C Sammon

The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns

BACKGROUND In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Evaluating the Hazard of Foetal Death following H1N1 Influenza Vaccination; A Population Based Cohort Study in the UK GPRD

Background To evaluate the risk of foetal loss associated with pandemic influenza vaccination in pregnancy. Retrospective cohort study. UK General Practice Research Database Pregnancies ending in delivery or spontaneous foetal death after 21 October 2009 and starting before 01 January 2010. Methodology/Principal Findings Hazard ratios of foetal death for vaccinated compared to unvaccinated pregnancies were estimated for gestational weeks 9 to 12, 13 to 24 and 25 to 43 using discrete-time survival analysis. Separate models were specified to evaluate whether the potential effect of vaccination on foetal loss might be transient (for ∼4 weeks post vaccination only) or more permanent (for the duration of the pregnancy). 39,863 pregnancies meeting our inclusion criteria contributed a total of 969,322 gestational weeks during the study period. 9,445 of the women were vaccinated before or during pregnancy. When the potential effect of vaccination was assumed to be transient, the hazard of foetal death during gestational weeks 9 through 12 (HRunadj 0.56; CI95 0.43 to 0.73) and 13 through 24 (HRunadj 0.45; CI95 0.28 to 0.73) was lower in the 4 weeks after vaccination than in other weeks. Where the more permanent exposure definition was specified, vaccinated pregnancies also had a lower hazard of foetal loss than unvaccinated pregnancies in gestational weeks 9 through 12 (HRunadj 0.74; CI95 0.62 to 0.88) and 13 through 24 (HRunadj 0.59; CI95 0.45 to 0.77). There was no difference in the hazard of foetal loss during weeks 25 to 43 in either model. Sensitivity analyses suggest the strong protective associations observed may be due in part to unmeasured confounding. Conclusions/Significance Influenza vaccination during pregnancy does not appear to increase the risk of foetal death. This study therefore supports the continued recommendation of influenza vaccination of pregnant women.

Factors associated with uptake of seasonal and pandemic influenza vaccine among clinical risk groups in the UK: an analysis using the General Practice Research Database.

BACKGROUND Influenza vaccine uptake rates are low compared with uptake rates of many other vaccines. It is unclear how this differs between risk groups in the population and between pandemic and non-pandemic influenza vaccines. AIM This study sought to estimate uptake rates of pandemic and seasonal influenza vaccines among clinical risk groups in the UK during the 2009/2010 influenza season and to identify predictors of vaccine uptake in this cohort. METHODS Uptake rates were calculated using data from the UK General Practice Research Database (GPRD). Predictors of vaccination were identified using a modified Poisson regression with robust standard error estimates. RESULTS Uptake of pandemic influenza vaccine in clinical risk groups was 40.3% and uptake of seasonal influenza vaccine was 61.3%. Factors found to be predictive of seasonal and pandemic influenza vaccination included age and the total number of underlying health conditions an individual had. At risk individuals in those age groups in which universal vaccination of the general population was recommended were more likely to have been vaccinated than individuals in age groups in which only clinical risk groups were recommended for vaccination; hence children in clinical risk groups were more likely to receive pandemic than seasonal influenza vaccine. In older people, having a history of Guillain Barré syndrome was associated with a reduced likelihood of receipt of both seasonal (IRR(adj) 0.83, CI(95) 0.77-0.90) and pandemic influenza vaccines (IRR(adj) 0.82, CI(95) 0.73-0.92). DISCUSSION Uptake of pandemic influenza vaccine was lower than that of seasonal influenza vaccine among those at a clinically high risk of influenza related morbidity. This suggests that vaccination strategies may need to be altered during future pandemics. Recommending universal vaccination within age categories in which there is a large proportion of high risk individuals could be considered as this may result in higher uptake among clinical risk groups.

Pandemic influenza vaccination during pregnancy: An investigation of vaccine uptake during the 2009/10 pandemic vaccination campaign in Great Britain

Background: Pregnant women in Great Britain were recommended to receive influenza A(H1N1)pdm09 vaccines during the 2009/10 influenza pandemic, however uptake of the vaccines by pregnant women was reported to have been very low. Aim: We sought to estimate uptake of influenza A(H1N1)pdm09 vaccines and to investigate predictors of vaccine uptake in pregnant women in Great Britain during the 2009/10 pandemic. Methods: Uptake rates were calculated using data from the UK General Practice Research Database (GPRD). Predictors of vaccination were identified using a Cox proportional hazards model. Results: Uptake of influenza A(H1N1)pdm09 vaccines by pregnant women was 21.6%. Pregnant women with an underlying health condition increasing the risk of influenza-related complications had a higher vaccination rate than pregnant women without such conditions. The hazard ratio comparing these two groups decreased logarithmically throughout pregnancy from 9.3 in the first week to 1.3 by the end of pregnancy. Increasing maternal age (HR 1.01, CI95 1.01–1.01), having a previous delivery recorded (HR 1.21, CI95 1.16–1.27) and living in Scotland (HR 2.58, CI95 2.34–2.85) or Wales (HR 1.37, CI95 1.20–1.57) as opposed to England were all also associated with an increase in vaccination uptake rates throughout pregnancy. Discussion: Uptake of influenza A(H1N1)pdm09 vaccines by pregnant women was low. None of the potential predictors evaluated in this study were strong enough to account for this, however information on health beliefs and GP recommendation were not available. If the low rates reported here are to be improved new strategies to increase uptake of influenza vaccine in pregnant women need to be identified, evaluated and implemented.

The Clinical Practice Research Datalink for drug safety in pregnancy research: an overview.

Medicine use during pregnancy is common; however the safety of medicine use during pregnancy is largely unknown when a medicine comes to market. Electronic healthcare databases, including the Clinical Practice Research Datalink (CPRD), are increasingly being used for post-marketing surveillance in this field. The CPRD contains anonymised, longitudinal medical records routinely collected in primary care. Using CPRD data it is possible to identify medical records indicative of pregnancy, including pregnancy losses. Data on prescriptions issued can be used to determine maternal exposure and for about 80% of pregnancies it is possible to link the mothers medical record to the medical record of the child. Data in the medical records of the mother and child can then be used to identify adverse pregnancy outcomes, including congenital malformations. This paper describes some of the complexities involved in using CPRD data for pregnancy related research and discusses some of its strengths and limitations.

Missing laboratory test data in electronic general practice records: analysis of rheumatoid factor recording in the clinical practice research datalink

To investigate whether information from the literature could be used to identify periods of practice data in an electronic healthcare database during which rheumatoid factor (RF) test results are likely to be missing‐not‐at‐random (MNAR).

The incidence of childhood and adolescent seizures in the UK from 1999 to 2011: A retrospective cohort study using the Clinical Practice Research Datalink

BACKGROUND In postmarketing vaccine surveillance, adverse events observed in a vaccinated population are compared to the number expected based on a background incidence rate. The background rate should be accurate and obtained from a population comparable to the one vaccinated. Such rates are often not available. METHODS The incidence rate of generalised convulsive, febrile and afebrile seizures was estimated in individuals born after 01-January-1998 and aged between 2 months and 15 years of age using the UK Clinical Practice Research Datalink (1999-2011). RESULTS The study population consisted of 1532,992 individuals (4917,369 person years (PY) of follow up). A total of 28,917 generalised convulsive seizure events were identified during follow-up, the overall incidence rate was 5.88 per 1000PY. Age specific rates increased sharply from 4/1000PY at 2 months of age, peaked at 19/1000PY at 16 months and decreased until approximately 6 years of age at which point they became relatively stable at 2/1000PY. 67% of GCSs were categorised as febrile: 56% using Read codes, 11% using free text. Febrile seizures accounted for the age trend in GCS, with rates peaking at 16.1/1000PY at 16 months of age while afebrile seizure rates remained relatively stable across all ages (24 seizures per 1000PY). Analysis by first occurrence of febrile seizure showed a similar pattern, comparable to published studies on the incidence of seizures in childhood. DISCUSSION The rates reported in this study could be used in the postmarketing surveillance of infant vaccines. However, given the variation across strata, and the potential underascertainment of seizure events presenting to A&E, care must be taken when interpreting and using these rates.

Estimating the diagnostic accuracy of rheumatoid factor in UK primary care: a study using the Clinical Practice Research Datalink

OBJECTIVE To investigate the diagnostic accuracy of RF as a test for RA in primary care and its impact on referral times using the Clinical Practice Research Datalink. METHODS We identified all patients with a first RF test recorded in the Clinical Practice Research Datalink between 1 January 2000 and 31 December 2008 and those diagnosed with RA within 2 years of testing. We calculated likelihood ratios (LRs), sensitivity, specificity and predictive values of RF for a diagnosis of RA. We compared time to hospital referral in those testing positive and negative using Kaplan-Meier failure curves and log-rank tests. RESULTS Of 62 436 first RF tests, 4679 (7.5%) were positive. There were 1753 incident cases of RA, of which 57.8% were seropositive. The positive LR for RF was 9.5 (95% CI 9.0, 10.0) and the negative LR was 0.5 (95% CI 0.4, 0.5). Sensitivity and specificity were 57.8% (95% CI 55.4%, 60.1%) and 93.9% (95% CI 93.7%, 94.1%) and the positive predictive value and negative predictive value were 21.4% (95% CI 20.3%, 22.6%) and 98.7% (95% CI 98.6%, 98.8%), respectively. Median time to first hospital contact after the first RF test in those with seropositive vs seronegative results was 54 days (95% CI 49, 58) vs 150 (95% CI 147, 152). CONCLUSION Only 2.8% of patients undergoing RF testing were diagnosed with RA, suggesting that RF is used to screen patients with musculoskeletal symptoms rather than those with more specific features of RA. A positive RF test may be helpful in diagnosing RA in primary care but performs badly in excluding RA and may delay referral.

Swine flu vaccination in pregnancy and associated miscarriage risk

Background: Two case reports of polymyalgia rheumatica (PMR) and one case-report of PMR and temporalis arteritis (AT) suggest that the use of statins may have triggered the development of these inflammatory rheumatic diseases. PMR is closely linked to the disease arteritis temporalis which makes it difficult for physicians to distinguish these two diseases. Data on the association between the use of statins and PMR and/or AT are scarce. Objectives: To assess the association between statin use and the occurrence of PMR/AT. Methods: A case/non-case study based on individual case safety reports (ICSR) listed in the World Health Organisation (WHO) global ICSR database (Vigibase) was conducted. According to WHO adverse reaction terminology, cases were defined as reports of PMR. Each case was matched with five non-cases by age, gender and time of reporting. Non-cases were all other ADR-reports. Use of statins was classified according to the Anatomical Therapeutic Chemical (ATC) classification code system (C10AA, C10BA, C10BX). Potential confounders in the analysis, i.e., use of corticosteroids, immunosuppressive drugs, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, anti-epileptics, proton pump inhibitors and cardiovascular drugs were determined. Multivariate logistic regression was used to calculate the reporting odds ratios (RORs) with 95% confidence intervals (CI). In addition, three case-reports from the VigiBase were studied in detail. Results: We identified 327 reports of PMR/AT as cases and 1635 reports of other ADRs as non-cases. Among cases statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were statistically significantly associated with reports of PMR/AT (ROR 14.21; 95% CI 9.89-20.85). Conclusions: The result of this study underlines findings of the case reports that the use of statins may be associated with the occurrence of PMR/AT.Background: In The Netherlands, the largest outbreak of Q fever worldwide is ongoing. A particular risk group concerns pregnant women in which the infection is mostly asymptomatic. Q fever during pregnancy may cause both obstetric complications as well as chronic infection in the mother. Long term antibiotic treatment of infected women may reduce the risk of complications. Objectives: A clustered randomized controlled trial to assess the effects of screening for Q fever during pregnancy is ongoing (trial register number NL30340.042.09). The primary endpoint is a maternal or obstetric complication in Q fever positive women. Methods: Midwife centers in high-risk Q fever areas were randomized to recruit pregnant women for the screening or control strategy. In both groups a blood sample was taken between 20 and 32 weeks of gestation. In the screening group this sample was immediately analyzed with indirect immunofluorescence assay for the detection of IgG and IgM antibodies. Every positive sample was fully titrated. In case of acute or chronic infection antibiotic treatment advice was given. In the control group serum was frozen for analysis after delivery. Results: In all, 55 of 99 eligible midwife centers were randomized. They recruited 1222 pregnant women from which a blood sample was taken; 534 for the screening group and 688 for the controle group. Fourteen percent in both groups had serologic evidence for an acute or previous Q fever infection. Only 7 participants in the intervention group had evidence for an acute infection and were treated with antibiotics (erythromycin or cotrimoxazole). Three of them experienced side-effects, mainly gastro-intestinal, of which one consulted the gynecologist due to the side-effects. Since a part of the participants still have to deliver, data collection on clinical outcome is still ongoing. Conclusions: Fourteen percent of the pregnant women in high-risk Q fever areas have evidence of Q fever infection. Only a very small part has an acute infection, in which treatment is though to be needed. Clinical outcome data and cost-effectiveness analyses are expected in spring and will be presented.

Patterns of use of incretin-based therapies in Europe and USA:

Background: Sudden discontinuation of some antihypertensive agents such as beta-blockers and centrally acting antihypertensive agents are associated with increased risk of acute coronary events. Objectives: The aim of this study was to assess the association between discontinuation of different antihypertensive agents and the risk of acute myocardial infarction (AMI). Methods: A nested case control study was performed in a cohort of antihypertensive drug users from the Utrecht Cardiovascular Pharmacogenetics (UCP) database. Within this cohort, patients who were hospitalized for first AMI were considered cases. Cases were matched (1 up to 4) to controls at the same AMI date (index date). Antihypertensive users were defined as current users if the index date fell within prescribed duration or as stoppers if this date fell outside the prescribed duration. According to recency of stopping, stoppers were divided into recent stoppers (≤90 days), intermediate-term stoppers (91-180 days), and longterm stoppers (>180 days). The study included only antihypertensive users who were specifically current users or stoppers of one antihypertensive agent. Logistic regression analysis was used to assess the association between the discontinuation of antihypertensive agents and the risk of AMI and to control for confounding. Results: We included 1245 cases and 4994 controls in our analysis. The risk of AMI was significantly increased with all stoppers of beta-blockers (adjusted OR: 1.54, 95%CI (1.25-1.90)), calcium channel blockers (CCBs) (adjusted OR: 2.25, 95%CI (1.53- 3.30)), and diuretics (adjusted OR: 1.76, 95%CI (1.24-2.48)) compared with current users. Moreover, the risk of AMI was significantly increased for longterm stoppers (beta-blockers, CCBs, angiotensinconverting enzyme inhibitors, and diuretics) and intermediate- term stoppers (beta-blockers and CCBs) versus current users. There was no difference in AMI risk between recent stoppers of antihypertensive agents versus current users. Conclusions: Discontinuation of antihypertensive agents increases the risk of AMI after more than 90 days of stopping. Adherence to antihypertensive agents plays an important role in reducing the risk of AMI in patients with hypertension.Background: It has been reported that patients with type 1 diabetes (T1DM) have a decreased lung function. Studies on the association of T1DM and asthma in children show controversial results. Objectives: The aim of this study was to quantify asthma medication use in children and adolescents with and without (reference cohort) T1DM 5 years before and after the onset of diabetes. Methods: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System. All children (1. Modelling of Endpoint Postponement for All-Cause Mortality in Statin Trials Morten Rix Hansen, Anton Pottegård, Asbjørn Hróbjartsson, Per Damkier, René D Christensen, Kasper Søltoft Larsen, Malene EL Kristensen, Palle M Christensen, Jesper Hallas. Clinical Pharmacology, University of Southern Denmark, Odense, Denmark; Department of Clinical Chemistry and Pharmacology, Odense University Hospital, Odense, Denmark; The Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark; Research Unit for General Practice, University of Southern Denmark, Odense, Denmark. Background: The average postponement of the outcome event has been proposed as a novel method to present the magnitude of effect for preventive medications. This measure has been shown to have better agreement with patient preferences than conventional outcomemeasures, including the “number needed to treat” (NNT), possibly because it is more intuitively understood. For some interventions, it may also provide a better theoretical frame for how benefit is distributed among participants than the NNT measure. The aim of this study was to present a novel method for modelling endpoint postponement (EP) from trial data and compare it with the usual approach of measuring the area between survival curves. We also present a formalized meta-analysis of modelled EP for all-cause mortality in statin trials. Methods: We identified 17 placebo-controlled statin trials that fulfilled our inclusion criteria. Eleven of these presented Kaplan–Meier curves for all-cause mortality. Average EP was calculated as the area between Kaplan–Meier curves by counting pixels on magnified prints for these 11 trials. The modelled EP was computed for all trials on the basis of (1) hazard ratio, relative risk or odds ratio; (2) the cumulative event rate in the untreated group; and (3) the trial’s running time. The underlying assumption was that the mortality was reasonably stable within the trials’ running time. The modelled EP was subjected to a meta-analysis, using inverse variance weighting in a random effect model. Results: EPswere generally small for estimates based on pixel-counting, 10 and 27days for trials both primary and secondary intervention that typically ran over 1.9– 6.1years. The modelled EPs varied between 2 and 34days. The difference between modeled EP and EP based on pixel-counting was between 8 and 12days. The results of the meta-analyses will be presented at the meeting. Conclusions: Based on these trial data, statin treatment results in a surprisingly small gain in average survival. Our modelled EP estimates agreed reasonably with EPs based on pixel-counting. The modeled EP is amenable to meta-analyses and may be a useful approach to presenting the benefit of preventive treatment. 2. Permanent User Bias in Case–Crossover Studies in Pharmacoepidemiology Jesper Hallas, Shirley V. Wang, Joshua J. Gagne, Sebastian Schneeweiss, Anton Pottegård. Clinical Pharmacology, University of Southern Denmark, Odense C, Denmark; Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. Background: In pharmacoepidemiology, the case– crossover design is based on cases that have contrasting drug exposure at the time of an event and at a reference time in the past. If the drug in question should be taken permanently, only certain exposure patterns will occur. These patients cannot be unexposed at the event time and exposed at the reference time, while the opposite pattern can occur if the drug was initiated recently. The resulting odds ratio (OR) would thus be biased upward. As many drugs have a subpopulation of permanent users, this bias might pervade many case–crossover analyses of drug effects. Objectives: The aims of this study were to demonstrate this “permanent user bias” and to evaluate whether it can be remedied by including a control group (case–time–control design). Methods: Using nationwide Danish data resources, we conducted case–crossover and case–time–control analyses for combinations of three exposures that are