Sophie Dell'Aniello

Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality

Background The long-term natural history of chronic obstructive pulmonary disease (COPD) in terms of successive severe exacerbations and mortality is unknown. Methods The 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. Results The 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. Conclusions The 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.

Metformin and the incidence of prostate cancer in patients with type 2 diabetes

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. ©2010 AACR.

Initiation of warfarin in patients with atrial fibrillation: early effects on ischaemic strokes

AIMS An increased risk of stroke was observed in two atrial fibrillation (AF) trials of oral factor Xa inhibitors, when patients were transitioned to open label warfarin at the end of the study. The objective of this study is to determine whether initiation of warfarin is associated with an increased risk of stroke in patients with AF. METHODS AND RESULTS Using the UK Clinical Practice Research Datalink, a nested case-control analysis was conducted within a cohort of 70 766 patients with AF between 1993 and 2008. Stroke cases were randomly matched with up to 10 controls on age, sex, date of AF diagnosis, and time since AF diagnosis. Conditional logistic regression was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) of stroke associated with current warfarin use classified according to time since initiation of treatment (<30 days, 31-90 days, and >90 days), when compared with non-use. A total of 5519 patients experienced a stroke during follow-up. Warfarin was associated with a 71% increased risk of stroke in the first 30 days of use (RR: 1.71, 95% CI: 1.39-2.12), while decreased risks were observed with initiation >30 days before the event (31-90 days: RR: 0.50, 95% CI: 0.34-0.75 and >90 days: RR: 0.55, 95% CI: 0.50-0.61, respectively). CONCLUSION Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, supporting the biological plausibility of a transient hypercoagulable state at the start of the treatment, although additional studies are needed to confirm these findings.

Combination therapy with sulfonylureas and metformin and the prevention of death in type 2 diabetes: a nested case‐control study

To determine whether combination of sulfonylureas and metformin increases the risk of death from any cause in patients with type 2 diabetes.

Trends in the prescription of novel oral anticoagulants in UK primary care

AIMS Novel oral anticoagulants (NOACs) are alternatives to vitamin-K antagonists (VKAs) for the prevention of thromboembolism. It is unclear how NOACs have been adopted in the UK since first introduced in 2008. The present study was conducted to describe the trends in the prescription of NOACs in the UK, including dabigatran, rivaroxaban and apixaban. METHODS Using the UKs Clinical Practice Research Datalink, the rates of new use of NOACs and VKAs from 2009 to 2015 were calculated using Poisson regression. Patient characteristics associated with NOAC initiation were identified using multivariate logistic regression. RESULTS The overall rate of oral anticoagulant initiation increased by 58% over the study period [rate ratio (RR) 1.58; 95% confidence interval (CI) 1.23, 2.03], even as the rate of new VKA use decreased by 31% (RR 0.69; 95% CI 0.52, 0.93). By contrast, the rate of initiation of NOAC increased, particularly from 2012 onwards, with a 17-fold increase from 2012 to 2015 (RR 17.68; 95% CI 12.16, 25.71). In 2015, NOACs accounted for 56.5% of oral anticoagulant prescriptions, with rivaroxaban prescribed most frequently, followed by apixaban and then dabigatran. Compared to VKAs, new NOAC users were less likely to have congestive heart failure, coronary artery disease and peripheral vascular disease, and more likely to have a history of ischaemic stroke. CONCLUSIONS 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.

Dopamine agonist use and the risk of heart failure.

A potential risk of heart failure was recently observed in randomized trials of the dopamine agonist pramipexole. The extent of the risk with this and other dopamine agonists is unknown.

Thiazolidinediones and the risk of incident strokes in patients with type 2 diabetes: a nested case-control study†

To determine whether the use of thiazolidinediones (TZDs) decreases the risk of incident strokes in patients with type 2 diabetes.

Long-Acting Bronchodilator Initiation in COPD and the Risk of Adverse Cardiopulmonary Events: A Population-Based Comparative Safety Study

Background Long‐acting bronchodilators, including long‐acting beta2‐agonists (LABA) and the anticholinergic tiotropium, are recommended as initial maintenance therapy in COPD. Studies to date have been limited in size and reported ambivalent results on the comparative risk of cardiovascular, cerebrovascular, and pulmonary adverse events between these two long‐acting bronchodilators. Moreover, little information is available for the period when treatment is first initiated, a time when subjects may be especially at risk. Methods We identified a cohort of new users of long‐acting bronchodilators between 2002 and 2012, age 55 or older, from the United Kingdom’s Clinical Practice Research Datalink. Patients initiating tiotropium were matched on high‐dimensional propensity scores and prior inhaled corticosteroid use with patients initiating LABAs, and followed for 1 year for the occurrence of acute myocardial infarction, stroke, heart failure, arrhythmia, and pneumonia. Results A total of 26,442 tiotropium initiators were matched to 26,442 LABA initiators, mainly single inhalers combined with inhaled corticosteroids. The hazard ratio of acute myocardial infarction associated with tiotropium initiation, relative to LABA initiation, was 1.10 (95% CI, 0.88‐1.38), whereas for stroke it was 1.02 (95% CI, 0.78‐1.34), for arrhythmia 0.81 (95% CI, 0.60‐1.09), and heart failure 0.90 (95% CI, 0.79‐1.02). The incidence of pneumonia was significantly less with tiotropium (hazard ratio, 0.81; 95% CI, 0.72‐0.92). Conclusion COPD treatment initiation with tiotropium compared with LABA does not increase cardiovascular risk in the first year of treatment. The risk of pneumonia is higher with LABA, a likely effect of the inhaled corticosteroids present in many LABA inhalers used in real world clinical practice.

Risk of herpes zoster in patients prescribed inhaled corticosteroids: a cohort study

BackgroundLittle is known concerning risk factors for herpes zoster in the general population. We hypothesised that inhaled corticosteroids (ICS) are a risk factor for herpes zoster especially among users of inhibitors of cytochrome P450 enzymes involved in their metabolism.MethodsWe identified a cohort of adult users of respiratory medications in the General Practice Research Database and carried out a nested case control analysis of inhaled corticosteroid use among 8900 new cases of herpes zoster and 88032 controls matching on age and calendar time.ResultsThe adjusted odds ratio for the relationship between current use of ICS and the occurrence of herpes zoster was 1.00 (95% confidence interval (CI), 0.94-1.07). There was no increase in risk of herpes zoster even at higher ICS doses; odds ratio 1.05 (95% CI, 0.96-1.14). Among subjects with concomitant prescriptions for an ICS and an inhibitor of cytochrome P450 3A4, the point estimate for the association between herpes zoster and the use of higher doses of inhaled corticosteroids was 1.23 (95% CI, 0.81-1.88).ConclusionsThe use of inhaled corticosteroids, even at high doses and in conjunction with inhibitors of their metabolism, was not a significant risk factor for the occurrence of herpes zoster in adults.

Statins and Risk of Rheumatoid Arthritis ‐ A Nested Case‐Control Study

Statins have antiinflammatory/immunomodulatory effects that may be useful in preventing rheumatoid arthritis (RA), but previous observational studies about the risk of RA with statin use yielded conflicting results. The aim of this study was to determine whether high‐intensity statin treatment is associated with reduced risk of RA.