Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD.

The objective of this study was to describe risks of death and asthma outcomes with prescription of long-acting ß(2)-agonists (LABA), short-acting ß(2)-agonists (SABA) or inhaled corticosteroids (ICS) in general practice. The study population included ß(2)-agonist users aged ≥18 yrs, who were in the UK General Practice Research Database (GPRD), which is linked to the national registry of hospitalisations. The study included 507,966 patients with 5.5 million SABA, 4.0 million ICS and 1.3 million LABA prescriptions. Rates of asthma outcome increased with more severe treatment steps. The mortality rate was increased with least and most severe treatment steps. Higher relative rates (RR) of outcomes were found in recent starters and heavy long-term users with LABA, SABA and ICS. The RRs in heavy long-term users were 1.9 for all-cause mortality and 3.0 for asthma death with SABA, 1.4 and 1.6, respectively, with LABA and 1.7 and 2.2, respectively, with ICS. The RR of death was statistically similar over time between LABA and ICS despite changes in exposure. Risks for death and asthma outcomes varied substantially with exposure characteristics. The statistical power for detecting increases in asthma death was low. The results of this study did not indicate that LABA exposure was associated with an increased risk for all-cause mortality.

Does the varied use of NSAIDs explain the differences in the risk of myocardial infarction?

OBJECTIVE: To investigate the risk of myocardial infarction (MI) with diclofenac, ibuprofen and naproxen, taking into account the exposure patterns. DESIGN: Retrospective cohort study using the General Practice Research Database. Setting. UK primary care. Subjects. Patients aged 40+ years prescribed a traditional nonsteroidal anti-inflammatory drug (NSAID). The control cohort was frequency matched by disease risk score. INTERVENTION: Observational comparisons of MI rates. RESULTS: The study included 729,294 NSAID users and 443,047 controls. The relative rate (RR) for MI increased with cumulative and daily dose (RR = 1.05 with 0-4 prior prescriptions and RR = 1.49 with 30+; RR = 1.05 with daily dose of < 1200 mg ibuprofen and RR = 1.96 with dose of > or = 2400 mg per day; for diclofenac, the RR was 1.13 with < 150 mg per day and 2.03 with > or = 300 mg per day). Diclofenac users had higher risks of MI (RR = 1.21) than ibuprofen (RR = 1.04) or naproxen (RR = 1.03) users, but exposure varied between these drugs. Taking into account these exposure differences, it was found that the risk of MI was comparable in current and past long-term users. The patterns of hazard rates (i.e. absolute risks) of MI were similar in patients using ibuprofen, diclofenac or naproxen with similar history of NSAID use. There was no statistical difference between ibuprofen, diclofenac and ibuprofen in the linear trends for cumulative dose or daily dose. CONCLUSIONS: Long-term users of traditional NSAIDs have an increased risk of MI that is probably explained by the underlying disease severity. Most of the differences in MI risk between diclofenac, ibuprofen or naproxen may be explained by their varied use.

A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients.

The association of multiple sclerosis with alleles/haplotypes from the HLA region on chromosome 6p21 is well established although the remainder of the genome remains relatively unexplored. We have completed a genome-wide screen for linkage disequilibrium in a cohort of Australian multiple sclerosis patients positive for HLA-DRB1*1501. A total of 4346 microsatellite markers provided through the "Genetic Analysis of Multiple sclerosis in EuropeanS" (GAMES) collaborative were analysed in DNA separately pooled from cases (n=217) and controls (n=187). Associations were found in four genomic regions (12q15, 16p13, 18p11 and 19q13) previously identified in linkage genome screens. Three additional regions of novel association were also identified (11q12, 11q23 and 14q21). Further analysis of these regions is required to establish whether the associations observed are due to epistatic interaction with the HLA locus.

A genome screen for linkage disequilibrium in Turkish multiple sclerosis.

In order to screen the Turkish population for evidence of association with multiple sclerosis, we typed 6000 microsatellite markers in separately pooled DNA samples from 197 cases and 199 controls following the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) protocol. Twelve markers showing evidence for association were identified. One of these markers lying directly in a region which is also implicated in the Turkish linkage screen (chromosome 5p15) and thus shows evidence for both linkage and association in independent data sets.

A whole genome screen for association with multiple sclerosis in Portuguese patients.

Multiple sclerosis (MS) is common in Europe affecting up to 1:500 people. In an effort to identify genes influencing susceptibility to the disease, we have performed a population-based whole genome screen for association. In this study, 6000 microsatellite markers were typed in separately pooled DNA samples from MS patients (n=188) and matched controls (n=188). Interpretable data was obtained from 4661 of these markers. Refining analysis of the most promising markers identified 10 showing potential evidence for association.

A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice.

BACKGROUND: Anticoagulation management of patients with atrial fibrillation (AF) should be tailored individually on the basis of ischemic stroke risk. The objective of this study was to compare the predictive ability of 15 published stratification schemes for stroke risk in actual clinical practice in the UK. METHODS: AF patients aged ≥ 18 years in the General Practice Research Database, which contains computerized medical records, were included. The c-statistic was estimated to determine the predictive ability for stroke for each scheme. Outcomes included stroke, hospitalizations for stroke, and death resulting from stroke (as recorded on death certificates). RESULTS: The study cohort included 79,844 AF patients followed for an average of 4 years (average of 2.4 years up to the start of warfarin therapy). All risk schemes had modest discriminatory ability in AF patients, with c-statistics for predicting events ranging from 0.55 to 0.69 for strokes recorded by the general practitioner or in hospital, from 0.56 to 0.69 for stroke hospitalizations, and from 0.56 to 0.78 for death resulting from stroke as reported on death certificates. The proportion of patients assigned to individual risk categories varied widely across the schemes, with the proportion categorized as moderate risk ranging from 12.7% (CHA(2) DS(2)-VASc) to 61.5% (modified CHADS(2)). Low-risk subjects were truly low risk (with annual stroke events < 0.5%) with the modified CHADS(2), National Institute for Health and Clinical Excellence and CHA(2) DS(2) -VASc schemes. CONCLUSION: Current published risk schemes have modest predictive value for stroke. A new scheme (CHA(2) DS(2) -VASc) may discriminate those at truly low risk and minimize classification of subjects as intermediate/moderate risk. This approach would simplify our approach to stroke risk stratification and improve decision-making for thromboprophylaxis in patients with AF.

Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients.

Atrial fibrillation (AF) carries an increased risk of ischaemic stroke, and oral anticoagulation with warfarin can reduce this risk. The objective of this study was to evaluate the association between time in therapeutic International Normalised Ratio (INR) range when receiving warfarin and the risk of stroke and mortality. The study cohort included AF patients aged 40 years and older included in the UK General Practice Research Database. For patients treated with warfarin we computed the percentage of follow-up time spent within therapeutic range. Cox regression was used to assess the association between INR and outcomes while controlling for patient demographics, health status and concomitant medication. The study population included 27,458 warfarin-treated (with at least 3 INR measurements) and 10,449 patients not treated with antithrombotic therapy. Overall the warfarin users spent 63% of their time within therapeutic range (TTR). This percentage did not vary substantially by age, sex and CHA2DS2-VASc score. Patients who spent at least 70% of time within therapeutic range had a 79% reduced risk of stroke compared to patients with ≤30% of time in range (adjusted relative rate of 0.21; 95% confidence interval 0.18-0.25). Mortality rates were also significantly lower with at least 70% of time spent within therapeutic range. In conclusion, good anticoagulation control was associated with a reduction in the risk of stroke.

Changes in the characteristics of patients prescribed selective cyclooxygenase 2 inhibitors after the 2004 withdrawal of rofecoxib.

OBJECTIVE: To evaluate the impact of rofecoxib withdrawal on the characteristics of patients prescribed selective cyclooxygenase 2 (COX-2) inhibitors. METHODS: The General Practice Research Database was used to identify patients age > or =18 years who were prescribed a selective COX-2 inhibitor. Various patient characteristics were noted at the start of therapy: age, sex, nonsteroidal antiinflammatory drug-related risk factors for upper gastrointestinal (GI) events, and the Framingham risk score for cardiovascular disease. Logistic regression was used to compare patients using selective COX-2 inhibitors before and after September 2004. RESULT: The study population included 171,645 patients receiving selective COX-2 inhibitors. The number of users substantially increased over time until September 2004 and sharply declined thereafter. Approximately 80% stopped selective COX-2 inhibitor therapy within 6 months. Patients receiving selective COX-2 inhibitors after September 2004 were younger and included more men compared with those receiving therapy before September 2004. There was no change before and after September 2004 in the proportion of patients with GI risk factors or high Framingham risk scores, after adjustment for age and sex. A correlation was found between presence of GI risk factors and high Framingham risk scores. Only 20% of patients receiving selective COX-2 inhibitors had GI risk factors but low Framingham risk score, which did not change after September 2004. CONCLUSION: There was no channeling in the usage of selective COX-2 inhibitors toward patients with a high risk of GI and low risk of cardiovascular disease following the withdrawal of rofecoxib.