Paddy Farrington

General population based study of the impact of tricyclic and selective serotonin reuptake inhibitor antidepressants on the risk of acute myocardial infarction

Objective: To investigate the impact of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) on the risk of first acute myocardial infarction (MI). Design: Case–control analysis and a self controlled case series. Setting: 644 general practices throughout England, Scotland, Wales, and Northern Ireland. Patients: Over 60 000 cases of MI and 360 000 age, sex, and practice matched controls randomly selected from the UK General Practice Research Database. Main outcome measures: Matched odds ratios and incidence rate ratios estimating whether there is an acute or prolonged increased risk of MI after exposure to TCA and SSRI drugs and individual drugs within these families. Results: Case–control analysis found an initial increased risk of MI after TCA exposure (for example, at 1–7 days after the first dothiepin prescription: odds ratio (OR) 1.90, 95% confidence interval (CI) 1.15 to 3.14) or SSRI exposure (for example, at 1–7 days after first fluoxetine prescription: OR 2.59, 95% CI 1.44 to 4.66). In the self controlled analysis the equivalent risk estimates were an incidence rate ratio of 1.43, 95% CI 0.92 to 2.22 for dothiepin and an incidence rate ratio of 1.66, 95% CI 1.01 to 2.71 for fluoxetine. Conclusions: Antidepressant prescriptions are associated with an increased risk of MI. The size of these effects is similar for TCA and SSRI exposures; however, the lack of specificity between types of antidepressants and the lower risks found in the self controlled analysis suggest that these associations are more likely due to factors relating to underlying depression and health services utilisation than to specific adverse drug effects.

Use of nicotine replacement therapy and the risk of acute myocardial infarction, stroke, and death

Objective: To determine whether nicotine replacement therapy (NRT) is associated with an increased risk of acute myocardial infarction, acute stroke, or death. Design: Self control case series analysis of data from The Health Improvement Network (THIN) to estimate the relative incidence of myocardial infarction and stroke in four 14 day periods before and after the first prescription for NRT. Setting: THIN is a computerised general practice database. Subjects: Patients contributing data to THIN. Interventions: Observational study of NRT. Main outcomes: Acute myocardial infarction, acute stroke, and death. Results: 33 247 individuals had been prescribed NRT, of whom 861 had had a myocardial infarction and 506 a stroke. There was a progressive increase in the incidence of first myocardial infarction in the 56 days leading up to the first NRT prescription (overall incidence ratio 5.55, 95% confidence interval (CI) 4.42 to 6.98), but the incidence fell after this time and was not increased in the 56 days after starting NRT (incidence ratio 1.27, 95% CI 0.82 to 1.97). The results were similar for second myocardial infarction and stroke, and for subgroups of people with pre-existing angina and hypertension. There were 960 deaths in our cohort during a mean follow up period of 2.6 years after starting NRT, with no evidence of an increased mortality in the 56 days after the NRT prescription (incidence ratio 0.86, 95% CI 0.60 to 1.23). Conclusions: The use of NRT is not associated with any increase in the risk of myocardial infarction, stroke, or death.

Does influenza vaccination increase consultations, corticosteroid prescriptions, or exacerbations in subjects with asthma or chronic obstructive pulmonary disease?

Background: Concern over the safety of influenza vaccination in individuals with obstructive airways disease has contributed to suboptimal rates of vaccine uptake in this group. We investigated the safety of influenza vaccine in older people with asthma or chronic obstructive pulmonary disease (COPD) in a cohort from the UK General Practice Research Database (GPRD). Methods: A population based cohort study of 12 000 individuals with asthma or COPD from 432 general practices was conducted. Incidence rate ratios (IRR) were calculated for asthma or COPD diagnoses, prescriptions for oral corticosteroids, and acute exacerbations on the day of vaccination and on days 1–2 and 3–14 after vaccination compared with other time periods in the influenza season. Results: The IRRs for asthma or COPD diagnoses and oral corticosteroid prescriptions were increased on the day of vaccination (for example, the IRR for oral corticosteroid prescriptions for subjects with asthma during the 1992–3 influenza season was 8.24 (95% confidence interval 5.54 to 12.26)). However, there was no consistent increase in the IRR of any of the outcomes on days 1–2 or 3–14 after vaccination, and most of these IRRs were close to 1. Rates of exacerbation were low and showed no consistent statistically significant increase during any risk periods. Conclusions: Older people with asthma or COPD commonly have diagnoses recorded or prescriptions for oral corticosteroids given on the day of influenza vaccination, but there is no increased risk of adverse acute outcomes in the first 2 weeks after vaccination. Our findings strongly suggest that influenza vaccination is safe in this population.

Bupropion and the risk of sudden death: a self-controlled case-series analysis using The Health Improvement Network

Background: Bupropion is an effective smoking cessation therapy but its use in the UK has been limited by concerns that it may increase the risk of sudden death. Methods: Data for all patients prescribed bupropion within The Health Improvement Network (a computerised general practice database) were extracted and the self-controlled case-series method was used to estimate the relative incidence of death during the first 28 days of treatment. The incidence of seizures, a recognised adverse effect of bupropion, was also investigated during this period. Results: A total of 9329 individuals had been prescribed bupropion (mean age 44 years, 48% male). The total person-time after the first prescription for bupropion was 17 586 years, and during this time 121 people died. Two people died within the first 28 days of treatment, which was less than expected in comparison with the remaining observation period by an incidence ratio of 0.50 (95% confidence interval (CI) 0.12 to 2.05). Twenty eight people were recorded as having a total of 45 seizures (23 before starting bupropion, two in the first 28 days of treatment, and 20 at a later point). The relative incidence of seizures during the first 28 days of treatment was 3.62 (95% CI 0.87 to 15.09), equivalent to one additional seizure per 6219 first time bupropion users. Conclusions: Bupropion use is probably associated with an increased risk of seizures, but no evidence was found to suggest that the drug is associated with an increased risk of sudden death.

Does oral polio vaccine cause intussusception in infants? Evidence from a sequence of three self-controlled cases series studies in the united kingdom

Background: The use of live oral poliomyelitis vaccine (OPV) has led to the elimination of poliomyelitis disease in many countries since licensure in 1960. The discovery of an increased risk of an intestinal obstruction known as intussusception following live rotavirus vaccination raised questions about the possibility of a link between live OPV and intussusception. Methods: Three self-controlled case-series studies were carried out. The first was exploratory and included 218 intussusception episodes from hospital admissions data linked to vaccination records in the Thames region. The two subsequent studies, which used further hospital admissions data and the General Practice Research Database (GPRD) included 107 and 198 episodes respectively and were used to test hypotheses generated in the first study. Results: In the exploratory study risk periods of up to 6 weeks after each dose were examined. The only period with some evidence of an increased risk was the 14–27-day period after the third dose (relative incidence (RI) = 1.97, p = 0.011). The second hospital admissions study and the GPRD study showed no evidence of an increased relative incidence in any putative risk period and did not confirm the increased risk in the 14–27-day period after dose 3 with a combined RI of 1.03. Conclusions: The sequence of studies does not support the hypothesis that OPV causes intussusception. The increased RI in the first study may be explained as a chance finding due to the number of risk periods examined and highlights the need for caution when looking at many risk periods without an a priori hypothesis.

An improved algorithm for outbreak detection in multiple surveillance systems.

Objective To improve the performance of the England and Wales large scale multiple statistical surveillance system for infectious disease outbreaks with a view to reducing the number of false reports, while retaining good power to detect genuine outbreaks. Introduction There has been much interest in the use of statistical surveillance systems over the last decade, prompted by concerns over bioterrorism, the emergence of new pathogens such as SARS and swine flu, and the persistent public health problems of infectious disease outbreaks. In the United Kingdom (UK), statistical surveillance methods have been in routine use at the Health Protection Agency (HPA) since the early 1990s and at Health Protection Scotland (HPS) since the early 2000s (1,2). These are based on a simple yet robust quasi-Poisson regression method (1). We revisit the algorithm with a view to improving its performance. Methods We fit a quasi-Poisson regression model to baseline data. One of the limitations of the current algorithm is the small number of baseline weeks used. We propose a simple seasonal adjustment using factors. We extend the model to include a 10-level factor. We fit the trend component always irrespective of its statistical significance. We are concerned that the existing weighting procedure is too drastic. The baseline at a certain week is down-weighted if the standardized Anscombe residual for that week is greater than 1. This condition was chosen empirically to avoid reducing the sensitivity of the system in the presence of large outbreaks in the baselines, but may be increasing the FPR unduly when there are no or only small outbreaks in the baselines. We investigate several other options, including reducing the down-weighting to cases where the Anscombe residuals are greater than 2 or 3. We evaluate a new re-weighting scheme informed by past decisions. Using this adaptive scheme, baseline data where an alarm was flagged are down-weighted to reduce their effect on current predictions. The criterion we use for re-weighting, here, is the value of the exceedance score. Finally, we investigate the validity of the upper threshold values based on the quasi-Poisson model when the data are generated using known negative binomial distributions. Results Our evaluation of the existing algorithm showed that the false positive rate (FPR) is too high. A novel feature of our new models is that they make use of much more baseline data. This resulted in a better estimation of the trend and variance and decreased the FPR. In addition, we found that the trend should always be fitted even when non-significant (or extreme). This decreases the discrepancies in the results when moving from one week to another. The adaptive reweighting scheme was found to give broadly equivalent results to the reweighting method based on scaled Anscombe residuals. Using the latter as in the original HPA method, but with much higher threshold for reweighting decreased the FPR further. Our investigations also suggest that the negative binomial model is a reasonable one, though not ideal in all circumstances. Thus, there is a good case for replacing the quasi-Poisson model with the negative binomial. One of the unusual features of the HPA system is that it is run every week on a database of more than 3300 distinct organisms, which is likely to produce a large number of aberrances. We found that retaining the exceedance score approach based on the 0.995 quantile is perfectly reasonable. This involves ranking aberrant organisms in order of exceedance. Conclusions We have undertaken a thorough evaluation of the HPA’s outbreak detection system based on simulated and real data. The main conclusion from this evaluation is that the FPR is too high, owing to a combination of factors notably excessive down-weighting of high baselines and reliance on too few baseline weeks.

Validation of the French national health insurance information system as a tool in vaccine safety assessment: Application to febrile convulsions after pediatric measles/mumps/rubella immunization

In the French national health insurance information system (SNIIR-AM), routine records of health claimed reimbursements are linked to hospital admissions for the whole French population. The main focus of this work is the usability of this system for vaccine safety assessment programme. Self-controlled case series analyses were performed using an exhaustive SNIIR-AM extraction of French children aged less than 3 years, to investigate the relationship between MMR immunization and children hospitalizations for febrile convulsions, a well-documented rare adverse event, over 2009-2010. The results suggest a significant increase of febrile convulsions during the 6-11 days period following any MMR immunization (IRR=1.49, 95% CI=1.22, 1.83; p=0.0001) and no increase 15-35 days post any MMR immunization (IRR=1.03, 95% CI=0.89, 1.18; p=0.72). These results are in accordance with other results obtained from large epidemiologic studies, which suggest the usability of the SNIIR-AM as a relevant database to study the occurrence of adverse events associated with immunization. For future use, results associated with risk of convulsion during the day of vaccination should nevertheless be considered with particular caution.

Meningococcal vaccine trials.

The evaluation of meningococcal vaccines in humans is a challenging task. Issues of safety, and benefit to the individual patient and to the community may raise difficult ethical problems. The inherent variability of human responses, the rarity of clinical disease, age-dependence in the immune response, and the role of carriers complicates the evaluation process.

Regression models for censored serological data

The impact was assessed of censored serological measurements on regression equations fitted to data from panels of sera tested by different laboratories, for the purpose of standardizing serosurvey results to common units. Several methods that adjust for censoring were compared, such as deletion, simple substitution, multiple imputation and censored regression. Simulations were generated from different scenarios for varying proportions of data censored. The scenarios were based on serological panel comparisons tested by different national laboratories and assays as part of the European Sero-Epidemiology Network 2 project. The results showed that the simple substitution and deletion methods worked reasonably well for low proportions of data censored (<20 %). However, in general, the censored regression method gave estimates closer to the truth than the other methods examined under different scenarios, such as types of equations used and violation of regression assumptions. Interval-censored regression produced the least biased estimates for assay data resulting from dilution series. Censored regression produced the least biased estimates in comparison with the other methods examined. Moreover, the results suggest using interval-censored regression methods for assay data resulting from dilution series.

Estimating seroprevalence of vaccine-preventable infections: is it worth standardizing the serological outcomes to adjust for different assays and laboratories?

The aim of the European Sero-Epidemiology Network 2 (ESEN2) project was to estimate age-specific seroprevalence for a number of vaccine-preventable diseases in Europe. To achieve this serosurveys were collected by 22 national laboratories. To adjust for a variety of laboratory methods and assays, all quantitative results were transformed to a reference laboratorys units and were then classified as positive or negative to obtain age-specific seroprevalence. The aim of this study was to assess the value of standardization by comparing the crude and standardized seroprevalence estimates. Seroprevalence was estimated for measles, mumps, rubella, diphtheria, varicella zoster and hepatitis A virus (HAV) and compared before and after serological results had been standardized. The results showed that if no such adjustment had taken place, seroprevalence would have differed by an average of 3·2% (95% bootstrap interval 2·9-3·6) although this percentage varied substantially by antigen. These differences were as high as 16% for some serosurveys (HAV) which means that standardization could have a considerable impact on seroprevalence estimates and should be considered when comparing serosurveys performed in different laboratories using different assay methods.