Abatacept initiation in rheumatoid arthritis and the risk of cancer: a population-based comparative cohort study.

OBJECTIVE: To assess whether abatacept as initial biological DMARD (bDMARD) in the treatment of RA, when compared with other bDMARDs, is associated with an increased risk of cancer overall and by specific cancer sites (breast, lung, lymphoma, melanoma and non-melanoma skin cancer). METHODS: We performed a population-based cohort study among patients newly treated with bDMARDs within the US-based Truven MarketScan population and Supplemental US Medicare from 2007 to 2014. Cox proportional hazards models were used to estimate hazard ratios and 95% CIs of any cancer (and specific cancers) associated with initiation of abatacept, compared with initiation of other bDMARDs, adjusted for age and deciles of the propensity score. RESULTS: The cohort included 4328 patients on abatacept and 59 860 on other bDMARDs, of whom 409 and 4197 were diagnosed with any cancer during follow-up (incidence rates 4.76 per 100 per year and 3.41 per 100 per year, respectively). Compared with other bDMARDs, the use of abatacept was associated with an increased incidence of cancer overall (hazard ratioadjusted 1.17; 95% CI 1.06, 1.30). Analyses by specific cancer sites showed a significantly increased incidence of non-melanoma skin cancer (hazard ratioadjusted 1.20; 95% CI 1.03, 1.39), but no significant difference for other specific cancer sites. CONCLUSION: The use of abatacept as first bDMARD in the treatment of RA was associated with a slight increased risk of cancer overall and particularly non-melanoma skin cancer, compared with other bDMARDs. This potential signal needs to be replicated in other settings.

Trends in initiation of direct oral anticoagulant therapies for atrial fibrillation in a national population-based cross-sectional study in the French health insurance databases.

OBJECTIVE: Unlike several other national health agencies, French health authorities recommended that the newer direct oral anticoagulant (DOAC) agents only be prescribed as second choice for the treatment of newly diagnosed non-valvular atrial fibrillation (NVAF), with vitamin K antagonists (VKA) remaining the first choice. We investigated the patterns of use of DOACs versus VKA in the treatment of NVAF in France over the first 5 years of DOAC availability. We also identified the changes in patient characteristics of those who initiated DOAC treatment over this time period. METHODS: Based on the French National Health Administrative Database, we constituted a population-based cohort of all patients who were newly treated for NVAF between January 2011 and December 2015. Trends in drug use were described as the percentage of patients initiating each drug at the time of treatment initiation. A multivariate analysis using logistic regression model was performed to identify independent sociodemographic and clinical predictors of initial anticoagulant choice. RESULTS: The cohort comprised 814 446 patients who had received a new anticoagulant treatment for NVAF. The proportion of patients using DOACs as initial anticoagulant therapy reached 54% 3 months after the Health Ministry approved the reimbursement of dabigatran for NVAF, and 61% by the end of 2015, versus VKA use. In the multivariate analysis, we found that DOAC initiators were younger and healthier overall than VKA initiators, and this tendency was reinforced over the 2011-2014 period. DOACs were more frequently prescribed by cardiologists in 2012 and after (adjusted OR in 2012: 2.47; 95% CI 2.40 to 2.54). CONCLUSION: Despite recommendations from health authorities, DOACs have been rapidly and massively adopted as initial therapy for NVAF in France. Observational studies should account for the fact that patients selected to initiate DOAC treatment are healthier overall, as failure to do so may bias the risk-benefit assessment of DOACs.

Drospirenone-Containing Oral Contraceptive Pills and the Risk of Venous Thromboembolism: An Assessment of Risk in First-Time Users and Restarters.

INTRODUCTION: The effects of drospirenone-containing combined oral contraceptives (COCs) on the risk of venous thromboembolism (VTE) remain controversial due to the challenge in distinguishing between first-time users and restarters, and their different underlying VTE risks, in healthcare databases. OBJECTIVES: The aim of this study was to describe the challenge of studying the risk of VTE among first-time users of drospirenone-containing COCs in a healthcare database and assess the risk among first-time users and restarters. METHODS: We used data from the Clinical Practice Research Datalink to construct two cohorts. The first-time user cohort included all women aged 16-45 years who received a first ever prescription of drospirenone- or levonorgestrel-containing COCs between May 2002 and March 2015. The restarter cohort included those who were restarting a COC after a period of non-use of ≥6 months. Cox proportional hazards models adjusted for high dimensional propensity scores were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The final cohorts included 55,139 first-time users (3582 drospirenone and 51,557 levonorgestrel) and 162,959 restarters (23,191 drospirenone and 139,768 levonorgestrel). The adjusted HR of VTE associated with drospirenone versus levonorgestrel was 3.19 (95% CI 1.12-9.08) for first-time users and 1.96 (95% CI 1.12-3.41) for restarters. CONCLUSIONS: We found an elevated risk of VTE associated with drospirenone-containing COCs in comparison with levonorgestrel-containing COCs in both cohorts. While left truncation of healthcare databases is a concern for the identification of first-time users, the use of a more explicit cohort of restarters suggests a doubling of VTE risk with drospirenone-containing COCs.

Phosphodiesterase Type 5 Inhibitors and the Risk of Melanoma Skin Cancer.

BACKGROUND: The association between phosphodiesterase type 5 inhibitors (PDE5-Is), drugs used in the treatment of erectile dysfunction (ED), and melanoma skin cancer is controversial. OBJECTIVE: To assess whether the use of PDE5-Is is associated with an increased risk of melanoma skin cancer. DESIGN, SETTING, AND PARTICIPANTS: Using the UK Clinical Practice Research Datalink, we assembled a cohort of men newly diagnosed with ED between 1998 and 2014 and followed until 2015. PDE5-I exposure was considered as a time-varying variable lagged by 1 yr for latency purposes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of incident melanoma associated with PDE5-I use overall and by number of prescriptions and pills received. Identical analyses were conducted for basal and squamous cell carcinoma, two cancers for which PDE5-related pathways are not thought to be involved. RESULTS AND LIMITATIONS: The cohort included 142 983 patients, of whom 440 were newly diagnosed with melanoma during follow-up (rate: 63.0 per 100 000 person-years). Compared with nonuse, PDE5-I use was not associated with an overall increased risk of melanoma (rates: 66.7 vs 54.1 per 100 000 person-years; HR: 1.18; 95% CI, 0.95-1.47). The risk was significantly increased among those who had received seven or more prescriptions and ≥25 pills (HR: 1.30 [95% CI, 1.01-1.69] and 1.34 [95% CI, 1.04-1.72], respectively). In contrast, there was no overall association with basal and squamous cell carcinoma, with an unclear association with numbers of prescriptions and pills received. CONCLUSIONS: The use of PDE5-Is was not associated with an overall increased risk of melanoma skin cancer. The increased risks observed in the highest prescription and pill categories require further validation. PATIENT SUMMARY: In this study, the use of phosphodiesterase type 5 inhibitors was not associated with an increased risk of melanoma skin cancer.

Understanding and Avoiding Immortal-Time Bias in Gastrointestinal Observational Research.

Pharmacoepidemiologic analyses, in which observational data is interrogated to evaluate relationships between patterns of drug use and both beneficial and adverse outcomes, are being increasingly used in the study of inflammatory bowel disease. However, the results of many of these analyses may be corrupted by the presence of immortal person-time bias, an analytic error which can result in an overestimation of the benefits of medical therapy. In this report, we will describe immortal person-time bias, explain the mechanism through which it confers a false benefit, and guide the reader in how to identify this source of bias in the medical literature.

Measuring persistence to hormonal therapy in patients with breast cancer: accounting for temporary treatment discontinuation.

PURPOSE: Several studies have been conducted to estimate persistence to hormonal therapy among women with breast cancer (BC). Most studies focus on first treatment discontinuation. Patients, however, can have numerous periods of treatment discontinuation or treatment exposure. Our objective is to estimate persistence to tamoxifen in patients with BC while accounting for temporary treatment discontinuations and this by using multi-state (MS) models. METHODS: A cohort of 10,806 women with BC having received at least one prescription of tamoxifen between 1998 and 2008 was constituted from the UK General Practice Research Database. We fitted a semi-Markov model with three states to estimate the probability of being off treatment over a 5-year period while accounting for temporary treatment discontinuations (transition between on treatment and off treatment) and competing risks (recurrence of BC or death). RESULTS: Non-persistence, as estimated from the MS model, ranged from 12.1% (95% confidence interval [95%CI]: 9.2-15.1) at 1 year to 14.9% (95%CI: 11.7-18.1) at 5 years. Estimations of non-persistence based on the Kaplan-Meier model were higher, i.e., 29.3% (95%CI: 28.1-30.6) at 5 years, as well as those obtained from a competing risk model, i.e., 24.0% (95%CI: 22.9-25.1). Most temporary discontinuations (94.7%) lasted less than 6 months. Temporary treatment discontinuations are frequent and should be accounted for when measuring adherence to treatment. MS models can provide a useful framework for this sort of analysis insofar as they help describe patients' complex behavior. This may help tailor interventions that improve persistence to hormonal therapy among women with BC.

CNODES: the Canadian Network for Observational Drug Effect Studies.

Although administrative health care databases have long been used to evaluate adverse drug effects, responses to drug safety signals have been slow and uncoordinated. We describe the establishment of the Canadian Network for Observational Drug Effect Studies (CNODES), a collaborating centre of the Drug Safety and Effectiveness Network (DSEN). CNODES is a distributed network of investigators and linked databases in British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec and Nova Scotia. Principles of operation are as follows: (1) research questions are prioritized by the coordinating office of DSEN; (2) the linked data stay within the provinces; (3) for each question, a study team formulates a detailed protocol enabling consistent analyses in each province; (4) analyses are "blind" to results obtained elsewhere; (5) protocol deviations are permitted for technical reasons only; (6) analyses using multivariable methods are lodged centrally with a methods team, which is responsible for combining the results to provide a summary estimate of effect. These procedures are designed to achieve high internal validity of risk estimates and to eliminate the possibility of selective reporting of analyses or outcomes. The value of a coordinated multi-provincial approach is illustrated by projects studying acute renal injury with high-potency statins, community-acquired pneumonia with proton pump inhibitors, and hyperglycemic emergencies with antipsychotic drugs. CNODES is an academically based distributed network of Canadian researchers and data centres with a commitment to rapid and sophisticated analysis of emerging drug safety signals in study populations totalling over 40 million.

Infections requiring hospitalization in the abatacept clinical development program: an epidemiological assessment.

INTRODUCTION: Patients with rheumatoid arthritis (RA) have an increased risk of infection and this risk appears to be higher with anti-TNF (tumor necrosis factor) agents. We pooled data from the cumulative abatacept RA clinical development program, both double-blind and open-label periods, to estimate the incidence rates (IRs) of infections requiring hospitalization including pneumonia and opportunistic infections, in comparison with RA patients treated with non-biologic disease-modifying antirheumatic drugs (DMARDs) from several reference cohorts. METHODS: Infections reported in seven abatacept clinical trials of RA patients (double-blind and open-label periods) were tabulated. Comparisons were made between the observed IRs in abatacept-treated patients and those in over 133,000 patients exposed to non-biologic DMARDs in six reference RA cohorts. Age- and sex-adjusted IRs of infections requiring hospitalization, including pneumonia (most frequent hospital infection), were used to estimate the expected IRs with abatacept by the method of indirect adjustment. Standardized incidence ratios (SIR) and 95% CI were calculated comparing incidence in the cumulative abatacept experience with incidence in each RA cohort. RESULTS: A total of 1,955 (double-blind period) and 4,134 (double-blind + open-label periods with a cumulative exposure of 8,392 person-years) abatacept-treated RA patients were analyzed. Observed IRs for infections requiring hospitalization during the double-blind period were 3.05 per 100-patient years for abatacept-treated patients and 2.15 per 100 patient years for placebo. In the cumulative population, observed IR for infections requiring hospitalization was 2.72 per 100-patient years. Rates for abatacept were similar to expected IRs based on other RA non-biologic DMARD cohorts. CONCLUSIONS: IRs of infections requiring hospitalization and pneumonia in abatacept trials are consistent with expected IRs based on reference RA DMARD cohorts. RA patients are at higher risk of infection compared with the general population, making the RA DMARD cohorts an appropriate reference group. The safety of abatacept, including incidence of infections requiring hospitalization, will continue to be monitored in a post-marketing surveillance program.

The impact of unmeasured baseline effect modification on estimates from an inverse probability of treatment weighted logistic model.

We present the results of a Monte Carlo simulation study in which we demonstrate how strong baseline interactions between a confounding variable and a treatment can create an important difference between the marginal effect of exposure on outcome (as estimated by an inverse probability of treatment weighted logistic model) and the conditional effect (as estimated by an adjusted logistic regression model). The scenarios that we explored included one with a rare outcome and a strong and prevalent effect measure modifier where, across 1,000 simulated data sets, the estimates from an adjusted logistic regression model (mean beta = 0.475) and an inverse probability of treatment weighted logistic model (mean beta = 2.144) do not coincide with the known true effect (beta = 0.68925) when the effect measure modifier is not accounted for. When the marginal and conditional estimates do not coincide despite a rare outcome this may suggest that there is heterogeneity in the effect of treatment between individuals. Failure to specify effect measure modification in the statistical model appears to results in systematic differences between the conditional and marginal estimates. When these differences in estimates are observed, testing for or including interactions or non-linear modeling terms may be advised.

Clinically informative measures of the effect of drugs or other interventions.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Several comparative measures (ratios, differences, or the number needed to treat) are used to express the effect of a drug or another intervention. These measures can vary in the way they are affected by the background risk measured from the reference group. WHAT THIS STUDY ADDS: This paper reviews the formulation, interpretation and limitations of measures of effect. We describe a little-known parameter, the attained effect or clinical result ratio, a positive reformulation of the relative risk difference, and suggest how available parameters can be best used to summarize results of studies of the effect of drugs. AIMS Measures to compare two drugs are often affected by the background risk in the reference group; a ceiling effect results when the background risk is small. We review measures of the effect of drugs, including a special formulation of the relative risk difference, the attained effect or clinical result ratio, that addresses background risk and ceiling effect. METHODS: Existing measures are the risk and odds ratios, the absolute and relative risk differences, and the number needed to treat. The attained effect is defined as the observed gain in success (the difference of proportion of success between the two interventions), divided by the maximum attainable gain, the maximum proportion of success one can expect. We illustrate the relationship between these measures with published results of two meta-analyses. RESULTS: In studies of the effectiveness of cell salvage, the baseline risk ranged between 8 and 95%. This variability affected the risk difference and number needed to treat, while the attained effect, with a ceiling residual risk of 2%, showed that the gain in success was half the maximum attainable gain. In studies of the effectiveness of therapy in patients infected by the human immunodeficiency virus, where the baseline risk was less variable, and there was no ceiling effect, the maximum attained effect indicated that the gain could be much smaller. CONCLUSION: The attained effect, interpreted as the proportion of effectiveness that remains to gain for future interventions, can usefully complete the number needed to treat as a clinically informative effect measure.

TNF-alpha antagonists and the prevention of hospitalisation for chronic obstructive pulmonary disease.

BACKGROUND: TNF-alpha may be important in the pathogenesis of COPD. Consequently, the use of TNF-alpha antagonists has been advocated for its treatment. METHODS: We conducted an observational study to evaluate the effectiveness of TNF-alpha antagonists in preventing COPD hospitalisations in a cohort of patients diagnosed with both RA and COPD identified from a health claims database. A nested case-control approach was used to match each case hospitalised to 10 controls on age and cohort entry date. Data on prescribed medications during the year prior to the index date were obtained. Rate ratios (RR) of COPD hospitalisation were estimated by conditional logistic regression, after adjustment for COPD severity and concomitant RA medication use. RESULTS: The cohort included 15,771 subjects with both RA and COPD, of which 1205 were hospitalised for COPD during follow-up. The adjusted RR of COPD hospitalisation associated with the use of TNF-alpha antagonists was 0.62 (95% confidence interval (CI) 0.43-0.89). This rate reduction was due to etanercept (RR 0.49, 95% CI 0.29-0.82) but not infliximab (RR 0.95, 95% CI 0.59-1.52). CONCLUSION: Our finding of a halving in the rate of COPD hospitalisation associated with the use of etanercept corroborates the potential importance of TNF-alpha in the pathogenesis of COPD. This study supports the initiation of randomised controlled trials of this TNF-alpha antagonist among COPD patients at high risk of severe exacerbations.

Assessing a whiplash management model: a population-based non-randomized intervention study.

OBJECTIVE: To evaluate the effectiveness of a multidisciplinary clinical management approach for whiplash-associated disorders (WAD) following a motor vehicle injury in Quebec. METHODS: A clinical management model was implemented in 5 geographic regions of the Province of Quebec, Canada, in 7 hospitals and 19 clinics. A 2-group population-based parallel design was used to assess its effectiveness. All patients with a new whiplash injury seen in these 26 centers between March and September, 2001 were entered into the Whiplash Management Model (experimental group). A reference group included all subjects who had a whiplash injury during this same period but were not seen in these 26 intervention centers. All subjects were followed for up to a year. The outcome variables were time on compensation, time to file closure, and total direct costs. RESULTS: A total of 288 patients with WAD were identified in the experimental group and 1,875 patients in the reference group. The rate of ending of compensation was significantly higher in patients who received the experimental treatment model than those receiving the reference treatment approach (rate ratio, RR: 3.2; 95% confidence interval, CI: 2.8-3.6). The rate of file closure was also significantly higher with the experimental treatment (RR: 1.5; 95% CI: 1.2-1.8). The average cost per patient was significantly reduced with the experimental intervention. CONCLUSION: A coordinated whiplash management approach can lead to earlier return to work and lower costs for patients who have sustained a whiplash injury.

Risk factors of poor prognosis after whiplash injury.

Whiplash, a common injury following motor vehicle crashes, is associated with high costs and a prognosis that is variable and difficult to predict. In this paper, we review findings from the Quebec cohort epidemiological study on predictive factors of recovery from whiplash injury after a motor vehicle crash. We formed a population-based incident cohort of all 4,759 individuals who sustained a whiplash injury resulting from a motor vehicle crash in the province of Québec, Canada, in 1987, and followed these patients for up to seven years. The data were obtained from the universal automobile insurance plan (SAAQ) that covers all seven million residents of the Province for all vehicular-related injuries. From this cohort, we formed the cohort of 3,014 for whom a police report was completed. For this cohort, we obtained data on crash-related factors directly from the police report. We also formed the cohort of 2,627 subjects who had strictly a whiplash injury, without associated injuries. For this cohort, the data on signs and symptoms were obtained from the medical charts kept by the SAAQ. For both cohorts, data on the outcome, the recovery time from whiplash, was obtained from the SAAQ databases. The crash-related cohort study found that socio-demographic factors associated with a longer recovery from whiplash include older age, female sex, having dependents and not being employed full time and that each decreases the rate of recovery by 14 to 16 per cent. Factors related to the crash conditions indicate that being in a truck or bus, with a decrease of 52% in the rate of recovery, being a passenger in the vehicle (15%), colliding with a moving vehicle (16%), and a side or frontal collision (15%) all decrease the rate of recovery. We introduce a combined risk score that predicts longer recovery. In the cohort of subjects with signs and symptoms, the median recovery time was 32 days and 12% of subjects had still not recovered after 6 months. The signs and symptoms that were found to be independently associated with a slower recovery from whiplash, besides female gender and older age, were neck pain on palpation; muscle pain; pain or numbness radiating from neck to arms, hands or shoulders; and headache. Together, the presence of all these factors in females aged 60 predicted a median recovery time of 262 days, compared with 17 days for younger males aged 20 who do not have any of these factors. In contrast, using the Quebec classification of signs and symptoms, the median recovery time varied from 17 to 123 days. We conclude that several socio-demographic and crash-related factors, as well as several signs and symptoms, including a combination of specific musculoskeletal and neurological ones that whiplash patients present with, are predictive of a longer recovery period. These patients should be targeted for an early intervention programme aimed at managing whiplash patients with a poor prognosis.