with thrombophlebitis/thrombosis, and 1.5% of BC patients compared to 1.0% of controls were diagnosed with pulmonary heart disease according to hospital records. Furthermore, we found that the risk of heart failure and thrombophlebitis/thrombosis was higher after chemotherapy. Conclusions Focus on CVD in BC patients is important to ensure optimum treatment with regard to BC as well as possible CVD. Strategies to minimise and manage the increased risk of heart failure, thrombophlebitis/thrombosis and pulmonary heart disease including pulmonary embolism in BC patients are especially important.
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2-10% of patients with vascular liver disease (VLD) have paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab reduces complement-mediated haemolytic activity in PNH. This study aimed at assessing the impact of eculizumab on VLD outcome. Retrospective cohort of PNH patients, in Valdig registry having VLD diagnosed between 1997 and 2019. Eculizumab was the exposure of interest. Studied outcomes were death, venous thrombosis, bleeding, arterial ischemic event, infection, and liver-related complications. We compared survival and new thrombotic events from PNH/VLD cohort to Envie2 non-PNH cohort. Sixty-two patients (33 women), median age 35 years (28-48), median follow-up VLD diagnosis 4.7 years (1.2-9.5) were included. Clone size was 80% (70-90), median hemoglobin concentration 10.0 g/dL (8-11), LDH 736 IU (482-1744). Forty-two patients (68%) had eculizumab, median exposure time was 40.1 [9.3-72.6] months. Mortality was significantly lower in exposed versus non-exposed period: 2.6 vs 8.7 per 100 (PY), IRR 0.29 95%CI (0.1-0.9), p = 0.035. Thrombosis recurrence occurred less frequently during exposure to eculizumab: 0.5 vs 2.8 per 100 PY, IRR 0.22 (0.07-0.64). Other secondary end-points (bleeding, arterial ischemic lesions, infection and liver complications) were less common during exposure to eculizumab, although not reaching statistical significance. Six years-thrombosis free survival was 70%, 95%IC [0.60-0.83] for PNH cohort and 83%, 95%IC [0.70-1.00] for non PNH Envie 2 patients, (p < 0.001). In conclusion, patients with PNH and VLD are at higher risk of recurrent thrombosis than non-PNH patients. Eculizumab is significantly associated with a lower mortality and less thrombotic recurrence in patients with PNH and VLD. This article is protected by copyright. All rights reserved.
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Health authorities throughout the world have regulations for requesting additional research in the post-approval setting. This chapter focuses on the regulations in the USA and European Union (EU). The history of post-approval studies can be traced through changing regulations enforced by the US Food and Drug Administration (FDA) and the EU European Medicines Agency (EMA). Post-approval studies are either clinical trials (interventional) or observational (non-interventional) studies. Choosing a study design may be influenced by the strengths and weaknesses of the design options and available data sources. Imposed post-approval studies are reviewed for compliance by the regulatory agencies. For clinical trials that are ongoing at the time of approval, often these are classified as post-marketing commitment (PMC) in the USA or post-authorization measure (PAM) in the EU. Findings of these trials can be submitted to the health authorities for addition to the prescribing information. The FDA and EMA both track progress on PMC/PMRs and PAMs, respectively. Post-approval studies are necessary to continually gather data on the safety and effectiveness of approved drugs. These studies are regulated by health authorities, included in registries (e.g., ClinicalTrials.gov, ENCePP), and tracked to completion. This chapter reviews the history of the regulations, terminology, study designs, and systematic reviews of the published post-approval studies.
Article
Despite its low efficacy, chemotherapy with dacarbazine remains an option in metastatic melanoma patients after failure of immune checkpoint inhibitors (ICI) ± targeted therapy. Some observations suggested an increased efficacy of chemotherapy in melanoma or lung cancer patients previously treated with ICI; we aimed to evaluate the efficacy of dacarbazine in a controlled-group study of patients pre-treated or not with ICI. We retrospectively collected data from all consecutive patients treated with dacarbazine for advanced cutaneous melanoma without brain metastasis, in our skin cancer centre between June 2006 and September 2019. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rates (ORR), overall survival (OS) and safety of dacarbazine. Among 72 patients, 17 (23.6%) received dacarbazine after ICI and 55 (76.3%) without prior ICI. Despite less favourable prognostic factors in patients ICI-pre-treated, median PFS was 4.27 months (range 0.89–43.69) in this group versus 2.04 months (range 1.25–39.25) P = 0.03 in non-ICI-pre-treated patients; ORR were 35.3% and 12.7%, respectively. The median OS and the occurrence of adverse events were similar in both groups. Dacarbazine seems to offer a short-lived benefit in patients with progressive advanced disease despite ICI (±targeted therapy), and could be an alternative before considering best supportive care.
Article
Objective Several observational studies reported that allopurinol, an effective treatment for gout, was associated with important reductions in cardiovascular events, with calls for large randomized trials, though some results were conflicting. We assessed the extent of time-related biases in these observational studies. Methods We searched the literature for all observational studies reporting on allopurinol and cardiovascular events, focusing on two time-related biases. Time-related confounding bias results from studies using cohorts of patients all exposed to allopurinol, with comparisons based on episodes of allopurinol discontinuation, where confounding factors are not updated over follow-up time. Immortal time bias arises from the exposure misclassification of periods of cohort follow-up during which the outcome under study cannot occur. Results We identified 12 studies, of which eight were affected by time-related confounding bias or immortal time bias, while the remaining four studies avoided these biases. The studies affected by time-related confounding bias resulted in significant reductions in the incidence of cardiovascular events with allopurinol use (pooled hazard ratio 0.88; 95% CI: 0.85-0.92), as did the studies affected by immortal time bias (pooled hazard ratio 0.79; 95% CI: 0.72-0.87). The four studies that avoided these biases resulted in a pooled hazard ratio of 1.07 (95% CI: 0.91-1.25). Conclusions Observational studies reporting significantly reduced incidence of cardiovascular events with allopurinol use were affected by time-related biases. Overall, studies that avoided these biases did not find a protective effect. The ALL-HEART randomised trial will provide important and accurate evidence on the potential effectiveness of allopurinol on cardiovascular outcomes.
Article
Background: Proton pump inhibitors (PPIs) have been used to treat Barrett's esophagus (BE), but there seems to be insufficient evidence that PPIs can prevent esophageal adenocarcinoma (EAC) and high grade dysplasia (HGD). This study aimed to evaluate the effects of PPIs in BE patients. Methods: PubMed and EMBASE were systematically searched. Stata13 and trial sequential analysis (TSA) software were used to carry out related statistics. Pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Results: Using PPIs to reduce the incidence of EAC and HGD has not been confirmed (OR, 0.61; 95% CI, 0.29-1.26). The pooled results of three cohort studies reported that PPIs use was protective (OR 0.48; 95% CI, 0.33-0.70). But the pooled results of five case-control study indicating PPIs use does not prove this protective effect (OR 0.73; 95% CI, 0.21-2.48). On pooled analysis of 4 US studies 2 Netherlands, protective effect on development of EAC and HGD was noted (OR, 0.59; 95% CI, 0.43-0.80) and (OR, 0.16; 95% CI, 0.03-0.75). Conclusions: According to the Meta analysis and TSA of existing studies, the protective effect of PPIs on the progression of BE patients to EAC and/or HGD has not been confirmed. TSA shows that more patients are needed before a clear conclusion can be reached.
Article
Time‐to‐event data such as time to death are broadly used in medical research and drug development to understand the efficacy of a therapeutic. For time‐to‐event data, right censoring (data only observed up to a certain point of time) is common and easy to recognize. Methods that use right censored data, such as the Kaplan–Meier estimator and the Cox proportional hazard model, are well established. Time‐to‐event data can also be left truncated, which arises when patients are excluded from the sample because their events occur before a specific milestone, potentially resulting in an immortal time bias. For example, in a study evaluating the association between biomarker status and overall survival, patients who did not live long enough to receive a genomic test were not observed in the study. Left truncation causes selection bias and often leads to an overestimate of survival time. In this tutorial, we used a nationwide electronic health record‐derived de‐identified database to demonstrate how to analyze left truncated and right censored data without bias using example code from SAS and R.
Article
Governments and health insurers often make funding decisions based on health gains from randomised controlled trials. These decisions are inherently uncertain because health gains in trials may not translate to practice owing to differences in the population, treatment use and setting. Post-market analysis of real-world data can provide additional evidence but estimates from standard matching methods may be biased when unobserved characteristics explain whether a patient is treated and their outcomes. We propose a new untreated matching approach that can reduce this bias. Our approach utilises the outcomes of contemporaneous untreated patients to improve the matching of treated and historical control patients. We assess the performance of this new approach compared to standard matching using a simulation study and demonstrate the steps required using a funding decision for prostate cancer treatments in Australia. Our simulation study shows that our new matching approach eliminates nearly all bias when unobserved treatment selection is related to outcomes, and outperforms standard matching in most scenarios. In our empirical example, standard matching overestimated survival by 15% (95% confidence interval 2–34) compared to our untreated matching approach. The health gains estimated using our approach were slightly lower than expected based on the trial evidence, but we also found evidence that in practice prescribers ceased prior therapies earlier, treated a more vulnerable population and continued treatment for longer. Our untreated matching approach offers researchers a new tool for reducing uncertainty in healthcare funding decisions using real-world data.
Article
Observational studies in critical care medicine offer a popular and practical approach to questions of treatment effectiveness. Although observational research is widely understood to be susceptible to design and interpretation challenges, one well-described source of bias - immortal time bias (ITB) - is frequently present yet often overlooked. ITB may be introduced by study design oversights or mishandled during data analysis. When present, ITB can create inappropriate estimates of the benefit or harm of an exposure or intervention. Studies examining treatments in critically ill patients may be particularly susceptible to ITB, with consequences for clinical adoption and design and initiation of randomized trials. In this Critical Care Perspective, we illustrate the persistent problem of ITB in observational research using recent studies of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy in patients with sepsis and septic shock. Of the eight studies examined, none contained enough design or reporting elements to rule out the presence of ITB. To mitigate the influence of ITB in future observational studies, we present a novel checklist to help readers assess the features of study design, analysis, and reporting that introduce ITB or obscure its presence. We recommend that commonly used tools designed to evaluate observational research studies should include an ITB assessment.
Article
Importance: Biologics and targeted therapies, such as apremilast, are efficient treatments to manage moderate to severe psoriasis. More information about the risk of serious infection is needed for the newest treatment options in a real-world setting. Objective: To assess the risk of serious infection among biologics and apremilast used to treat psoriasis, with etanercept as the comparator. Design, setting, and participants: This nationwide cohort study from France involved data from the National Health Data System covering approximately 99% of the French population. All adults with psoriasis, defined as receiving at least 2 prescriptions of a topical vitamin D derivative within a 2-year period, registered in the database between January 1, 2008, and May 31, 2019, were eligible. The study population included those who were new users of biologic agents or apremilast (ie, without any prescriptions of a biologic or apremilast during the previous year). Patients with HIV infection or a history of cancer, transplant, or serious infection were excluded. End of follow-up was January 31, 2020. Main outcome measures: The primary end point was a serious infection in a time-to-event analysis using propensity score-weighted Cox proportional hazards regression models, estimating weighted hazard ratios (wHRs) and 95% CIs. Results: A total of 44 239 new users of biologic treatment were identified (mean [SD] age, 48.4 [13.8] years; 22 866 [51.7%] men; median follow-up, 12 months [interquartile range, 7-24 months]). A total of 29 618 (66.9%) were prescribed a tumor necrosis factor inhibitor first, 6658 (15.0%) an interleukin (IL) 12/23 inhibitor, 4093 (9.3%) an IL-17 inhibitor, 526 (1.2%) an IL-23 inhibitor, and 3344 (7.6%) apremilast. The total number of serious infections was 1656, and the overall crude incidence rate was 25.0 (95% CI, 23.8-26.2) per 1000 person-years. The most frequent serious infections were gastrointestinal infections (645 patients [38.9%]). After adjusting for time-dependent covariables, risk of serious infections was higher for new users of adalimumab (wHR, 1.22; 95% CI, 1.07-1.38) or infliximab (wHR, 1.79; 95% CI 1.49-2.16) vs etanercept, whereas ustekinumab was associated with a lower risk of having a serious infection (wHR, 0.79; 95% CI, 0.67-0.94). Risk of serious infections was not increased for new users of IL-17 and the IL-23 inhibitor guselkumab or apremilast vs etanercept. Risk of serious infections was increased with concomitant nonsteroidal anti-inflammatory drugs or systemic corticosteroids. Conclusions and relevance: In this cohort study of individuals with moderate to severe psoriasis, risk of serious infections was increased in new users of infliximab and adalimumab vs etanercept, whereas ustekinumab users had lower risk of having a serious infection but not new users of IL-17 and IL-23 inhibitors or apremilast. Other observational studies are needed to confirm results for the most recent drugs.
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Studies that generate real-world evidence on the effects of medical products through analysis of digital data collected in clinical practice provide key insights for regulators, payers, and other healthcare decision-makers. Ensuring reproducibility of such findings is fundamental to effective evidence-based decision-making. We reproduce results for 150 studies published in peer- reviewed journals using the same healthcare databases as original investigators and evaluate the completeness of reporting for 250. Original and reproduction effect sizes were positively correlated (Pearson’s correlation = 0.85), a strong relationship with some room for improvement. The median and interquartile range for the relative magnitude of effect (e.g., hazard ratiooriginal/ hazard ratioreproduction) is 1.0 [0.9, 1.1], range [0.3, 2.1]. While the majority of results are closely reproduced, a subset are not. The latter can be explained by incomplete reporting and updated data. Greater methodological transparency aligned with new guidance may further improve reproducibility and validity assessment, thus facilitating evidence-based decision-making. Study registration number: EUPAS19636.
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Real-world Evidence (RWE), the understanding of treatment effectiveness in clinical practice generated from longitudinal patient-level data from the routine operation of the healthcare system, is thought to complement evidence on the efficacy of medications from RCTs. RWE studies follow a structured approach: (1) A design layer decides on the study design, which is driven by the study question and refined by a medically informed target population, patient-informed outcomes, and biologically informed effect windows. Imagining the randomized trial we would ideally perform before designing an RWE study in its likeness reduces bias; the new-user active comparator cohort design has proven useful in many RWE studies of diabetes treatments. (2) A measurement layer transforms the longitudinal patient-level data stream into variables that identify the study population, the pre-exposure patient characteristics, the treatment, and the treatment-emergent outcomes. Working with secondary data increases the measurement complexity compared to primary data collection that we find in most RCTs. (3) An analysis layer focuses on the causal treatment effect estimation. Propensity score analyses have gained in popularity to minimize confounding in healthcare database analyses. Well-understood investigator errors, like immortal time bias, adjustment for causal intermediates, or reverse causation, should be avoided. To increase reproducibility of RWE findings, studies require full implementation transparency. This article integrates state-of-the-art knowledge on how to conduct and review RWE studies on diabetes treatments to maximize study validity and ultimately increased confidence in RWE-based decision making.
Article
The use of big data containing millions of primary care medical records provides an opportunity for rapid research to help inform patient care and policy decisions during the first and subsequent waves of the coronavirus disease 2019 (COVID-19) pandemic. Routinely collected primary care data have previously been used for national pandemic surveillance, quantifying associations between exposures and outcomes, identifying high risk populations, and examining the effects of interventions at scale, but there is no consensus on how to effectively conduct or report these data for COVID-19 research. A COVID-19 primary care database consortium was established in April 2020 and its researchers have ongoing COVID-19 projects in overlapping data sets with over 40 million primary care records in the United Kingdom that are variously linked to public health, secondary care, and vital status records. This consensus agreement is aimed at facilitating transparency and rigor in methodological approaches, and consistency in defining and reporting cases, exposures, confounders, stratification variables, and outcomes in relation to the pharmacoepidemiology of COVID-19. This will facilitate comparison, validation, and meta-analyses of research during and after the pandemic.
Article
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.
Article
Background Alcohol use disorder (AUD) reduces the health of soldiers and the readiness of the Armed Forces. It remains unknown if engagement in substance use treatment in the Military Health System improves retention in the military. Methods The sample consisted of active duty soldiers returning from an Afghanistan/Iraq deployment in fiscal years 2008-2010 who received an AUD diagnosis within 150 days of completing a post-deployment health re-assessment survey (n = 4,726). A Heckman probit procedure was used to examine predictors of substance use treatment initiation and engagement in accordance with Healthcare Effectiveness Data and Information Set (HEDIS) criteria. Cox proportional hazard modeling was used to examine the association between treatment engagement and retention, defined as a negative separation for a non-routine cause (e.g., separation due to misconduct, poor performance, disability) from the military in the two years following the index AUD diagnosis. Results 40% of soldiers meeting HEDIS AUD criteria initiated and 24% engaged in substance use treatment. Among soldiers diagnosed with AUD, meeting criteria for treatment engagement was associated with a significantly higher hazard of having a negative separation compared to soldiers who did not engage in treatment. Conclusions Rates of initiation and engagement in substance use treatment for post-deployment AUD were relatively low. Soldiers with AUD who engaged in substance use treatment were more likely to have a negative separation from the military than soldiers with AUD who did not engage. Our findings imply that in the study cohort, treatment did not mitigate negative career consequences of AUD.
Article
Many real‐word evidence (RWE) studies that utilize existing healthcare data to evaluate treatment effects incur substantial, but avoidable bias from methodologically flawed study design; however, the extent of preventable methodological pitfalls in current RWE is unknown. To characterize the prevalence of avoidable methodological pitfalls with potential for bias in published claims‐based studies of medication safety or effectiveness, we conducted an English‐language search of PubMed for articles published from January 1, 2010 to May 20, 2019 and randomly selected 75 studies (10 case‐control and 65 cohort studies) that evaluated safety or effectiveness of cardiovascular, diabetes, or osteoporosis medications using US health insurance claims. General and methodological study characteristics were extracted independently by two reviewers and potential for bias was assessed across 9 bias domains. Nearly all studies (95%) had at least one avoidable methodological issue known to incur bias and 81% had potentially at least one of the four issues considered major due to their potential to undermine study validity: time‐related bias (57%), potential for depletion of outcome‐susceptible individuals (44%), inappropriate adjustment for postbaseline variables (41%), or potential for reverse causation (39%). Median number of major issues per study was 2 (interquartile range [IQR], 1 to 3) and was lower in cohort studies with a new‐user, active‐comparator design (median 1, IQR 0 to1) than in studies of prevalent users and a non‐user comparator (median 3, IQR 3 to 4). Recognizing and avoiding known methodological study design pitfalls could substantially improve the utility of RWE and confidence in its validity.
Article
Evidence suggests that Ras-related C3 botulinum toxin substrate 1 (Rac1) might be a target in atherosclerotic disease (AD). We hypothesize that due to their ability to inhibit Rac1, thiopurines are associated with a lower risk of AD. We fit a time-dependent cox proportional hazards model estimating the hazard of AD among a national cohort of US veterans with inflammatory bowel disease. Patients exposed to thiopurines had a 7.5% lower risk of AD (HR = 0.925; 95% CI = (0.87–0.984)) compared to controls. The propensity score weighted analysis reveals thiopurine exposure reduces the risk of AD by 6.6% (HR = 0.934; 95% CI = (0.896–0.975)), compared to controls. Further exploration and evaluation of Rac1 inhibition as a target for AD is warranted.
Article
PURPOSE Late breast cancer (BC) recurrence (ie, ≥ 10 years after primary diagnosis) may have a more favorable prognosis than earlier recurrence. We investigated the risk of BC death after late recurrence, identified prognostic factors, and compared survival after early and late recurrence. METHODS Using the Danish Breast Cancer Group and other nationwide databases, we identified women with early or late BC recurrence during 2004-2018, who were alive 6 months after recurrence. We followed them until BC death, death from other causes, emigration, 10 years, or December 31, 2018, whichever came first. We calculated mortality rates (MRs) per 1,000 person-years (PY) and cumulative BC mortality, for early versus late recurrence, and by characteristics of the primary tumor and the late recurrence. Using Cox regression, we calculated adjusted hazard ratios (HRs) for BC death, accounting for death from other causes as competing risks. RESULTS Among 2,004 patients with late recurrence, 721 died of BC with a median survival time of 10 years (MR = 84.8 per 1,000 PY; 10-year cumulative mortality = 50%). Among 1,528 patients with early recurrence, 1,092 BC deaths occurred with a median survival time of 4 years (MR = 173.9 per 1,000 PY; 10-year cumulative mortality = 72%). We observed a lower hazard of BC-specific death among patients who developed late compared with early recurrence (hazard ratio = 0.72; 95% CI, 0.62 to 0.85). Advanced stage at primary diagnosis, distant metastases, adjuvant treatment for locoregional recurrence, and systemic treatment for distant recurrence were associated with increased mortality after late recurrence. Breast-conserving surgery at primary diagnosis, locoregional recurrence, and surgery for recurrence were associated with lower mortality after late recurrence. CONCLUSION Patients with late recurrence had more favorable prognosis than patients with early recurrence. The localization of recurrent disease was the main prognostic factor for BC death.
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Background: Prior studies reported survival benefits from early initiation of adjuvant chemotherapy for stage III colon cancer, but this evidence was derived from studies that may be sensitive to time-related biases. Therefore, we aimed to estimate the effect of initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks on overall and disease-free survival among stage III colon cancer patients using a study design that helps address time-related biases. Methods: We used institutional registry data from JPS Oncology and Infusion Center, a Comprehensive Community Cancer Program. Eligible patients were adults aged < 80 years, diagnosed with first primary stage III colon cancer between 2011 and 2017, and received surgical resection with curative intent. We emulated a target trial with sequential eligibility. We subsequently pooled the trials and estimated risk ratios (RRs) along with 95% confidence limits (CL) for all-cause mortality and recurrence or death at 5-years between initiators and non-initiators of adjuvant chemotherapy ≤8 or ≤ 12 weeks using pseudo-observations and a marginal structural model with stabilized inverse probability of treatment weights. Results: Our study population comprised 222 (for assessing initiation ≤8 weeks) and 310 (for assessing initiation ≤12 weeks) observations, of whom the majority were racial/ethnic minorities (64-65%), or uninsured with or without enrollment in our hospital-based medical assistance program (68-71%). Initiation of adjuvant chemotherapy ≤8 weeks of surgical resection did not improve overall survival (RR for all-cause mortality = 1.04, 95% CL: 0.57, 1.92) or disease-free survival (RR for recurrence or death = 1.07, 95% CL: 0.61, 1.88). The results were similar for initiation of adjuvant chemotherapy ≤12 weeks of surgical resection. Conclusions: Our results suggest that the overall and disease-free survival benefits of initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks of surgical resection may be overestimated in prior studies, which may be attributable to time-related biases. Nevertheless, our estimates were imprecise and differences in population characteristics are an alternate explanation. Additional studies that address time-related biases are needed to clarify our findings.
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Background Immortal time bias is common in observational studies but is typically described for pharmacoepidemiology studies where there is a delay between cohort entry and treatment initiation. Methods This study used the Clinical Practice Research Datalink (CPRD) and linked national mortality data in England from 2000 to 2019 to investigate immortal time bias for a specific life-long condition, intellectual disability. Life expectancy (Chiang’s abridged life table approach) was compared for 33,867 exposed and 980,586 unexposed individuals aged 10+ years using five methods: (1) treating immortal time as observation time; (2) excluding time before date of first exposure diagnosis; (3) matching cohort entry to first exposure diagnosis; (4) excluding time before proxy date of inputting first exposure diagnosis (by the physician); and (5) treating exposure as a time-dependent measure. Results When not considered in the design or analysis (Method 1), immortal time bias led to disproportionately high life expectancy for the exposed population during the first calendar period (additional years expected to live: 2000–2004: 65.6 [95% CI: 63.6,67.6]) compared to the later calendar periods (2005–2009: 59.9 [58.8,60.9]; 2010–2014: 58.0 [57.1,58.9]; 2015–2019: 58.2 [56.8,59.7]). Date of entry of diagnosis (Method 4) was unreliable in this CPRD cohort. The final methods (Method 2, 3 and 5) appeared to solve the main theoretical problem but residual bias may have remained. Conclusions We conclude that immortal time bias is a significant issue for studies of life-long conditions that use electronic health record data and requires careful consideration of how clinical diagnoses are entered onto electronic health record systems.
Article
Objectives: We aimed to assess the risk of chemotherapy- and radiotherapy-related cognitive impairment in colorectal cancer patients. Methods: Medical use data of colorectal cancer patients were obtained from Korean National Health Insurance Database (NHID), 2004-2018. We randomly selected 40% of colorectal cancer patients (N=148,848). Cognitive impairment cases were defined as having one or more ICD-10 diagnostic codes for dementia or mild cognitive impairment. Patients aged 18 or younger, patients diagnosed with cognitive impairment before colorectal cancer diagnosis (N=8,225) and those who did not receive primary resection (N=45,320) were excluded. The effects of each chemotherapy regimen on cognitive impairment were estimated. We additionally estimated the effect of radiotherapy in rectal cancer patients. Time-dependent competing risk Cox regression was conducted to estimate overall and age-specific hazard ratios (HR) separately for colon and rectal cancer. Landmark analyses with different lag times were conducted as sensitivity analyses. Results: Chemotherapy did not increase the risk of cognitive impairment in colorectal cancer (colon cancer: HR=0.92, 95% CI 0.83-1.03; rectal cancer: HR=0.88, 95% CI 0.75-1.04). Radiotherapy was negatively associated with cognitive impairment in rectal cancer (HR=0.01, 95% CI 0.84-0.99). Heterogeneous direction of association by regimen combination was detected. Adverse cognitive effect of certain chemotherapy regimen was more prominent in elderly patients. Conclusion: Chemotherapy and radiotherapy did not increase the risk of cognitive impairment. Elderly patients with low cognitive reserve could be affected by adverse cognitive effects of chemotherapy. Folate administration showed protective effect against possible cognitive impairment.
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The highly lethal brain cancer glioblastoma (GBM) poses a daunting challenge because the blood-brain barrier renders potentially druggable amplified or mutated oncoproteins relatively inaccessible. Here, we identify sphingomyelin phosphodiesterase 1 (SMPD1), an enzyme that regulates the conversion of sphingomyelin to ceramide, as an actionable drug target in GBM. We show that the highly brain-penetrant antidepressant fluoxetine potently inhibits SMPD1 activity, killing GBMs, through inhibition of epidermal growth factor receptor (EGFR) signaling and via activation of lysosomal stress. Combining fluoxetine with temozolomide, a standard of care for GBM, causes massive increases in GBM cell death and complete tumor regression in mice. Incorporation of real-world evidence from electronic medical records from insurance databases reveals significantly increased survival in GBM patients treated with fluoxetine, which was not seen in patients treated with other selective serotonin reuptake inhibitor (SSRI) antidepressants. These results nominate the repurposing of fluoxetine as a potentially safe and promising therapy for patients with GBM and suggest prospective randomized clinical trials.
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Background When including data from an external control arm to estimate comparative effectiveness, there is a methodological choice of when to set “time zero,” the point at which a patient would be eligible/enrolled in a contemporary study. Where patients receive multiple lines of eligible therapy and thus alternative points could be selected, this issue is complex. Methods A simulation study was conducted in which patients received multiple prior lines of therapy before entering either cohort. The results from the control and intervention data sets are compared using 8 methods for selecting time zero. The base-case comparison was set up to be biased against the intervention (which is generally received later), with methods compared in their ability to estimate the true intervention effectiveness. We further investigate the impact of key study attributes (such as sample size) and degree of overlap in time-varying covariates (such as prior lines of therapy) on study results. Results Of the 8 methods, 5 (all lines, random line, systematically selecting groups based on mean absolute error, root mean square error, or propensity scores) showed good performance in accounting for differences between the line at which patients were included. The first eligible line can be statistically inefficient in some situations. All lines (with censoring) cannot be used for survival outcomes. The last eligible line cannot be recommended. Conclusions Multiple methods are available for selecting the most appropriate time zero from an external control arm. Based on the simulation, we demonstrate that some methods frequently perform poorly, with several viable methods remaining. In selecting between the viable methods, analysts should consider the context of their analysis and justify the approach selected. Highlights There are multiple methods available from which an analyst may select “time zero” in an external control cohort. This simulation study demonstrates that some methods perform poorly but most are viable options, depending on context and the degree of overlap in time zero across cohorts. Careful thought and clear justification should be used when selecting the strategy for a study.
Article
Purpose: This study aimed to determine whether the use of drugs in the treatment of inflammatory bowel disease is related to the risk of colorectal cancer using a Cox proportional hazards model with the landmark method to minimize immortal time bias. Materials and methods: This study was conducted as national cohort-based study using data from Korea's Health Insurance Corporation. Newly diagnosed patients with inflammatory bowel disease from 2006 to 2010 were monitored for colorectal cancer until 2015. Hazard ratios and 95% confidence intervals were calculated and compared with the incidence of colorectal cancer with or without medications by applying various landmark points. Results: In patients with Crohn's disease, the prevention of colorectal cancer in the group exposed to immunomodulators was significant in the basic Cox model; however, the effect was not statistically significant in the model using the landmark method. The preventive effect of 5-aminosalicylic acid in patients with ulcerative colitis was significant in the basic and 6-month landmark point application models, but not in the remaining landmark application models. Conclusion: In patients with inflammatory bowel disease, the preventive effect of drug exposure on colorectal cancer varies depending on the application of the landmark method. Hence, the possibility of immortal time bias should be considered.
Article
BACKGROUND: The gap method is an extensively used approach for defining episodes of continuous treatment in pharmacoepidemiology. This method uses the amount of drug redeemed and researcher-defined temporal gaps to fill the interval between consecutive dates of redemption of prescriptions in the same treatment episode. The final scope is defining periods of continuous use of medication. There are strong pharmacological and epidemiological arguments for adding the gap at the end of each treatment episode. However, the evidence is scarce on the impact that such a practice has on measures of association. This study aims to compare the impact of adding or not adding the gap time to the end of a treatment episode on drug discontinuation and the incidence rate for a simulated outcome that occurred during an observation window. METHODS: We used a simulated dataset of 100 patients available in the R package AdhereR that contains 1080 redeemed prescriptions. A gap time of 90 days for building treatment episodes in an observational window of 365 days following the first redeemed prescription was used. Two approaches were used for defining treatment episodes that were named “gap+” and “gap-” and that respectively add and did not add the gap time at the end of the treatment episode. We simulated an outcome by using a baseline hazard function being exponential with scale parameter λ=0.5 and censoring at time t=365 days. We computed the incidence rate ratio for the simulated outcome between the two approaches. RESULTS: The 100 patients were followed for 183 days (interquartile range, IQR 50-365 days) and 273 days (IQR 140-365 days), respectively using “gap-” and “gap+”. During the first 100 days of the follow-up period, none of the patients was found to discontinue treatment with method “gap+” while 38 patients discontinued using the method “gap-”. The approach “gap+” exerted a higher incidence rate among the exposed for the simulated outcome (0.98 events/person-years) when compared to the “gap-” (0.82 events/person-years) during defined periods of continuous treatment. The incidence rate ratio for the simulated outcome was 1.20 (95% confidence interval: CI 0.72 – 2.02) among the exposed using the method “gap-” as the reference group. CONCLUSIONS: This study showed that not adding the gap at the end of the treatment episodes leads to an overestimation of drug discontinuation, particularly at the beginning of the observational window, and an underestimation of the incidence rate of a hypothetical outcome during the period of exposure to the medication.
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Background In the setting of kidney transplantation (KT), we assessed the efficacy of desensitization and compared the survival of desensitized patients (HLA-incompatible KT) with similarly sensitized patients receiving HLA-compatible KT or sensitized patients still on a waiting-list after adjusting for the usually unaccounted immortal time bias. Methods All patients in a French KT center on waiting list between August 1994 and December 2019 with a high level of sensitization (panel-reactive antibodies (PRA)≥80%) were included. The primary outcome was all-cause mortality. A time-varying covariate Cox survival model was used to account for the immortal time bias. A landmark analysis was used as a sensitivity analysis. Results During the study period, 326 patients with high PRA were followed, among which 147 (45%) remained on the waiting list at the time of last follow-up and 179 benefited from a KT. Thirty-six patients were desensitized, of which 30 received a kidney transplant, including 8 deceased kidney donors. There were no differences in mortality rates between desensitized KT patients, non-desensitized KT patients and waitlisted patients after adjusting for immortal time bias (HR=0.48, p=0.22). Death-censored graft survival was similar between desensitized and non-desensitized KT patients (HR=0.92, p=0.88 adjusting for donor age >65 years, donor status, and time on the waiting list). Mean estimated glomerular-filtration rate at 1 year post KT was similar for desensitized KT patients (53.3±21 vs. 53.6±21 mL/min/1.73m² for non-desensitized patients, p=0.95). Conclusions HLA-desensitization was effective for highly-sensitized patients and gave access to KT without detrimental effects on patient- or graft-survival rates.
Article
Background: Time-related biases, such as immortal time and time-window bias, frequently occur in pharmacoepidemiologic research. However, the prevalence of these biases in perinatal pharmacoepidemiology is not well understood. Objective: To describe the frequency of time-related biases in observational studies of medications commonly used during pregnancy (antibiotic, antifungal, and antiemetic drugs) via systematic review. Method: We searched Medline and EMBASE for observational studies published, between January 2013 and September 2020, examining the association between antibiotic, antifungal, or antiemetic drugs and adverse pregnancy outcomes, including spontaneous abortion, stillbirth, preterm delivery, small-for-gestational age, pre-eclampsia, and gestational diabetes. The proportion of studies with time-related biases was estimated overall and by type (immortal time bias, time-window bias). Results: Our systematic review included 20 studies (16 cohort studies, 3 nested case-control studies, and 1 case-control study), of which 12 examined antibiotic, 6 antiemetic, and 2 anti-fungal drugs. Eleven studies (55%) had immortal time bias due to the misclassification of unexposed, event-free person-time between cohort entry and exposure initiation as exposed. No included study had time-window bias. The direction of effect varied for both studies with and without time-related bias, with many studies reporting very wide confidence intervals around the effect estimates, thus making the direction of effect less interpretable. However, studies with time-related bias were more likely to show protective or null associations compared with studies without time-related bias. Conclusion: Time-related biases occur frequently in observational studies of drug effects during pregnancy. The use of appropriate study design and analytical approaches is needed to prevent time-related biases and ensure study validity.
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The impact of cycle completion rates of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer in real-world practice is unknown. We assessed its impact, and that of treatment modification, on 3-year cancer-specific mortality. 4147 patients with pathological stage III colon cancer undergoing major resection from 2014 to 2017 in the English National Health Service were included. Chemotherapy data came from linked national administrative datasets. Competing-risk regression analysis for 3-year cancer-specific mortality was performed according to completion of <6, 6-11, or 12 FOLFOX cycles, or < 4, 4-7, or 8 CAPOX cycles, adjusted for patient, tumour and hospital-level characteristics. Median age was 64 years. 32% of patients had at least one comorbidity. 42% of patients had T4 disease, and 40% N2 disease. Compared to completion of 12 FOLFOX cycles, cancer-specific mortality was higher in patients completing <6 cycles (sHR 2.17; 95% CI, 1.56 to 3.03) or 6-11 cycles (sHR 1.40; 95% CI, 1.09 to 1.78) (P < 0.001). Compared to completion of 8 CAPOX cycles, cancer-specific mortality was higher in patients completing <4 cycles (sHR 2.02; 95% CI 1.53 to 2.67) or 4-7 cycles (sHR 1.63; 95% CI 1.27 to 2.10) (P < 0.001). Dose reduction and early oxaliplatin discontinuation did not impact mortality in patients completing all cycles. Completion of all cycles of chemotherapy was associated with improved cancer-specific survival in real-world practice. Poor prognostic factors may have affected findings, however, patients completing <50% of cycles had poor outcomes. Clinicians may wish to facilitate completion with treatment modification in those able to tolerate it. This article is protected by copyright. All rights reserved.
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Several observational studies report decreased incidence of mortality and of exacerbations with aspirin use in patients with chronic obstructive pulmonary disease (COPD), with calls for a large randomized trial. Aspirin does have local and systemic pulmonary mechanisms of action that could make this drug beneficial in the treatment of COPD. However, the potential for biases in the observational studies has not been examined. We searched the literature for all observational studies reporting on the effect of aspirin in COPD patients on exacerbation and mortality. We reviewed the studies for the presence of time-related and other biases. We identified eight observational studies reporting an overall reduction in all-cause mortality or exacerbation with aspirin use of 21% (pooled rate ratio (RR) 0.79; 95% CI 0.71–0.86). We found two studies affected by immortal time bias (pooled RR 0.81; 95% CI 0.74–0.89), three studies affected by collider-stratification bias (pooled RR 0.66; 95% CI 0.55–0.79) and three that involved some exposure misclassification (pooled RR 0.85; 95% CI 0.78–0.92). Moreover, while adjusting for cardiovascular factors, six of the eight studies did not adjust for important markers of COPD severity and thus remain susceptible to confounding bias. In conclusion, all observational studies reporting on the effectiveness of aspirin on major outcomes of COPD are affected by biases known to exaggerate the effectiveness of a drug. As these studies cannot be used to support a beneficial effect for aspirin in COPD, it would be premature to consider a randomized trial to investigate this question until methodologically rigorous studies are available.
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Previous studies have reported lower fracture risks in patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). To investigate risk of fracture among statin users. Case-control study of data from the General Practice Research Database (GPRD). A total of 683 general clinical practices in the United Kingdom. Cases were 81 880 patients aged 50 years or older who had a fracture of the vertebrae, clavicle, humerus, radius/ulna, carpus, hip, ankle, or foot occurring between the enrollment date of their practice into the GPRD and July 1999, paired with 81 880 age-, sex-, and practice-matched controls. Risk of fracture in current users vs nonusers of statins. Odds ratios were estimated from conditional logistic regression and adjusted for smoking, medications and illnesses associated with fracture risk, and body mass index when known. The adjusted odds ratio (OR) for current use of statins compared with nonuse was 1.01 (95% confidence interval [CI], 0.88-1.16). For forearm, hip, and vertebral fractures, the ORs were 1.01 (95% CI, 0.80-1.27), 0.59 (95% CI, 0.31-1.13), and 1.15 (95% CI, 0.62-2.14), respectively. Relative to nonuse, a statin dosage of less than 20 mg/d (standardized to simvastatin) was associated with an adjusted OR of fracture of 1.13 (95% CI, 0.96-1.33); this OR was 1.07 (95% CI, 0.82-1.38) at dosages of 20 to 39.9 mg/d and 0.85 (95% CI, 0.47-1.53) at dosages of 40 mg/d or more. The adjusted OR was 0.71 (95% CI, 0.50-1.01) for statin use durations of 0 to 3 months, 1.31 (95% CI, 0.87-1.95) for durations of 3 to 6 months, 1.14 (95% CI, 0.82-1.58) for durations of 6 to 12 months, and 1.17 (95% CI, 0.99-1.40) for durations of more than 12 months. In this study, use of statins at dosages prescribed in clinical practice was not associated with a reduction in risk of fracture.
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Loss of bone mass accompanies the aging process and increases risk of fracture, particularly in women. The principal sites of osteoporotic fractures are the forearm, vertebral body, and hip.1 Pharmacological theory2 and in vivo3 and animal4 model observations have suggested that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may increase bone mineral density, raising the hope that these drugs also may be useful in reducing risk of osteoporotic fractures.
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Background: The benefits of lipid-lowering drug treatment for the secondary prevention of coronary heart disease have been well established by randomized, controlled trials. Nonetheless, the risk of events has not been compared directly for inhibitors of hydroxymethylglutaryl coenzyme A reductase (statins) and non-statin lipid-lowering drugs. Further, it remains uncertain whether patients in usual practice who are treated with lipid-lowering drugs after myocardial infarction (MI) gain a similar benefit with regard to the risk of cardiovascular events compared with patients in randomized, controlled trials. Objective: To assess the association between lipid-lowering drug therapies in usual clinical practice and the risk of cardiovascular events in patients with a first MI who were discharged alive from the hospital. Methods: An inception-cohort study was performed among 1956 enrollees of Group Health Cooperative who sustained an incident MI between July 1986 and December 1996 and survived for at least 6 months after hospitalization. Subjects with untreated low-density-lipoprotein cholesterol concentrations > 130 mg/dL or untreated total cholesterol concentrations >200 mg/dL were included. The median duration of follow-up after the first MI was 3.3 years. Medical record review was used to collect information on cardiovascular risk factors. Computerized pharmacy records were used to assess antihyperlipidemic drug use during the first 6 months after hospitalization. Results: Compared with 1263 subjects who did not receive lipid-lowering drug treatment, 373 subjects who received statins had a lower risk of recurrent coronary events (relative risk [RR] 0.59; 95% CI 0.39 to 0.89), stroke (RR 0.82; 95% CI 0.35 to 1.95), atherosclerotic cardiovascular mortality (RR 0.49; 95% CI 0.21 to 1.13), and any atherosclerotic cardiovascular event (RR 0.63; 95% CI 0.40 to 0.98). Among 320 subjects who used non-statin drug therapies, the RRs were 0.66 (95% CI 0.45 to 0.97) for recurrent coronary events, 0.95 (95% CI 0.46 to 1.95) for stroke, 0.68 (95% CI 0.35 to 1.32) for cardiovascular mortality, and 0.77 (95% CI 0.53 to 1.11) for any atherosclerotic cardiovascular event, compared with untreated hyperlipidemic patients. Conclusions: In this study of MI survivors, the use of lipid-lowering drug therapies after hospitalization was associated with a reduced risk of cardiovascular events. These results emphasize the importance of lipid-lowering drug treatment in patients with hyperlipidemia who survive a first MI.
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Previous studies have provided conflicting evidence as to the possible benefits of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD). Using the Saskatchewan healthcare databases subjects were identified who were aged > or = 55 yrs, initiating regular treatment for COPD but without any prior treatment for asthma. In the current nested case-control analysis, the authors concentrated on 1,742 subjects with a first hospitalisation for COPD after January 1, 1990 and examined whether the use of inhaled corticosteroids was associated with a change in the risk of a subsequent hospitalisation for COPD. The cases consisted of 846 patients with a subsequent hospitalisation for COPD. These were matched on age, time since the prior hospitalisation and use of other respiratory therapy to all possible person moments in the cohort without rehospitalisation. After further adjustment for comorbidity, sex, calendar year and intensity of other drug therapy, inhaled corticosteroids were not significantly associated with risk of a subsequent COPD hospitalisation. Even relatively high doses of inhaled corticosteroids, >800 microg of beclomethasone or the equivalent per day, were not associated with the risk of COPD hospitalisation. No reduction in chronic obstructive pulmonary disease exacerbations requiring hospitalisation, in relation to the use of inhaled corticosteroids, were observed.
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A possible association between lipid-lowering drug therapy and psychological well-being remains an issue of debate. To provide more information, we performed a nested case-control study to evaluate the effect of lipid-lowering drugs on depression and suicidal behavior. Within the United Kingdom General Practice Research Database, we identified all cases with newly treated depression needing a referral or hospitalization and all cases with first-recorded diagnosis of suicidal behavior between January 1, 1991, and December 31, 1999, from a study base that comprised all patients who were aged between 40 and 79 years and who had various exposures of interest. Each case was matched with up to 4 controls, randomly selected from the study base, on age, sex, medical practice, calendar time, and years since enrollment in the General Practice Research Database. A nested case-control analysis comprised 458 newly diagnosed cases of depression with 1830 controls, and 105 cases of suicidal behavior with 420 controls. The adjusted odds ratio of depression was 0.4 (95% confidence interval, 0.2-0.9) for current statin use, compared with hyperlipidemic nonuse. The adjusted odds ratios for other exposures were all around 1.0. None of the adjusted odds ratios for suicidal behavior were significantly different from unity. The use of statins and other lipid-lowering drugs is not associated with an increased risk of depression or suicide. On the contrary, individuals with current statin use may have a lower risk of developing depression, an effect that could be explained by improved quality of life due to decreased risk of cardiovascular events or more health consciousness in patients receiving long-term treatment.
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A recent observational study, which suggested that inhaled corticosteroids (ICS) with or without long-acting bronchodilators are effective at reducing all-cause mortality in chronic obstructive pulmonary disease (COPD) patients, may be subject to immortal time bias. This bias was assessed using a population-based cohort of 3,524 newly treated COPD patients from Saskatchewan, Canada, observed from 1990-1999. Regular users of bronchodilators or ICS were followed for 3 yrs, during which time 860 deaths occurred. Cox's proportional hazards model was used to compare the hierarchical intention-to-treat approach employed in the recent study, a technique subject to bias from two sources of immortal time, with the conventional intention-to-treat approach and the according-to-treatment approach. The adjusted rate ratio of death using the hierarchical intention-to-treat approach was 0.66 (95%) confidence interval (CI) 0.57-0.76) for ICS use relative to bronchodilator use, compared with 0.75 (95% CI 0.62-0.90) with the conventional intention-to-treat approach. Conversely, the rate ratio was 0.94 (95% CI 0.81-1.09) with the according-to-treatment approach, which accounts for both sources of immortal time. In this study, regular inhaled corticosteroid use in chronic obstructive pulmonary disease was not found to reduce all-cause mortality. Suggestion of this benefit from a previous observational study is the result of bias from unaccounted immortal time in its cohort design and analysis.
Article
BACKGROUND: Dementia affects an estimated 10% of the population older than 65 years. Because vascular and lipid-related mechanisms are thought to have a role in the pathogenesis of Alzheimer's disease and vascular dementia, we did an epidemiological study of the potential effect of HMGCoA (3 hydroxy-3methylglutaryl-coenzyme A) reductase inhibitors (statins) and other lipid-lowering agents on dementia. METHODS: We used a nested case-control design with information derived from 368 practices which contribute to the UK-based General Practice Research Database. The base study population included three groups of patients age 50 years and older: all individuals who had received lipid-lowering agents (LLAs); all individuals with a clinical diagnosis of untreated hyperlipidaemia; and a randomly selected group of other individuals. From this base population, all cases with a computer-recorded clinical diagnosis of dementia were identified. Each case was matched with up to four controls derived from the base population on age, sex, practice, and index date of case. FINDINGS: The study encompassed 284 cases with dementia and 1080 controls. Among controls 13% had untreated hyperlipidaemia, 11% were prescribed statins, 7% other LLAs, and 69% had no hyperlipidaemia or LLA exposure. The relative risk estimates of dementia adjusted for age, sex, history of coronary-artery disease, hypertension, coronary-bypass surgery and cerebral ischaemia, smoking and body mass index for individuals with untreated hyperlipidaemia (odds ratio 0.72 [95% CI 0.45-1.14]), or treated with nonstatin LLAs (0.96 [0.47-1.97], was close to 1.0 and not significant compared with people who had no diagnosis of hyperlipidaemia or exposure to other lipid-lowering drugs. The adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002). INTERPRETATION: Individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidaemia, or exposure to nonstatin LLAs. The available data do not distinguish between Alzheimer's disease and other forms of dementia.
Article
Objective. —To determine if anti-inflammatory treatment for asthma reduces the risk of asthma hospitalization.Design. —Retrospective cohort study.Setting. —A health maintenance organization (HMO) in eastern Massachusetts.Participants. —Members of the HMO who were identified during the period October 1991 through September 1994 as having a diagnosis of asthma using a computerized medical record system.Main Outcome. —Hospitalization for asthma.Results. —Of the 16 941 eligible persons, 742 (4.4%) were hospitalized for asthma. The overall relative risk (RR) of hospitalization among those who received inhaled steroids was 0.5 (95% confidence interval [CI], 0.4-0.6) after adjustment for β-agonist dispensing. Additional adjustment for age, race, other asthma medications, and amount and type of ambulatory care for asthma did not substantially affect the inverse relationship between use of inhaled steroids and hospitalization. Cromolyn was similarly associated with reduced risk, especially among children (RR,0.8;95%CI,0.7-0.9). In contrast, increasing β-agonist use was associated with increasing hospitalization risk even after adjustment for other factors and medications. The steroid-associated protection was most marked among individuals who received the largest amount of β-agonist.Conclusions. —Inhaled steroids and, to a lesser extent, cromolyn confer significant protection against exacerbations of asthma leading to hospitalization. These results support the use of inhaled steroids by individuals who require more than occasional β-agonist use to control asthma symptoms.
Article
Written for those who are familiar with the basic strategies of analytic epidemiology, Epidemiology: Beyond the Basics takes readers through a more rigorous discussion of key epidemiologic concepts and methods such as study design, measures of association, research assessment, and more. With real-life examples throughout, the book avoids complex statistical formulations and is an invaluable resource for intermediate students and practicing epidemiologists who wish to expand their knowledge of epidemiology and its role in the medical and public health sciences. The Third Edition offers a completely revamped page design that will make it easier for your students to navigate through the many charts, graphs, and mathematical formulas. It also offers expanded chapter exercises, new and updated references throughout, as well as coverage of some new topics including: * Over-diagnosis Bias (Ch. 4); * "Joint Presence of Two Factors that Interact as a Confounding Variable" (Ch. 6); * "Alternative Approaches for the Control of Confounding" (Ch. 7); * "Final Considerations" (Ch.8); * Decision trees (Ch. 10) This edition also offers an updated package of instructor materials including instructor's manual, PowerPoint lecture slides, and a test bank.
Article
Context Recent animal studies have suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) increase bone formation, volume, and density. It is unknown whether use of statins is associated with a decreased risk of fractures in humans.Objective To determine whether exposure to statins, fibrates, or other lipid-lowering drugs is associated with reduced bone fracture risk.Design Population-based, nested case-control analysis.Setting The UK-based General Practice Research Database (GPRD), comprising some 300 practices, with data collection from the late 1980s until September 1998.Subjects Within a base population of 91,611 individuals aged at least 50 years (28,340 individuals taking lipid-lowering drugs, 13,271 untreated individuals with a diagnosis of hyperlipidemia, and 50,000 randomly selected individuals without diagnosis of hyperlipidemia), we identified 3940 case patients who had a bone fracture and 23,379 control patients matched for age (±5 years), sex, general practice attended, calendar year, and years since enrollment in the GPRD.Main Outcome Measures Use of statins, fibrates, or other lipid-lowering drugs in case patients vs control patients.Results After controlling for body mass index, smoking, number of physician visits, and corticosteroid and estrogen use, current use of statins was associated with a significantly reduced fracture risk (adjusted odds ratio [OR], 0.55; 95% confidence interval [CI], 0.44-0.69) compared with nonuse of lipid-lowering drugs. Current use of fibrates or other lipid-lowering drugs was not related to a significantly decreased bone fracture risk (adjusted OR, 0.87; 95% CI, 0.70-1.08 and adjusted OR, 0.76; 95% CI, 0.41-1.39, respectively).Conclusions This study suggests that current exposure to statins is associated with a decreased risk of bone fractures in individuals age 50 years and older. This finding has a potentially important public health impact and should be confirmed further in controlled prospective trials. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia.1- 6 In addition to the ability of statins to decrease serum cholesterol levels, recent studies in animals showed that these agents have pharmacologic effects on bones. Mundy et al7 recently reported substantial increases in bone formation and trabecular bone volume in female rats after 5 weeks of oral simvastatin administration. Additional animal studies indicated that statins may decrease the severity of steroid-induced osteonecrosis.8- 9 These results from animal studies were partly supported in a cross-sectional study by Bauer et al10 in older women taking lipid-lowering agents (mainly lovastatin). Preliminary results of this small study suggested that statin use may be accompanied by increased hip bone mineral density, thereby potentially lowering the risk of hip fractures. Furthermore, Chung et al11 suggested in a recent study that statins may increase femur mineral density in men with type 2 diabetes mellitus. It currently is not known whether the observed effects on bone density have clinical relevance in preventing bone fractures in patients treated with statins. If this is the case, elderly patients with hyperlipidemia who are also at increased risk of developing osteoporosis (particularly postmenopausal women) potentially may have an additional benefit from therapy with statins. We conducted a large nested case-control analysis using the UK-based General Practice Research Database (GPRD) to determine whether use of statins, fibrates, or other lipid-lowering drugs is associated with a reduced risk of bone fractures.
Article
To determine if anti-inflammatory treatment for asthma reduces the risk of asthma hospitalization. Retrospective cohort study. A health maintenance organization (HMO) in eastern Massachusetts. Members of the HMO who were identified during the period October 1991 through September 1994 as having a diagnosis of asthma using a computerized medical record system. Hospitalization for asthma. Of the 16941 eligible persons, 742 (4.4%) were hospitalized for asthma. The overall relative risk (RR) of hospitalization among those who received inhaled steroids was 0.5 (95% confidence interval [CI], 0.4-0.6) after adjustment for beta-agonist dispensing. Additional adjustment for age, race, other asthma medications, and amount and type of ambulatory care for asthma did not substantially affect the inverse relationship between use of inhaled steroids and hospitalization. Cromolyn was similarly associated with reduced risk, especially among children (RR,0.8; 95% CI, 0.7-0.9). In contrast, increasing beta-agonist use was associated with increasing hospitalization risk even after adjustment for other factors and medications. The steroid-associated protection was most marked among individuals who received the largest amount of beta-agonist. Inhaled steroids and, to a lesser extent, cromolyn confer significant protection against exacerbations of asthma leading to hospitalization. These results support the use of inhaled steroids by individuals who require more than occasional beta-agonist use to control asthma symptoms.
Article
Ipratropium is commonly used for the management of elderly patients with obstructive airway disease. However, a recent report suggested that its use might be associated with a significant increase in mortality. A study was therefore conducted to compare all-cause mortality rates between users and non-users of ipratropium in elderly patients with either asthma or chronic obstructive pulmonary disease (COPD). A retrospective cohort study was performed using linked data from the Canadian Institute for Health Information, the Ontario Drug Benefit Program, the Ontario Health Insurance Plan, and the Ontario Registered Persons database. A total of 32 393 patients were identified who were aged 65 years or older and who had been discharged from hospital with asthma or COPD between 1 April 1992 and 31 March 1997. All-cause mortality rates were compared between those treated and those not treated with ipratropium following discharge from hospital. In total, 49% of patients received ipratropium within 90 days of discharge. After adjusting for age, sex, comorbidity, use of health services, and other airway medications there was no significant association in patients with COPD between the use of ipratropium and mortality (relative risk (RR) 1.03; 95% confidence interval (CI) 0.98 to 1.08). In patients with asthma, however, there was a slight increase in the relative risk of mortality associated with the use of ipratropium (RR 1.24; 95% CI 1.11 to 1.39). A dose-response increase in the mortality rate was not observed with increasing use of ipratropium in either COPD or asthma. The use of ipratropium in patients with COPD was not associated with an increase in mortality. However, in asthma there was a small increase in the mortality rate. Since asthmatic patients who received ipratropium had greater use of other airway medications and health services, the difference in mortality rate between users and non-users may be a reflection of unmeasured differences in asthma severity.
Article
Recent animal studies have suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) increase bone formation, volume, and density. It is unknown whether use of statins is associated with a decreased risk of fractures in humans. To determine whether exposure to statins, fibrates, or other lipid-lowering drugs is associated with reduced bone fracture risk. Population-based, nested case-control analysis. The UK-based General Practice Research Database (GPRD), comprising some 300 practices, with data collection from the late 1980s until September 1998. Within a base population of 91,611 individuals aged at least 50 years (28,340 individuals taking lipid-lowering drugs, 13,271 untreated individuals with a diagnosis of hyperlipidemia, and 50,000 randomly selected individuals without diagnosis of hyperlipidemia), we identified 3940 case patients who had a bone fracture and 23,379 control patients matched for age (+/-5 years), sex, general practice attended, calendar year, and years since enrollment in the GPRD. Use of statins, fibrates, or other lipid-lowering drugs in case patients vs control patients. After controlling for body mass index, smoking, number of physician visits, and corticosteroid and estrogen use, current use of statins was associated with a significantly reduced fracture risk (adjusted odds ratio [OR], 0.55; 95% confidence interval [CI], 0.44-0.69) compared with nonuse of lipid-lowering drugs. Current use of fibrates or other lipid-lowering drugs was not related to a significantly decreased bone fracture risk (adjusted OR, 0.87; 95% CI, 0.70-1.08 and adjusted OR, 0.76; 95% CI, 0.41-1.39, respectively). This study suggests that current exposure to statins is associated with a decreased risk of bone fractures in individuals age 50 years and older. This finding has a potentially important public health impact and should be confirmed further in controlled prospective trials. JAMA. 2000;283:3205-3210
Article
Many older people do not receive beta-blocker therapy after myocardial infarction or receive doses lower than those tested in trials, perhaps because physicians fear that beta-blockers may precipitate heart failure. We examined the relation between use of beta-blockers, the dose used, and hospital admission for heart failure and 1-year survival in a cohort of all older patients surviving myocardial infarction in Ontario, Canada. We collected data on a cohort of 13,623 patients aged 66 years or older who were discharged from hospital after a myocardial infarction and who did not receive beta-blocker therapy or received low, standard, or high doses. We used Cox's proportional-hazards models to study the association of dose with admission for heart failure and survival with adjustment for factors including age, sex, and comorbidity. Among 8232 patients with no previous history of heart failure, dispensing of beta-blocker therapy was associated with a 43% reduction in subsequent admission for heart failure (adjusted risk ratio 0.57 [95% CI 0.48-0.69]) compared with patients not dispensed this therapy. Among the 4681 patients prescribed beta-blockers, the risk of admission was greater in the high-dose than in the low-dose group (1.53 [1.01-2.31]). Among all 13,623 patients in the cohort, 2326 (17.1%) died by 1 year. Compared with those not dispensed beta-blocker therapy, the adjusted risk ratio for mortality was lower for all three doses (low 0.40 [0.34-0.47], standard 0.36 [0.31-0.42], high 0.43 [0.33-0.56]). Compared with high-dose beta-blocker therapy, low-dose treatment is associated with a lower rate of hospital admission for heart failure and has a similar 1-year survival benefit. Our findings support the need for a randomised controlled trial comparing doses of beta-blocker therapy in elderly patients.
Article
Dementia affects an estimated 10% of the population older than 65 years. Because vascular and lipid-related mechanisms are thought to have a role in the pathogenesis of Alzheimer's disease and vascular dementia, we did an epidemiological study of the potential effect of HMGCoA (3 hydroxy-3methylglutaryl-coenzyme A) reductase inhibitors (statins) and other lipid-lowering agents on dementia. We used a nested case-control design with information derived from 368 practices which contribute to the UK-based General Practice Research Database. The base study population included three groups of patients age 50 years and older: all individuals who had received lipid-lowering agents (LLAs); all individuals with a clinical diagnosis of untreated hyperlipidaemia; and a randomly selected group of other individuals. From this base population, all cases with a computer-recorded clinical diagnosis of dementia were identified. Each case was matched with up to four controls derived from the base population on age, sex, practice, and index date of case. The study encompassed 284 cases with dementia and 1080 controls. Among controls 13% had untreated hyperlipidaemia, 11% were prescribed statins, 7% other LLAs, and 69% had no hyperlipidaemia or LLA exposure. The relative risk estimates of dementia adjusted for age, sex, history of coronary-artery disease, hypertension, coronary-bypass surgery and cerebral ischaemia, smoking and body mass index for individuals with untreated hyperlipidaemia (odds ratio 0.72 [95% CI 0.45-1.14]), or treated with nonstatin LLAs (0.96 [0.47-1.97], was close to 1.0 and not significant compared with people who had no diagnosis of hyperlipidaemia or exposure to other lipid-lowering drugs. The adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002). Individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidaemia, or exposure to nonstatin LLAs. The available data do not distinguish between Alzheimer's disease and other forms of dementia.
Article
Although the efficacy of inhaled antiinflammatory therapy in improving symptoms and lung function in childhood asthma has been shown in clinical trials, the effectiveness of these medications in real-world practice settings in reducing acute health care use has not been well-evaluated. This study examined the effect of inhaled antiinflammatory therapy on hospitalizations and emergency department (ED) visits by children for asthma. Defined population cohort study over 1 year. Setting. Three managed care organizations (MCOs) in Seattle, Boston, and Chicago participating in the Pediatric Asthma Care-Patient Outcome Research and Treatment II trial. Participants. All 11 195 children, between 3 to 15 years old, with a diagnosis of asthma who were enrolled in the 3 MCOs between July 1996 and June 1997. We identified children with 1 or more asthma diagnoses using automated encounter data. Medication dispensings were identified from automated pharmacy data. Multivariate logistic regression analysis was used to calculate effects of inhaled antiinflammatory therapy on the adjusted relative risk (RR) for hospitalization and ED visits for asthma. Over 12 months, 217 (1.9%) of children had an asthma hospitalization, and 757 (6.8%) had an ED visit. After adjustment for age, gender, MCO, and reliever dispensing, compared with children who did not receive controllers, the adjusted RRs for an ED visit were: children with any (>/=1) dispensing of cromolyn, 0.4 (95% confidence interval [CI]: 0.3, 0.5); any inhaled corticosteroid (ICS), 0.5 (95% CI: 0.4, 0.6); any cromolyn or ICS combined (any controller), 0.4 (95% CI: 0.3, 0.5). For hospitalization, the adjusted RR for cromolyn was 0.6 (95% CI: 0.4, 0.9), for ICS 0.4 (95% CI: 0.3, 0.7), and for any controller 0.4 (95% CI: 0.3, 0.6). A significant protective effect for both events was seen among children with 1 to 5 and with >5 antiinflammatory dispensings. When the analysis was stratified by frequency of reliever dispensing, there was a significant protective effect for controllers on ED visits for children with 1 to 5 and with >5 reliever dispensings and on the risk of hospitalization for children with >5 reliever dispensings. Inhaled antiinflammatory therapy is associated with a significant protective effect on the risk for hospitalization and ED visits in children with asthma. Cromolyn and ICSs were associated with similar effects on risks.asthma drug therapy, inhaled antiinflammatory agents, health maintenance organizations, hospitalization, emergency department.
Article
Elderly patients with asthma have relatively high rates of hospitalization and mortality. Although inhaled corticosteroids have been shown to improve outcomes among younger patients with asthma, their usefulness in elderly patients has not been established. Therefore, a population-based study of patients 65 yrs of age or older, who have been hospitalized at least once with asthma in Ontario, Canada was conducted to determine the impact of inhaled corticosteroids on rehospitalization for asthma and all-cause mortality rates. Data from the Canadian Institute of Health Information was used to capture all patients 65 yrs of age and older who were hospitalized at least once, with the most responsible diagnosis of asthma in Ontario, Canada between fiscal year 1992 and 1996. This database was then linked with drug claims, physician billing and mortality databases. In total, 6,254 consecutive elderly patients with asthma were identified. Sixty percent of these patients were given at least one prescription for inhaled corticosteroids within 90 days postdischarge from their index hospitalization for asthma. Users of inhaled corticosteroids postdischarge were 29% (95% confidence interval (CI) 20%-38%) less likely to be readmitted to hospital for asthma and 39% (95% CI, 20%-53%) less likely to experience all-cause mortality compared to those who did not receive these drugs postdischarge over a one year follow-up period. These findings suggest that inhaled corticosteroids are beneficial in reducing the risk for rehospitalization and all-cause mortality in elderly patients with asthma who have recently been hospitalized for their disease.
Article
There is considerable controversy concerning the utility of inhaled corticosteroids for the long-term treatment of patients with COPD. Recent studies have suggested that although inhaled corticosteroids do not alter the rate of decline in lung function, they may reduce airway hyperresponsiveness, decrease the frequency of exacerbations, and slow the rate of decline in the patients' health status. The relationship between inhaled corticosteroids and subsequent risk of hospitalization or mortality remains unknown. We therefore conducted a population-based cohort study using administrative databases in Ontario, Canada (n = 22,620) to determine the association between inhaled corticosteroid therapy and the combined risk of repeat hospitalization and all-cause mortality in elderly patients with COPD. Patients who received inhaled corticosteroid therapy postdischarge (within 90 d) had 24% fewer repeat hospitalizations for COPD (95% confidence interval [CI], 22 to 35%) and were 29% less likely to experience mortality (95% CI, 22 to 35%) during 1 yr of follow-up after adjustment for various confounding factors. This cohort study has suggested that inhaled corticosteroid therapy is associated with reduced COPD-related morbidity and mortality in elderly patients. Although not definitive, because of the observational nature of these findings, these data provide a compelling rationale for a large randomized trial to determine the effect of inhaled corticosteroids on COPD-related morbidity and mortality.
Article
To examine the relation between follow-up office visits after emergency discharge and the risk of emergency readmissions in patients with asthma or chronic obstructive pulmonary disease (COPD). We used population-based data to identify all patients in Alberta, Canada, who had at least one emergency visit for asthma or COPD between April 1, 1996, and March 31, 1997 (N = 25 256). A Cox proportional hazards model was used to estimate the adjusted relative risk (RR) of a repeat visit to an emergency department within 90 days of an initial emergency visit in patients who did or did not have an office follow-up within the first 30 days. There were 7829 patients (31%) who had an office visit during the 30 days after their initial emergency encounter. Follow-up visits were associated with a significant reduction in the 90-day risk of an emergency readmission (RR = 0.79; 95% confidence interval [CI]: 0.73 to 0.86). Sensitivity analyses showed that a follow-up visit was inversely associated with a repeat emergency visit after adjusting for age, sex, area of residence, and income. Although these data should be interpreted with caution because of missing information on factors such as quality of care, they suggest that follow-up office visits are effective in reducing early relapses in patients who have been recently treated in emergency departments for asthma or COPD.
Article
In patients with asthma, treatment for associated conditions, such as rhinitis, is recommended. It is unknown whether this treatment can reduce the risk for emergency department (ED) visits for asthma. We sought to determine whether treatment with intranasal steroids or prescription antihistamines in persons with asthma is associated with a reduced risk for ED visits caused by asthma. We performed a retrospective cohort study of members of a managed care organization aged greater than 5 years who were identified during the period of October 1991 to September 1994 as having a diagnosis of asthma by using a computerized medical record system. The main outcome measure was an ED visit for asthma. Of the 13,844 eligible persons, 1031 (7.4%) had an ED visit for asthma. The overall relative risk (RR) for an ED visit among those who received intranasal corticosteroids, adjusted for age, sex, frequency of orally inhaled corticosteroid and beta-agonist dispensing, amount and type of ambulatory care for asthma, and diagnosis of an upper airways condition (rhinitis, sinusitis, or otitis media), was 0.7 (95% confidence interval [CI], 0.59-0.94). For those receiving prescription antihistamines, the risk was indeterminate (RR, 0.9; 95% CI, 0.78-1.11). When different rates of dispensing for intranasal steroids were examined, a reduced risk was seen in ED visits in those with greater than 0 to 1 (RR, 0.7; 95% CI, 0.57-0.99) and greater than 3 (RR, 0.5; 95% CI, 0.23-1.05) dispensed prescriptions per year. Treatment of nasal conditions, particularly with intranasal steroids, confers significant protection against exacerbations of asthma leading to ED visits for asthma. These results support the use of intranasal steroids by individuals with asthma and upper airways conditions.
Article
Patients who visit the emergency department (ED) because of asthma frequently have a relapse. While the use of inhaled corticosteroids has been demonstrated to improve asthma symptoms and lung function, it is not clear whether their use after discharge from the ED reduces asthma relapse rates. To determine whether inhaled corticosteroid therapy reduces ED asthma relapse rates. We analyzed ED visit and medication data on patients 5 to 60 years of age who were enrolled in a government-sponsored drug plan and who visited an ED because of asthma between April 1, 1997, and March 31, 1999, in Alberta, Canada (N = 1293). Using a Cox proportional hazards model, we determined the relative risk (RR) of relapse ED visits among users and nonusers of inhaled corticosteroids after discharge from the ED. We also compared the RR of relapse ED visits across different dose categories. Users of inhaled corticosteroids after ED discharge had 45% fewer relapse ED visits than did nonusers (adjusted RR, 0.55; 95% confidence interval [CI], 0.44-0.69). Low-, medium-, and high-dose therapies were associated with similar reductions in the risk of relapse ED visits: low-dose therapy (RR, 0.52; 95% CI, 0.39-0.68), medium-dose therapy (RR, 0.51; 95% CI, 0.34-0.76), and high-dose therapy (RR, 0.67; 95% CI, 0.47-0.94). Inhaled corticosteroid therapy after ED discharge is associated with a significant reduction in the risk of subsequent ED visits. Low-dose therapy appears to be as effective as high-dose therapy. However, further studies are needed to determine the optimal dosing regimen for inhaled corticosteroid therapy for asthma.
Article
Despite substantial evidence regarding the benefits of combined use of inhaled corticosteroids and long-acting beta2-agonists in asthma, such evidence remains limited for chronic obstructive pulmonary disease (COPD). Observational data may provide an insight into the expected survival in clinical trials of fluticasone propionate (FP) and salmeterol in COPD. Newly physician-diagnosed COPD patients identified in primary care during 1990-1999 aged > or = 50 yrs, of both sexes and with regular prescriptions of respiratory drugs were identified in the UK General Practice Research Database. Three-year survival in 1,045 COPD patients treated with FP and salmeterol was compared with that in 3,620 COPD patients who regularly used other bronchodilators but not inhaled corticosteroids or long-acting beta2-agonists. Standard methods of survival analysis were used, including adjustment for possible confounders. Survival at year 3 was significantly greater in FP and/or salmeterol users (78.6%) than in the reference group (63.6%). After adjusting for confounders, the survival advantage observed was highest in combined users of FP and salmeterol (hazard ratio (HR) 0.48 (95% confidence interval 0.31-0.73)), followed by users of FP alone (HR 0.62 (0.45-0.85)) and regular users of salmeterol alone (HR 0.79 (0.58-1.07)) versus the reference group. Mortality decreased with increasing number of prescriptions of FP and/or salmeterol. In conclusion, regular use of fluticasone propionate alone or in combination with salmeterol is associated with increased survival of chronic obstructive pulmonary disease patients managed in primary care.
Article
Randomized trials have shown that beta-blockers prevent morbidity and mortality in heart failure. However, whether beta-blockers are effective in older patients or those with conditions that would have led to their exclusion from these trials remains unclear. The associations between beta-blocker use and outcomes were examined in a population-based cohort of 11,942 older (age >/=65 years) patients with incident heart failure between 1994 and 1999. Cox proportional hazards models were used to adjust for propensity scores, age, sex, comorbid conditions, and other medications. The mean (+/- SD) age of the patients was 79 +/- 8 years, 5819 (49%) were men, and 2569 (22%) had Charlson comorbidity scores of at least 2. During follow-up (median, 21 months), 3539 patients were hospitalized for heart failure and 6757 died. Overall, 1162 patients received beta-blockers. After adjustment, beta-blocker use was associated with substantial reductions in all-cause mortality (hazard ratio [HR] = 0.72; 95% confidence interval [CI]: 0.65 to 0.80), mortality due to heart failure (HR = 0.65; 95% CI: 0.47 to 0.90), and hospitalizations for heart failure (HR = 0.82; 95% CI: 0.74 to 0.92). These endpoints were less frequent in patients treated with beta-blockers than in untreated patients in all examined subgroups. All doses of beta-blockers were associated with benefit, but there was a trend towards greater benefit in patients prescribed higher doses. The benefits of beta-blockers seen in randomized trials extend to older patients and to those with conditions that would have led to their exclusion from the trials. There is a need for a randomized trial comparing different doses of beta-blockers in heart failure.
Article
Recent data suggest that inhaled corticosteroids reduce the number of clinical exacerbations in chronic obstructive pulmonary disease (COPD). It remains unknown whether a dose/response relationship exists. The present study was conducted to evaluate the long-term impact of varying doses of inhaled corticosteroids on COPD mortality. Hospital discharge data were used to identify all patients aged > or = 65 yrs recently hospitalised due to COPD in Alberta, Canada (n = 6,740). The relative risk (RR) for all-cause mortality was compared across different dose categories of inhaled corticosteroids (none and low, medium and high doses) following hospital discharge. Inhaled corticosteroid therapy after discharge was associated with a 25% relative reduction in risk for all-cause mortality (RR 0.75, 95% confidence interval (CI) 0.68-0.82). Patients on medium- or high-dose therapy showed lower risks for mortality than those on low doses (RR 0.77, 95% CI 0.69-0.86 for low dose; RR 0.48, 95% CI 0.37-0.63 for medium dose; and RR 0.55, 95% CI 0.44-0.69 for high dose). Use of inhaled corticosteroids following hospital discharge for chronic obstructive pulmonary disease was associated with a significant reduction in the overall mortality rate. Low- was inferior to medium- or high-dose therapy in protecting against mortality in chronic obstructive pulmonary disease.
Article
Recent large-scale cohort studies that reported an important reduction in mortality and chronic obstructive pulmonary disease (COPD) morbidity with inhaled corticosteroids may be biased. We used a population-based cohort of Saskatchewan residents 55 years of age or over, first hospitalized for COPD during 1990 to 1997, to study this potential bias. These 979 subjects were followed for a year from discharge until their first readmission for COPD or death (389 subjects). Inhaled corticosteroid exposure was measured as any dispensing within 90 days after discharge. Cox's proportional hazards model was used to compare the time-fixed analysis employed in the recent studies with the alternative time-dependent analysis. The time-fixed adjusted rate ratio was 0.69 (95% CI: 0.55-0.86) for inhaled corticosteroid use within 90 days, whereas the time-dependent rate ratio was 1.00 (95% CI: 0.79-1.26). With the time-fixed analysis, the rate ratios were affected by the length of the exposure period, decreasing from 0.98 for a 15-day exposure period to 0.51 for 365 days, but remained stable between 1.06 and 0.94 with the time-dependent analysis. Inhaled corticosteroid use after hospitalization for COPD was not found to reduce mortality and morbidity. Although observational studies can be valuable, the recent reports of reductions in mortality and morbidity with inhaled corticosteroids are biased by their inappropriate allocation of exposure and analysis of immortal time.
Article
The aim of this study was to evaluate the effect of oral N-acetylcysteine in the prevention of re-hospitalisation for chronic obstructive pulmonary disease (COPD) exacerbations. Using the PHARmacoMOrbidity linkage (PHARMO) system the authors included all patients aged > or = 55 yrs who had been dispensed medication, labelled for respiratory indications (anatomical therapeutic chemical (ATC) classification system: R03), between 1986-1998 and who had also been hospitalised for COPD (International Classification of Diseases (ICD)-9: 491, 492, 496) in this time frame. These subjects were subsequently divided into two groups, those who had received N-acetylcysteine following discharge from their first admission between 1986-1998 and those who had not. All the patients were studied starting from their initial discharge, until their first readmission, death or end of data collection period. The maximum follow-up period was 1 yr. A total of 1,219 patients, who were hospitalised for COPD between 1986-1998, were included in this study. After adjustment for disease severity, it was observed that the use of N-acetylcysteine was significantly associated with a reduced risk of readmission. The readmission risk was significantly lower in patients with high average daily doses of N-acetylcysteine. In conclusion it was observed that N-acetylcysteine reduces the risk of rehospitalisation for chronic obstructive pulmonary disease by approximately 30% and that this risk reduction is dose-dependent.
Article
In patients with COPD who have recently been hospitalized for their disease, we examined whether treatment with inhaled corticosteroids without or with long-acting beta-adrenoceptor agonists (beta-agonists) reduced rehospitalization and mortality. Retrospective cohort analysis in the UK General Practice Research Database. We compared rehospitalization for a COPD-related medical condition or death within 1 year after first hospitalization, in 3636 COPD patients receiving prescriptions for inhaled corticosteroids or long-acting beta-agonists compared with 627 reference patients with COPD who were prescribed short-acting bronchodilators only. Rehospitalization within a year occurred in 13.2% of the reference COPD patients, 14.0% of users of long-acting beta-agonists only, 12.3% of users of inhaled corticosteroids only, and 10.4% of users of inhaled corticosteroids and long-acting beta-agonists. Death within a year occurred in 24.3% of the reference COPD patients, 17.3% of users of long-acting beta-agonists only, 17.1% of users of inhaled corticosteroids only, and in 10.5% of users of inhaled corticosteroids and long-acting beta-agonists. In multivariate analyses the risk of rehospitalization or death was reduced by 10% in users of long-acting beta-agonists only (NS), by 16% in users of inhaled corticosteroids only, and by 41% in users of combined inhaled corticosteroids and long-acting beta-agonists (both p < 0.05). Use of inhaled corticosteroids with/without long-acting beta-agonists was associated with a reduction of rehospitalization or death in COPD patients.
Article
Rates of asthma-related hospitalizations and emergency department (ED) visits continue to rise in the United States. The National Asthma Education and Prevention Program recommends the use of controller pharmacotherapy for patients with persistent asthma. To investigate the influence of initiating inhaled anti-inflammatory (IAI) pharmacotherapy following an asthma-related hospitalization or ED visit on risk of subsequent morbid events. Texas Medicaid asthma-related medication and medical services claims for September 1997 to July 2001 were extracted. An asthma-related morbid event served as the index event (ED visit or hospitalization for cohort 1; hospitalization for cohort 2). Members of both cohorts were then followed up until a subsequent morbid event occurred or until 1 year after index. Logistic regression was used to compare patients who used IAI medication within 100 days following their index event with nonusers. Controlling for demographic and resource use variables, there was a 52% reduction in the risk of a subsequent ED visit or hospitalization in the year following the index event among users of IAI medication within cohort 1 (risk ratio [RR], 0.485; 95% confidence interval [CI], 0.416-0.565; P < .001). There was a 61% reduction in the risk of a subsequent hospitalization among users of IAI medication within cohort 2 (RR, 0.393; 95% CI, 0.284-0.545; P < .001). Less than half of the patients had a prescription claim for an IAI medication within 100 days following their index event. Patients who received these medications had a lower risk of a subsequent asthma-related morbid event for the next year.
Article
It has been suggested that HMG Co-A reductase inhibitors ('statins') may reduce the risk of developing Type 2 diabetes mellitus. This study was designed to evaluate whether use of statins would also delay progression to insulin therapy. This was a retrospective cohort study using Saskatchewan Health databases to identify subjects newly started on oral antidiabetic agents from 1991 to 1996. < 30 years of age or with previous lipid-lowering drug use were excluded. Medications known to influence glycaemic control, co-morbidity, and demographic data were collected. Statin exposure was defined as at least 1 year of use. Primary outcome was starting insulin treatment. Multivariate Cox proportional hazards models were used to examine the association between statin use and starting insulin. The final cohort included 10,996 new users of oral antidiabetic agents, of which 484 (4.4%) used statins. Mean age was 64 years and 55% were male. Mean duration of follow-up was 5.1 years; 11.1% (n = 1221) eventually started insulin treatment. Statin users were no less likely than non-users to start insulin treatment eventually (11.6% vs. 11.1%, P = 0.74). After multivariate adjustment, however, statin use was associated with a 10-month delay before newly treated diabetic subjects needed to start insulin treatment (adjusted hazard ratio 0.74; 95% confidence interval 0.56, 0.97, P = 0.028). The use of statins is associated with a delay in starting insulin treatment in patients with Type 2 diabetes initially treated with oral antidiabetic agents. Whether this relationship exists for patients at high risk of developing diabetes should be examined in a randomized trial.
Article
A recent observational study suggests that intranasal corticosteroids used to treat allergic rhinitis are effective at preventing asthma outcomes, such as emergency visits. The approach to data analysis may have led to biased results because of misclassification of immortal time. To illustrate the bias in the cohort approach and to present the proper time-dependent analysis by replicating the recent study using data from another source. From an existing cohort of 30,569 patients with asthma age 5 to 44 years and identified from the Saskatchewan Health databases (1975-1997), we formed the cohort of all subjects who were in the source population between January 1, 1989, and December 31, 1991. Subjects were followed to the first asthma hospitalization. All prescriptions dispensed during follow-up were identified. We replicated the time-fixed approach to data analysis used in the recent study and compared it with time-dependent approaches. The cohort included 20,173 subjects, of whom 1849 were hospitalized for asthma between January 1, 1989, and December 31, 1991. The time-fixed approach misclassified more than 5000 person-years of follow-up, corresponding to 44% of the exposed person-time. As a result, the rate ratio of asthma hospitalization after any use of nasal corticosteroids (NCSs) was 0.57 by the biased time-fixed approach compared with 1.13 by the proper time-dependent approach. The time-fixed approach produced a paradoxical protective effect of NCS with 1 or less canisters dispensed per year (odds ratio, 0.47), which was further exaggerated when the cohort was extended to 5 years (odds ratio, 0.33). Adjusted time-dependent analyses found no protective effect, even when NCSs were dispensed regularly (rate ratio, 1.10; 95% CI, 0.54-2.21). The time-fixed approach to the analysis of the effectiveness of NCSs on asthma outcomes leads, by its inherent misclassification of immortal time, to a considerable exaggeration of the protective effect of these medications in preventing severe asthma exacerbations.
Article
The authors compared five methods of studying survival bias associated with time-to-treatment initiation in a drug effectiveness study using medical administrative databases (1996-2002) from Quebec, Canada. The first two methods illustrated how survival bias could be introduced. Three additional methods were considered to control for this bias. Methods were compared in the context of evaluating statins for secondary prevention in elderly patients post-acute myocardial infarction who initiated statins within 90 days after discharge and those who did not. Method 1 that classified patients into users and nonusers at discharge resulted in an overestimation of the benefit (38% relative risk reduction at 1 year). In method 2, following users from the time of the first prescription and nonusers from a randomly selected time between 0 and 90 days attenuated the effect toward the null (10% relative risk reduction). Method 3 controlled for survival bias by following patients from the end of the 90-day time window; however, it suffered a major loss of statistical efficiency and precision. Method 4 matched prescription time distribution between users and nonusers at cohort entry. Method 5 used a time-dependent variable for treatment initiation. Methods 4 and 5 better controlled for survival bias and yielded similar results, suggesting a 20% risk reduction of recurrent myocardial infarction or death events.