Evaluating different physician's prescribing preference based instrumental variables in two primary care databases: a study of inhaled long-acting beta2-agonist use and the risk of myocardial infarction.

PURPOSE: Instrumental variable (IV) analysis with physician's prescribing preference (PPP) as IV is increasingly used in pharmacoepidemiology. However, it is unclear whether this IV performs consistently across databases. We aimed to evaluate the validity of different PPPs in a study of inhaled long-acting beta2-agonist (LABA) use and myocardial infarction (MI). METHODS: Information on adults with asthma and/or COPD and at least one prescription of beta2-agonist, or muscarinic antagonist was extracted from the CPRD (UK) and the Mondriaan (Netherlands) databases. LABA exposure was considered time-fixed or time-varying. We measured PPPs using previous LABA prescriptions of physicians or proportion of LABA prescriptions per practice. Correlation (r) and standardized difference (SDif) were used to assess assumption of IV analysis. RESULTS: For time-fixed LABA, the IV based on 10 previous prescriptions outperformed the other IVs regarding strength of the IV (r ≥ 0.15) and balance of confounders between IV categories (SDif < 0.10). None of the IVs we considered appeared to be valid for time-varying LABA. In CPRD (n = 490,499), which included approximately 18 times more subjects than Mondriaan (n = 27,459), IVs appeared more valid. LABA was not associated with MI; hazard ratios ranged from 0.86 to 1.18 for conventional analysis, and from 0.61 to 1.24 for the IV analyses with apparent valid IVs. CONCLUSIONS: The validity of physician's prescribing preference as IV strongly depends on how this IV is defined and in which database it is applied. Hence, general recommendations cannot be made, other than to generate several plausible IVs, assess their validity, and report the estimate(s) from apparently valid IVs.

Antiepileptic drug use in seven electronic health record databases in Europe: a methodologic comparison.

OBJECTIVE: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries due to use of different type of data sources, time periods, population distribution, and methodologic differences. This study aimed to measure prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, The Netherlands, the United Kingdom, and Germany using a standardized methodology and to investigate sources of variation. METHODS: Analyses on the annual prevalence of AEDs were stratified by sex, age, and AED. Overall prevalences were standardized to the European 2008 reference population. RESULTS: Prevalence of any AED varied from 88 per 10,000 persons (The Netherlands) to 144 per 10,000 in Spain and Denmark in 2001. In all databases, prevalence increased linearly: from 6% in Denmark to 15% in Spain each year since 2001. This increase could be attributed entirely to an increase in "new," recently marketed AEDs while prevalence of AEDs that have been available since the mid-1990s, hardly changed. AED use increased with age for both female and male patients up to the ages of 80 to 89 years old and tended to be somewhat higher in female than in male patients between the ages of 40 and 70. No differences between databases in the number of AEDs used simultaneously by a patient were found. SIGNIFICANCE: We showed that during the study period of 2001-2009, AED prescribing increased in five European Union (EU) countries and that this increase was due entirely to the newer AEDs marketed since the 1990s. Using a standardized methodology, we showed consistent trends across databases and countries over time. Differences in age and sex distribution explained only part of the variation between countries. Therefore, remaining variation in AED use must originate from other differences in national health care systems.

Inhaled anticholinergic drugs and risk of acute urinary retention.

UNLABELLED: Study Type--Harm (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Inhaled anticholinergic drugs have been associated with the risk of acute urinary retention (AUR), but this association was never studied under real life circumstances nor was this risk ever quantified. Use of inhaled anticholinergic drugs increases the risk of AUR by 40%. The risk of AUR is highest in recent starters, in patients with benign prostatic hyperplasia (BPH), and in patients receiving their anticholinergic drugs via nebulizer. It might be advisable to consider alternatives for inhaled anticholinergic drugs in COPD patients with BPH. OBJECTIVE: • To investigate the association between the use of inhaled anticholinergic drugs and the risk of acute urinary retention (AUR) under real-life circumstances. PATIENTS AND METHODS: • We conducted a nested case-control study within a cohort of patients with chronic obstructive pulmonary disease (COPD; as AUR has been associated with the use of inhaled anticholinergic drugs, which are used as first-line treatment for COPD) from the Integrated Primary Care Information (IPCI) database. • The cohort consisted of all patients with COPD aged ≥45 years, registered between 1996 and 2006, with ≥12 months of valid history. Cases were patients with a first diagnosis of AUR. • To each case, controls were selected matched for age, gender and index date. • Multivariate conditional logistic regression analysis was used to calculate adjusted odds ratios (OR(adj)) with 95% confidence intervals (95% CI). RESULTS: • Within the cohort of 22,579 patients with COPD, 209 cases were identified. • Current use of inhaled anticholinergic drugs was associated with a 40% increase in risk for AUR (OR(adj) 1.40; 95% CI 0.99-1.98) compared with non-users. • Among current users, the risk was highest for the recent starters (OR(adj) 3.11; 95% CI 1.21-7.98). The risk of long-acting anticholinergic drug tiotropium was not substantially different from that of the short-acting anticholinergic ipratropium. • The association was not dose-dependent, but changed by mode of administration, with nebulizers having the highest risk (OR(adj) 2.92; 95% CI 1.17-7.31). • In men with COPD and benign prostatic hyperplasia (BPH) the association was strongest (OR(adj) 4.67; 95% CI 1.56-14.0). CONCLUSION: • Current use of inhaled anticholinergic drugs increases the risk of AUR, especially in patients with BPH or if administered via a nebulizer.

Calcium channel blockers and cancer: a risk analysis using the UK Clinical Practice Research Datalink (CPRD).

OBJECTIVE: The evidence of an association between calcium channel blockers (CCBs) and cancer is conflicting. The objective of the present study was to evaluate the risk of cancer (all, breast, prostate and colon cancers) in association with exposure to CCB. METHODS: This is a population-based cohort study in patients exposed to CCBs from across the UK, using two comparison cohorts: (1) patients with no exposure to CCB (non-CCB) matched on age and gender and (2) unmatched patients unexposed to CCB and at least one other antihypertensive (AHT) prescription. Cancer incidence rates computed in the exposed and the two unexposed groups were compared using HRs and 95% CIs obtained from multivariate Cox regression analyses. RESULTS: Overall, 150,750, 557,931 and 156,966 patients were included, respectively, in the CCB, non-CCB and AHT cohorts. Crude cancer incidence rates per 1000 person-years were 16.51, 15.75 and 10.62 for the three cohorts, respectively. Adjusted HRs (CI) for all cancers comparing CCB, non-CCB and AHT cohorts were 0.88 (0.86 to 0.89) and 1.01 (0.98 to 1.04), respectively. Compared to the AHT cohort, adjusted HRs (CI) for breast, prostate and colon cancer for the CCB cohort were 0.95 (0.87 to 1.04), 1.07 (0.98 to 1.16) and 0.89 (0.81 to 0.98), respectively. Analyses by duration of exposure to CCB did not show excess risk. CONCLUSIONS: This large population-based study provides strong evidence that CCB use is not associated with an increased risk of cancer. The analyses yielded robust results across all types of cancer and different durations of exposure to CCBs.

COPD in the general population: prevalence, incidence and survival.

Worldwide, COPD is a leading cause of chronic morbidity and mortality. Although its prevalence is already well documented, very few studies have measured its incidence. We therefore investigated the prevalence, incidence and lifetime risk of COPD in the general population. In a population-based study including subjects ≥ 40, with 12 months of history available in the Dutch IPCI database, we identified COPD cases by a two-step validation algorithm. Among 185,325 participants with 601,283 years of follow-up, 7308 subjects with COPD were identified, and 1713 had incident COPD. The overall IR of physician-diagnosed COPD was 2.92/1000PY (95%CI 2.78-3.06). The incidence of COPD was higher in men (3.54; 95%CI 3.33-3.77) than in women (2.34; 95%CI 2.17-2.52), and the overall baseline prevalence of COPD was 3.02% (95%CI 2.94-3.10). For people who had entered the study free of COPD at the age of 40, the risk of developing COPD within the next 40 years was 12.7% for men and 8.3% for women. In patients with very severe COPD, 26% died after 1 year of follow-up, whereas 2.8% died among the non-COPD subjects. In the general population in the Netherlands, three on 1000 subjects were diagnosed with COPD per year. The incidence increased rapidly with age and was higher in men than in women. One in eight men and one in 12 women, being COPD free at the age of 40, will develop COPD during their further life. Mortality rates differed substantially between COPD patients and non-COPD subjects of the same age, underlining the burden of this disease.