BackgroundThe long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown.MethodsThe authors formed an inception cohort of patients from their first ever hospitalisation for COPD during 1990–2005, using the healthcare databases from the province of Quebec, Canada. Patients were followed until death or 31 March 2007, and all COPD hospitalisations occurring during follow-up were identified. The hazard functions of successive hospitalised COPD exacerbations and all-cause mortality over time were estimated, and HRs adjusted for age, sex, calendar time and comorbidity.ResultsThe cohort included 73 106 patients hospitalised for the first time for COPD, of whom 50 580 died during the 17-year follow-up, with 50% and 75% mortality at 3.6 and 7.7 years respectively. The median time from the first to the second hospitalised exacerbation was around 5 years and decreased to <4 months from the 9th to the 10th. The risk of the subsequent severe exacerbation was increased threefold after the second severe exacerbation and 24-fold after the 10th, relative to the first. Mortality after a severe exacerbation peaked to 40 deaths per 10 000 per day in the first week after admission, dropping gradually to 5 after 3 months.ConclusionsThe course of COPD involves a rapid decline in health status after the second severe exacerbation and high mortality in the weeks following every severe exacerbation. Two strategic targets for COPD management should include delaying the second severe exacerbation and improving treatment of severe exacerbations to reduce their excessive early mortality.

In the UK, the rate of initiation of NOACs has increased substantially since 2009, and these agents have now surpassed VKAs as the anticoagulant of choice. Moreover, the characteristics of patients initiated on NOACs have changed over time, and this should be accounted for in future studies comparing NOACs and VKAs.

The proposed prevalent new-user cohort design for comparative drug effects studies allows the use of all or most patients exposed to the newer drug, thus permitting a more comprehensive assessment of a new drug's safety. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives To determine the risk of stroke associated with oral and transdermal routes of administration of hormone replacement therapy.

IMPORTANCE Selective serotonin reuptake inhibitors (SSRIs) may increase the risk for spontaneous intracranial hemorrhage (ICH), an effect that is in theory linked to the strength of inhibition of serotonin reuptake of an antidepressant. However, whether antidepressants that are strong inhibitors of serotonin reuptake actually increase the risk for ICH and the effect of concomitant use of antithrombotics are unknown.OBJECTIVES To assess the risk for ICH associated with the use of SSRIs compared with tricyclic antidepressants (TCAs) among new users of antidepressants and according to the relative affinity of the antidepressant for the serotonin transporter and to assess whether concomitant use of antithrombotics modifies this risk. DESIGN, SETTING, AND PARTICIPANTSThis population-based cohort study included new users of antidepressants 18 years or older from January 1, 1995, to June 30, 2014. More than 650 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink enrolled patients. with use of a nested case-control approach, each case of a first ICH identified during follow-up was matched with as many as 30 control individuals by age, sex, calendar time, and duration of follow-up. Follow-up was completed on October 31, 2014.INTERVENTIONS Current use of SSRIs compared with TCAs and strong compared with weak serotonin reuptake inhibitors. MAIN OUTCOMES AND MEASURES Incidence rate ratios (RRs) of ICH.RESULTS Among a cohort of 1 363 990 incident users of antidepressants (36.8% male; 63.2% female; mean [SD] age, 47.9 [18.5] years), 3036 cases of ICH were identified during follow-up and matched to 89 702 controls. Current SSRI use was associated with an increased risk for ICH (RR, 1.17; 95% CI, 1.02-1.35) relative to TCAs, highest during the first 30 days of use (RR, 1.44; 95% CI, 1.04-1.99), and translating in very few additional events. Similarly, the risk was increased by 25% with strong inhibitors (RR, 1.25; 95% CI, 1.01-1.54) and highest during the first 30 days of use (RR, 1.68; 95% CI, 0.90-3.12). Concomitant use of anticoagulants may increase the risk substantially (RR, 1.73; 95% CI, 0.89-3.39). CONCLUSIONS AND RELEVANCEThe use of SSRIs and more generally of antidepressants with strong inhibition of serotonin reuptake are associated with an increased risk for ICH, particularly in the first 30 days of use and when used concomitantly with oral anticoagulants.

Background: Several in vitro studies have indicated that metformin may reduce the risk of prostate cancer; however, epidemiologic studies have been inconclusive. The objective of this study was to determine whether metformin decreases the risk of prostate cancer in patients with type 2 diabetes.Methods: A nested case-control analysis was conducted within a population-based cohort from the UK General Practice Research Database. The cohort included patients over the age of 40 who were prescribed a first oral hypoglycemic agent (OHA) between 1988 and 2009. Cases of prostate cancer were matched up to ten controls on year of birth, date of cohort entry, and duration of follow-up. Adjusted rate ratios (RR) were estimated using conditional logistic regression.Results: The cohort included 63,049 incident users of OHAs, in which 739 cases of prostate cancer were matched to 7,359 controls. Metformin use did not decrease the risk of prostate cancer (RR: 1.23, 95% CI: 0.99-1.52). In secondary analyses, prostate cancer risk was found to increase as a function of the number of metformin prescriptions received (one to seven prescriptions: RR: 1.05, 95% CI: 0.80-1.37; seven to eighteen prescriptions: RR: 1.29, 95% CI: 0.99-1.69; eighteen to thirty-six prescriptions: RR: 1.37, 95% CI: 1.04-1.81; more than thirty-six prescriptions: RR: 1.40, 95% CI: 1.03-1.89).Conclusion: The results of this study indicate that metformin does not reduce the risk of prostate cancer in patients with type 2 diabetes.Impact: The secondary analyses need to be interpreted with caution given the inverse association between type 2 diabetes and prostate cancer. Cancer Epidemiol Biomarkers Prev; 20(2); 337-44. Ó2010 AACR.

Purpose Observational studies using computerized healthcare databases have become popular to investigate the potential effectiveness of old drugs for new indications. Many of these studies reporting remarkable effectiveness were shown to be affected by different time‐related biases. We describe these biases and illustrate their effects using a cohort of patients treated for chronic obstructive pulmonary disease (COPD). Methods The Quebec healthcare databases were used to form a cohort of 124 030 patients with COPD, 50 years or older, treated between 2000 and 2015. Inhaled corticosteroids (ICS) and long‐acting bronchodilators were used as exposures, with diverse outcomes, including lung cancer, acute myocardial infarction and death, to illustrate protopathic, latency time, immortal time, time‐window, depletion of susceptibles, and immeasurable time biases. Results Protopathic bias affected bronchodilator‐defined cohort entry with an incident rate of lung cancer of 23.9 per 1000 in the first year, compared with around 12.0 in the subsequent years. When latency and immortal times were misclassified, ICS were associated with decreased incidence of lung cancer (hazard ratio [HR] 0.32; 95% CI: 0.30‐0.34), compared with 0.50 (95% CI: 0.48‐0.53) after correcting for immortal time bias and 0.96 (95% CI: 0.91‐1.02) after also correcting for latency time bias. Time‐window, depletion of susceptibles and immeasurable time biases also affected the findings similarly. Conclusions Many observational studies of new indications for older drugs reporting unrealistic effectiveness were affected by avoidable time‐related biases. The apparent effectiveness often disappears with proper design and analysis. Future studies should consider these time‐related issues to avoid severely biased results.

Time-related biases in cohort studies can produce illusory "beneficial" effects of medications due entirely to an artifact of the analytic design. We describe "time-window bias" in the context of a case-control study, reporting that statin use was associated with a 45% reduction in the incidence of lung cancer. This bias results from the use of time-windows of different lengths between cases and controls to define time-dependent exposures. We illustrate the bias using a population of 365,467 patients from the United Kingdom's General Practice Research Database, including 1786 incident cases of lung cancer during 1998-2004. The case-control approach used in the published study yielded a rate ratio of lung cancer incidence of 0.62 with statin use (95% confidence interval = 0.55-0.71). A case-control approach that properly accounts for time produces a rate ratio of 0.99 (0.85-1.16)-suggesting no benefit of statins on lung cancer risk. We show analytically that the magnitude of the bias is proportional to the ratio of the unequal time-window lengths.